!"#"$ %&#'( ") *++,-"#".

/
!"#$%&'
($)*"# +'#,"-."#/ 0121
3#45"--4# 45 0"$)6)7"
89:#)."; <7)="#-).> ?4-@).:A
?',B4A$. <7)="#-).> 45 +"#A)7
+"#A)7/ !"#,:7>

C7.47)4 3"DD'..4/ 0121

3#45"--4# 45 ?",:.4A4*> :7$ E764A4*>
89:#)."; <7)="#-).> ?4-@).:A
?',B4A$. <7)="#-).> 45 +"#A)7
+"#A)7/ !"#,:7>

F).9 647.#)B'.)47- B>

G),4 <A#)69- :7$ CA"H:7$#: C)69"#

IJI 64A4# @A:."- B> K'

( #*"7 F)#.9
IJ .:BA"-

G9)","
L.'..*:#. M N"O P4#Q
!"

!"#$%$& '( )'*+$,-- )%.%/'+"*+0"*012#/"3%."'* 4%.%
"- %5%"/%#/, ($'6 .7, 82#/"-7,$
!"#$%&'($"%)*
9"6' :/$"37-; <=4=
<%>01/%*3?0@*-.".2.,
('$ @*(,3."'* A"'/'+&
%*B @*-.".2., '( @*(,3."'* <,B"3"*,
C$,, :*"5,$-".& '( A,$/"*
A,$/"*; D,$6%*&
E/,>%*B$% E"37,$; <=4=
<'/,32/%$ )%$B"'/'+&
4,8%$.6,*. '( @*.,$*%/ <,B"3"*, @F
:*"5,$-".& '( C$%*?(2$.
C$%*?(2$.; D,$6%*&
G2H$+,* I"$.7
1$'(,--'$ '( F"-2%/ )'662*"3%."'*
:*"5,$-".& '( E88/",B J3",*3,-
4%$6-.%B.; D,$6%*&
97"- #''? "- %* %2.7'$"K,B %*B 28B%.,B .$%*-/%."'*
'( .7, D,$6%* ,B"."'* 82#/"-7,B %*B 3'8&$"+7.,B
LMMN #& D,'$+ 97",6, F,$/%+; J.2..+%$.; D,$6%*&=
9"./, '( .7, D,$6%* ,B"."'*O
9%-37,*%./%- B,$ @662*'/'+",=
D$2*B/%+,*; !%#'$; P/"*"?
9$%*-/%.,B #&
J2K&'* QRS,%/ I%*B$,&; A,$/"*; D,$6%*&
! TUUV D,'$+ 97",6, F,$/%+;
W2HB"+,$-.$%--, LX; 40YUXZM J.2..+%$.; D,$6%*&
7..8O[[\\\=.7",6,=B,
97",6, S,\ ]'$?; VVV J,5,*.7 E5,*2,;
S,\ ]'$?; S] LUUUL; :=J=E=
7..8O[[\\\=.7",6,=3'6
)'5,$ B,-"+*O )&3/2-; J.2..+%$.
9&8,-,.."*+ #& <"..,$\,+,$ ^ 1%$.*,$
P'662*"?%."'*-+,-,//-37%(. 6#_; 1/%*?-.%B.
+,-"%$.#$ /"$0O <,B"3"*, "- %* ,5,$037%*+"*+ -3"0
,*3, 2*B,$+'"*+ 3'*."*2%/ B,5,/'86,*.= W,-,%$37
%*B 3/"*"3%/ ,>8,$",*3, %$, 3'*."*2%//& ,>8%*B"*+
'2$ ?*'\/,B+,; "* 8%$."32/%$ '2$ ?*'\/,B+, '( 8$'0
8,$ .$,%.6,*. %*B B$2+ .7,$%8&= @*-'(%$ %- .7"-
#''? 6,*."'*- %*& B'-%+, '$ %88/"3%."'*; $,%B,$-
6%& $,-. %--2$,B .7%. .7, %2.7'$-; ,B".'$-; %*B 82#0
/"-7,$- 7%5, 6%B, ,5,$& ,(('$. .' ,*-2$, .7%. -237
$,(,$,*3,- %$, "* %33'$B%*3, \".7 $10 )$.$0 "2
3#"450670 .$ $10 $&,0 "2 -%"6(8$&"# "2 $10
'""39
S,5,$.7,/,--; .7"- B',- *'. "*5'/5,; "68/&; '$
,>8$,-- %*& +2%$%*.,, '$ $,-8'*-"#"/".& '* .7,
8%$. '( .7, 82#/"-7,$- "* $,-8,3. .' %*& B'-%+,
"*-.$23."'*- %*B ('$6- '( %88/"3%."'* -.%.,B "*
.7, #''?= :;0%< ()0% &) %0=(0)$06 $" 0>.,&#0
8.%02(55< .7, 6%*2(%3.2$,$R- /,%(/,.- %33'68%*&"*+
,%37 B$2+ %*B .' 37,3?; "( *,3,--%$& "* 3'*-2/.%."'*
\".7 % 87&-"3"%* '$ -8,3"%/"-.; \7,.7,$ .7, B'-%+,
-37,B2/,- 6,*."'*,B .7,$,"* '$ .7, 3'*.$%"*B"3%0
."'*- -.%.,B #& .7, 6%*2(%3.2$,$- B"((,$ ($'6 .7,
-.%.,6,*.- 6%B, "* .7, 8$,-,*. #''?= J237 ,>%60
"*%."'* "- 8%$."32/%$/& "68'$.%*. \".7 B$2+- .7%.
%$, ,".7,$ $%$,/& 2-,B '$ 7%5, #,,* *,\/& $,/,%-,B
'* .7, 6%$?,.= c5,$& B'-%+, -37,B2/, '$ ,5,$&
('$6 '( %88/"3%."'* 2-,B "- ,*."$,/& %. .7, 2-,$R-
'\* $"-? %*B $,-8'*-"#"/".&= 97, %2.7'$- %*B 82#0
/"-7,$- $,d2,-. ,5,$& 2-,$ .' $,8'$. .' .7, 82#/"-70
,$- %*& B"-3$,8%*3",- '$ "*%332$%3",- *'."3,B=
J'6, '( .7, 8$'B23. *%6,-; 8%.,*.-; %*B $,+"-0
.,$,B B,-"+*- $,(,$$,B .' "* .7"- #''? %$, "* (%3. $,0
+"-.,$,B .$%B,6%$?- '$ 8$'8$",.%$& *%6,- ,5,*
.7'2+7 -8,3"("3 $,(,$,*3, .' .7"- (%3. "- *'. %/\%&-
6%B, "* .7, .,>.= 97,$,('$,; .7, %88,%$%*3, '( %
*%6, \".7'2. B,-"+*%."'* %- 8$'8$",.%$& "- *'. .'
#, 3'*-.$2,B %- % $,8$,-,*.%."'* #& .7, 82#/"-7,$
.7%. ". "- "* .7, 82#/"3 B'6%"*=
97"- #''?; "*3/2B"*+ %// 8%$.- .7,$,'(; "- /,+%//&
8$'.,3.,B #& 3'8&$"+7.= E*& 2-,; ,>8/'".%."'*; '$
3'66,$3"%/"K%."'* '2.-"B, .7, *%$$'\ /"6".- -,.
#& 3'8&$"+7. /,+"-/%."'*; \".7'2. .7, 82#/"-7,$R-
3'*-,*.; "- "//,+%/ %*B /"%#/, .' 8$'-,32."'*= 97"-
%88/",- "* 8%$."32/%$ .' 87'.'-.%. $,8$'B23."'*;
3'8&"*+; 6"6,'+$%87"*+ '$ B28/"3%."'* '( %*&
?"*B; .$%*-/%."*+; 8$,8%$%."'* '( 6"3$'("/6-; %*B
,/,3.$'*"3 B%.% 8$'3,--"*+ %*B -.'$%+,=

1$"*.,B "* D,$6%*& #& D$%66/"37; 1/",K7%2-,*

@JAS V0LV0LTZYXL0U `D9Fa
@JAS U0NZbYY0MZX0V `9S]a L T V X b

%0",& &12 %,&1"$(
)*+,-./0,$1*+ 2/+3*4&*+ 5(&'($' 6*77/&&'
?0%6@A( B 6&70% C(%,0)$0% \%- #'$* "* _%*'5,$;
D,$6%*& "* LMbV= _, -.2B",B 6,B"3"*, %. .7, :*"0
5,$-".& '( _%*'5,$ <,B"3%/ J37''/ ($'6 LMYT .'
LMYN %*B B"B 7"- B'3.'$%/ $,-,%$37 2*B,$ .7, %,+"-
'( 1$'(,--'$ G'%37"6 W= P%/B,* "* _%*'5,$= _"- %30
."5, "*.,$,-. "* 3/"*"3%/ "662*'/'+& %*B $7,26%.'/0
'+& #,+%* B2$"*+ 6,B"3%/ -37''/ %*B "*.,*-"(",B
%(.,$ 7"- -.2B",- %- % 1'-.B'3.'$%/ C,//'\ "* .7, /%0
#'$%.'$",- '( 1$'(,--'$- _,*$& P2*?,/ %*B W'#,$.
I"*37,-.,$ %. .7, W'3?,(,//,$ :*"5,$-".& "* S,\
]'$? '* % -37'/%$-7"8 ($'6 .7, 4,2.-37, C'$0
-372*+-+,6,"*-37%(.= 4$= A2$6,-.,$ -2#-,d2,*./&
.''? 28 % .,%37"*+ 8'-"."'* %. .7, :*"5,$-".& '( c$0
/%*+,* <,B"3%/ J37''/= _, 3'68/,.,B 7"- %BB"."'*%/
$,-,%$37 $,d2"$,6,*.- ('$ % !"#$%$&"&$'( `D,$6%*
d2%/"("3%."'* ('$ 8$'(,--'$-7"8a "* LMNM %*B \%-
%88'"*.,B E--'3"%., 1$'(,--'$ "* LMMU= _, /%.,$ %30
3,8.,B % 37%"$ %. .7, 4,8%$.6,*. '( W7,26%.'/'+&
%*B )/"*"3%/ @662*'/'+&; )7%$".,e _'-8".%/; _260
#'/B. :*"5,$-".& "* A,$/"*= 1$'(,--'$ A2$6,-.,$ "-
,*+%+,B "* 3/"*"3%/ %*B ,>8,$"6,*.%/ $7,26%.'/'+&
%*B 3/"*"3%/ "662*'/'+&= Q.7,$ "*.,$,-.- "*3/2B,
6,B"3%/ B"B%3."3- '* #'.7 .7, 2*B,$+$%B2%., %*B
8'-.+$%B2%., /,5,/-= 1$'(,--'$ A2$6,-.,$ 7%- %
\"(, %*B .\' 37"/B$,*=
"
8/0+1*( 9$+&:
97"- 8'3?,. %./%- \%- 6%B, \".7 -2#-.%*."%/ 7,/8
($'6 D&," E5%&81); <4 %. .7, 4,8%$.6,*. '( <"3$'0
#"'/'+&; C$,, :*"5,$-".& '( A,$/"*; %*B /,3.2$,$ %. .7,
4,8%$.6,*. '( W7,26%.'/'+&; )7%$".,e _'-8".%/= 4$=
:/$"37- -.2B",B "* <%$#2$+ %*B B"B 7"- B'3.'$%/ $,0
-,%$37 "* "662*'/'+&= _, "- 32$$,*./& ,*+%+,B
"* -.2B",- '( "662*'/'+"3%/ "*(,3.'/'+& "* .2#,$0
32/'-"- %*B 5%33"*, B,5,/'86,*.=
F#$"#&" G0HH($$" \%- #'$* "* <"$%*' *,%$ F,*"3,
"* LMbV= _, -.2B",B 6,B"3"*, %. .7, :*"5,$-".& '(
1%B2% ($'6 LMYT .' LMYN %*B B"B 7"- B'3.'$%/ $,0
-,%$37 "* .26'$ "662*'/'+& %*B \%- -2#-,d2,*./&
/"3,*-,B %- % -8,3"%/"-. ('$ 3/"*"3%/ 7,6%.'/'+& %*B
/%#'$%.'$& 7,6%.'/'+&= @* LMNV 7, .$%*-(,$$,B .'
.7, :*"5,$-".& '( _,"B,/#,$+R- <,B"3%/ )/"*"3 %*B
1'/"3/"*"3; \7,$, 7, \%- "*(/2,*3,B ('$ LU &,%$-
#& .7, ,>3,8."'*%/ 8$'(,--"'*%/ 3'68,.,*3, %*B
8,$-'*%/".& '( 1$'(,--'$ I,$*,$ _2*-.,"*= 4$= 1,K0
K2..' B"B 7"- !"#$%$&"&$'( "* 7,6%.'/'+& %*B 3/"*"3%/
"662*'/'+&= _, 7%- -,$5,B %- % 8$'(,--'$ %. .7,
4,8%$.6,*. '( _,6%.'/'+&; Q*3'/'+&; %*B 926'$
@662*'/'+&; )7%$".,e _'-8".%/; _26#'/B. :*"5,$0
-".& "* A,$/"* -"*3, LMMX= _, 7,%B- .7, I'$? D$'28
f<'/,32/%$ @662*'.7,$%8&g %. .7, <%>04,/#$2H3?0
),*.,$ ('$ <'/,32/%$ <,B"3"*, "* .7, A,$/"* B"-.$"3.
'( A237= _"- \'$? 6%"*/& ('32-,- '* .26'$ "6620
*'/'+&= 1$'(,--'$ 1,KK2..'R- \"(, "- % -3",*."-. ($'6
D$,%. A$".%"*h .7,& 7%5, .\' 37"/B$,*=
F50>.#6%. F&810% \%- ,--,*."%/ "* 3'68"/"*+ .7,
"//2-.$%."'*- %*B .,>.-= J7, '#.%"*,B 7,$ <=4= %.
.7, :*"5,$-".& '( :/6 "* LMMb %*B $,3,"5,B 8'-.0
B'3.'$%/ .$%"*"*+ %. .7, <%>04,/#$2H3?0),*.,$[
W'#,$.0W'H--/,0)/"*"3; A,$/"* 2*."/ LMMY= E(.,$ T &,%$-
%- 8'-.0B'3.'$%/ (,//'\ "* "662*'/'+& %*B 6"3$'0
#"'/'+& %. .7, :*"5,$-".& '( I%-7"*+.'* "* J,%../,;
:JE; -7, *'\ \'$?- "* 6'/,32/%$ 3%$B"'/'+& %. .7,
:*"5,$-".& '( C$%*?(2$.; D,$6%*&; ('32-"*+ '*
B,*B$"."3 3,//- %*B 6%3$'87%+,- "* %.7,$'-3/,$'-"-
%- \,// %- '* 7,6%.'8'",."3 -.,6 3,//- "* *,'5%-320
/%$"K%."'*=
I(B %70# J&%$1 #,+%* 7"- -.2B",- "* +$%87"3 B,-"+*
%. .7, Q((,*#%37 J37''/ '( I'$?"*+ E$.-= _, /%.,$
.$%*-(,$$,B .' .7, :*"5,$-".& '( D$%87"3 E$.- "*
A,$/"*; \7,$, 7, 6%i'$,B "* ($,, +$%87"3- %*B
"//2-.$%."'*= _, /%.,$ 3'68/,.,B 7"- 2*B,$+$%B2%.,
B,+$,, %. .7, Q((,*#%37 )'//,+, '( 4,-"+*= G2H$+,*
I"$.7 B,5,/'8,B "**'5%."5, ,>7"#"."'* 3'*3,8.-
%- % 6,6#,$ '( .7, ,>7"#"."'* B,-"+* .,%6 B2$"*+
.7, $,*'5%."'* '( .7, J,*3?,*#,$+ <2-,26 "*
C$%*?(2$.[<%"*= A& .7%. ."6,; 7, \%- %/-' \'$?"*+
%- % ($,,/%*3, +$%87"3 B,-"+*,$ ('$ -,5,$%/ 82#/"-70
"*+ 3'68%*",-; B,-"+*"*+ .7, "//2-.$%."'*- ('$ %
*26#,$ '( -37''/ .,>.#''?-; *'*("3."'* #''?-;
%*B -3",*."("3 82#/"3%."'*-= G2H$+,* I"$.7 7%- $,0
3,"5,B -,5,$%/ %\%$B- ('$ '2.-.%*B"*+ #''? +$%0
87"3- %*B B,-"+*= @* LMYN; 7, \%- %88'"*.,B 8$'0
(,--'$ %. .7, J37''/ '( 4,-"+* "* J37\%H#"-37
D62H*B= 1$'(,--'$ I"$.7 7%- .%2+7. ('2*B%."'*
-.2B",-; B,-"+*; %*B 5"-2%/"K%."'* %. .7, C%32/.& '(
4,-"+* %. .7, :*"5,$-".& '( E88/",B J3",*3,- "*
4%$6-.%B. -"*3, LMNZ=
 "!!

3$2)'42

@662*'/'+& "- % B&*%6"3 B"-3"8/"*, \".7 $%8"B $,0
-,%$37 B,5,/'86,*.- 2*8%$%//,/,B #& .7'-, '( %*&
'.7,$ (",/B ,>3,8.; 8,$7%8-; .7, *,2$'-3",*3,-=
97"- $,-,%$37 7%- 8$'5"B,B 5%/2%#/, *,\ B%.% ('$
6,B"3"*, %*B #"'/'+&= @662*'/'+&; "*3/2B"*+ ".-
(2*B%6,*.%/ 8$"*3"8/,- %*B 3/"*"3%/ %88/"3%."'*-;
"- % 5,$& ,>3"."*+ (",/B "* \7"37 .' -8,3"%/"K,=
S'\%B%&-; \, -."// /"5, .' % $"8, '/B %+, B,-8"., 7'-0
."/, %..%3?- #& 6&$"%B- '( 8%.7'+,*"3 '$+%*"-6-= @60
62*'/'+"3%/ 6,37%*"-6- 7%5, #,3'6, 7"+7/& -,*0
-"."5, %*B -8,3"("3 "* .7, 8$'3,--= 97"- 3'/'$ %./%-
+$%87"3%//& B,8"3.- .7,-, 6,37%*"-6-= @.- 6%"*
+'%/ "- .' ,>8/%"* .7, B"5,$-, "*.,$%3."'*- #,.\,,*
.7, (2*B%6,*.%/ 8$"*3"8/,- %*B .7, /%#'$%.'$& %*B
3/"*"3%/ %88/"3%."'*- '( "662*'/'+& -' %- .' 3$,%., %
5"5"B 6,*.%/ 8"3.2$,= 97, #''?R- 6%"* .%$+,. +$'28
"*3/2B,- 6,B"3%/ -.2B,*.-; #"'/'+& -.2B,*.-; %*B
-.2B,*.- "* '.7,$ #$%*37,- '( .7, #"'-3",*3,-= _'\0
,5,$; ". %/-' .%$+,.- 87&-"3"%*- %*B #"'/'+"-.- \7'
%$, %3."5, "* .7,"$ $,-8,3."5, (",/B-=
42, .' -8%3, /"6".%."'*- %*B .7, ,687%-"- '* 720
6%* 6,B"3"*,; .7, #''? 6%"*/& ('32-,- '* 726%*
"662*'/'+&h -8%3, B',- *'. 8,$6". 2- .' 8$,-,*.
%// %$,%- '( .7, "66,*-, (",/B '( "662*'/'+& "*
.7,"$ ,*."$,.&= E *26#,$ '( ,>3,//,*. .,>.#''?- '(
"662*'/'+& %$, %/$,%B& '* .7, 6%$?,.= J'6, '(
'2$ 3'//,%+2,- 6%& 8$,(,$ % 6'$, 3'68$,7,*-"5,
8$,-,*.%."'* '( .7, -2#i,3. 6%..,$= I, 62-. %/-' $,0
6,6#,$ .7, ,*'$6'2- B,5,/'86,*.- "* "662*'0
/'+"3%/ $,-,%$37; .7, 3'*-.%*. B"-3'5,$& '( *,\ "*0
('$6%."'* %*B 8$'3,--,- .7%. %$, -."// 2*3/,%$ .'B%&;
#2. \"// -''* #, \,// 2*B,$-.''B= E 3'*-.%*. ,>0
37%*+, '( 8%$%B"+6- "- .%?"*+ 8/%3,; ,-8,3"%//& '*
.7, -2#i,3. '( .'/,$%*3, %*B %2.'"662*".&= 97, 32$0
$,*. ,B"."'* 3%**'. 8$'5"B, (2// 3'5,$%+, '( .7"- *,\
"*('$6%."'*= I, *%.2$%//& 7'8, .7%. .7,$, \"// #,
6%*& (2.2$, ,B"."'*- .7%. \"// %//'\ 2- .' $,5"-,
.7, 3'*.,*.- '( .7, #''? .' ?,,8 %#$,%-. '( .7, /%.,-.
%B5%*3,-= I, \'2/B +$,%./& %88$,3"%., %*& -2++,-0
."'*-; %BB"."'*-; %*B 3'$$,3."'*- 8$'8'-,B #& .7,
$,%B,$- '( .7"- 3'/'$ %./%-=

A& B,("*"."'*; %* %./%- 62-. ('32- '* .7, +$%87"3 J8$"*+ TUUV )*+,-./0,$1*+ 2/+3*4&*+; A,$/"*
8$,-,*.%."'* '( -2#i,3. 6%..,$; .7, ,>8/%*%."'* '( 5(&'($' 6*77/&&'; A,$/"*
\7"37 "- /"6".,B .' #$",( .,>. -,+6,*.-= c-8,3"%//& 8/0+1*( 9$+&:; 4%$6-.%B.
"* "662*'/'+&; % +$%87"3 8$,-,*.%."'* '( .7, -2#0
i,3. 6%..,$ 62-. B,8"3. 3,$.%"* 8$'3,--,- %*B .7,"$
8$'+$,--"'* .7$'2+7 ."6, %*B B"((,$,*. 87%-,- %-
\,// %- .7, "*.,$%3."'*- #,.\,,* % *26#,$ '( B"((,$0
,*. -2#-.%*3,- %*B ,/,6,*.-= @* '$B,$ .' 8$,-,*. %*
2*6"-.%?%#/, 8"3.2$, '( .7,-, f8$'.%+'*"-.-;g .7,
+$%87"3 B,-"+*,$- 62-. 3$,%., %$37,.&8%/ 6'B,/-
%*B -?"//(2//& 2-, 3'/'$- .' ,*-2$, % 3/,%$ 2*B,$0
-.%*B"*+ '( .7, -2#i,3. 6%..,$= I, 7%5, 6%"*/& 3'*0
3,*.$%.,B '* 7%$6'*"K%."'* '( .7, 3'/'$ 8/%.,- ('$
B"((,$,*. .'8"3-= 97, +'%/ \%- .' ,*-2$, .7%. .7, 5"0
-2%/ ,/,6,*.- \,$, *'. '5,$/'%B,B \".7 "*.,$*%/
-.$23.2$,- %*B .' 7%5, .7, "*B"5"B2%/ 8",3,- 3'60
#"*, .' ('$6 % 6'-%"3 \7'/,= 97"- \%- -'6,."6,-
%37",5,B %. .7, ,>8,*-, '( %,-.7,."3-; %*B .7,$, "-
"*,5".%#/& % 3,$.%"* /'-- '( %*%.'6"3%/ B,.%"/=
"!!!

*-&$"5,4&6"-

97"- #''? .%$+,.- -.2B,*.- '( 6,B"3"*, %*B #"'0
-3",*3,- %- \,// %- 87&-"3"%*- %*B #"'-3",*."-.-=
E- \%- 6,*."'*,B "* .7, 8$,(%3,; .7, #''? 6%"*/&
('32-,- '* 726%* "662*'/'+&= 97"- "*('$6%."'*
\"// #, 3'*5,&,B "* LVL 3'/'$ 8/%.,- %33'68%*",B
#& ,>8/%*%.'$& .,>.- '* .7, (%3"*+ 8%+,-=
97, %./%- "- #$'?,* B'\* "*.' .7$,, 6%"* -,+6,*.-=
97, (2*B%6,*.%/ 8$"*3"8/,- '( 726%* "662*'/'+&
%$, 8$,-,*.,B "* .7, '8,*"*+ -,+6,*.; .7, ,--,*."%/
/%#'$%.'$& .,-.- 2-,B "* "662*'/'+& %$, B,-3$"#,B
"* .7, -,3'*B -,3."'*; %*B .7, 3/"*"3%/ %-8,3.- '( "60
62*'/'+"3%/ B"-,%-,- %$, 8$,-,*.,B "* .7, ("*%/ -,30
."'*= 97, %88,*B"> 3'*.%"*- % +/'--%$& '( "68'$.%*.
"662*'/'+"3%/ .,$6- %*B .%#/,- "*3/2B"*+ )4 *'0
6,*3/%.2$, ('$ "662*'/'+"3%//& $,/,5%*. 6'/,0
32/,-; 3$".,$"% ('$ 3/%--"("3%."'* '( $7,26%."3 B"-0
,%-,-; %* '5,$5",\ '( .7, 6'-. "68'$.%*.
3&.'?"*,- %*B +$'\.7 (%3.'$-; %*B "68'$.%*. $,(,$0
,*3, 5%/2,- ('$ "662*'/'+&= A,-"B,- 8$'5"B"*+ %*
"*.$'B23."'* .' %// $,/,5%*. %-8,3.- '( 6'B,$* "60
62*'/'+&; .7"- 3'/'$ %./%- %/-' -,$5,- %- %* "68'$0
.%*. -'2$3, '( $,(,$,*3, ('$ "68'$.%*. d2,-."'*- "*
3/"*"3%/ 6,B"3"*, %*B /%#'$%.'$& 8$%3."3,=
97, 5.'"%.$"%< .--5&8.$&"#) -,3."'* B,-3$"#,-
.7, 6'-. "68'$.%*. .,-. -&-.,6- "* "662*'/'+&=
f)'*5,*."'*%/g 6,.7'B- -237 %- 8$,3"8".%."'*;
%++/2."*%."'*; %*B 3'68/,6,*.0#"*B"*+ $,%3."'*-
%$, 8$,-,*.,B %/'*+ \".7 *,\,$ 6,.7'B- -237
%- "662*'#/'.."*+; 6'/,32/%$ #"'/'+& .,-.-; %*B
% *26#,$ '( .,-. -&-.,6- ('$ .7, B,.,3."'* '(
,>8$,--,B +,*,-=
97, 85&#&8.5 &,,(#"5"7< -,3."'* B,-3$"#,- "6620
*'B,("3",*3",- %*B .7, ,--,*."%/ "662*'/'+"3%/
(,%.2$,- '( % *26#,$ '( "662*, B"-,%-,-= 97,
6%"* ('32- "- '* $7,26%.'/'+& %*B 7,6%.'/'+&=
:*"('$6 -&6#'/- %$, 2-,B .' $,8$,-,*. .7, 5%$"'2-
3,// -&-.,6- %- \,// %- .7,"$ $,3,8.'$- %*B 8$'B23.-=
97, -&6#'/- %$, ,>8/%"*,B '* .7, "*-"B, ($'*. %*B
"*-"B, #%3? 3'5,$-=

97, 2(#6.,0#$.5 -%&#8&-50) -,3."'* #,+"*- \".7

.7, '$+%*- '( .7, "662*, -&-.,6; ('//'\,B #& % B,0
-3$"8."'* '( .7, $,/,5%*. 3,//- '( .7, "662*, -&-.,6
%*B .7, 6,37%*"-6- #& \7"37 9 %*B A /&687'3&.,-
%3d2"$, 7"+7 /,5,/- '( -8,3"("3".&= J2$(%3, 6'/,32/,-
%$, B,-3$"#,B "* B,.%"/ "* B,(,$,*3, .' .7, ,*'$0
6'2- ,687%-"- 8/%3,B '* .7,6 "* 6'-. "662*'0
/'+"3%/ 82#/"3%."'*-= E B,-3$"8."'* '( %33,--'$& 3,//-
%*B *%.2$%/ ?"//,$ 3,//- ('//'\-= S,>.; .7, 726%*
/&687'3&., %*."+,* -&-.,6 "- %*%/&K,B; ('//'\,B
#& .7, 8$"*3"8/,- '( %*."+,* 8$'3,--"*+ %*B 7&8,$0
-,*-"."5".& $,%3."'*-= E2.'"662*".& %*B .'/,$%*3,
%$, B,-3$"#,B "* .7, /%-. 8%$. '( .7, -,3."'*=

!"-&2-&(
#$%&'()%*'+ ,-.%/.0+)1
D10 +,,(#0 K<)$0, ============================================================ L
L%&7&# "2 !055) "2 $10 +,,(#0 K<)$0,
Q5,$5",\ ======================================================================================= T
L%7.#) "2 $10 M<,-1.$&8 K<)$0,
Q5,$5",\ ======================================================================================= X
97&62- =========================================================================================== Z
1,$"87,$%/ Q$+%*- ==================================================================== N
D@M<,-1"8<$0 N0;05"-,0#$
.#6 N&220%0#$&.$&"#
9 ),// 4,5,/'86,*. ============================================================== LU
90),// J,/,3."'* ======================================================================== LT
90),// W,3,8.'$- ======================================================================= LX
90),// E*."+,*- ========================================================================= LZ
90),// E3."5%."'* ====================================================================== LN
9_L %*B 9_T ),//- =================================================================== TU
C@M<,-1"8<$0 N0;05"-,0#$
.#6 N&220%0#$&.$&"#
A0),// Q*.'+,*,-"- ================================================================ TT
D,$6"*%/ ),*.,$ W,%3."'* ================================================ TX
@662*'+/'#2/"*- =================================================================== TZ
@662*'+/'#2/"* )/%--,- =================================================== TN
@662*'+/'#2/"* D,*, Q$+%*"K%."'* ========================= VU
@662*'+/'#2/"* D,*, 1$'B23. c>8$,--"'* ========== VT
@68'$.%*. A0),// E*."+,*- ================================================ VX
!055O!055 +#$0%.8$&"#)
@*.,$%3."'*- #,.\,,* 9 ),//-
%*B E*."+,*08$,-,*."*+ ),//- ========================================= VZ
/"#)-08&2&8 N020#)0 !055)
S%.2$%/ P"//,$ ),//- ================================================================ VN
2'34-'*4-5 600+./'*.4%1
F#$&70#OF#$&'"6< +#$0%.8$&"#)
4,("*"."'*- %*B 1$,3"8".%."'* 9,37*"d2,- ============== YZ
9,37*"d2,- '( c/,3.$'87'$,-"- ====================================== YN
E++/2."*%."'* 9,37*"d2,-[)'68/,6,*.0
#"*B"*+ W,%3."'* ==================================================================== NU
c!@JE; W@E; %*B @662*'#/'.."*+ ================================ NT
@662*'(/2'$,-3,*3, ========================================================== NX
@662*'7"-.'/'+& ================================================================== NZ
!7
P"#"8<$0) .#6 N0#6%&$&8 !055)
97, 17%+'3&., J&-.,6 ======================================================== XU
<'*'3&., C2*3."'* %*B E*."+,*- =============================== XT
4,*B$"."3 ),// 1'82/%."'*- ================================================ XX
4) <%.2$%."'*O )7%*+,- "* 17,*'.&8,
%*B C23."'* ================================================================================ XZ
QMF K<)$0, RPQ! K<)$0,S
D,*'6"3 Q$+%*"K%."'* '( .7, _!E )'68/,> ======== XN
_!E <'/,32/, J.$23.2$, %*B )/%-- @ E//,/,- ========== bU
_!E <'/,32/,-O )/%-- @@ E//,/,- `@@a ============================= bT
<_) )/%-- @@0B,8,*B,*. E*."+,* 1$,-,*.%."'* == bX
<_) )/%-- @0B,8,*B,*. E*."+,* 1$,-,*.%."'* === bZ
D10 !",-50,0#$ K<)$0,
E3."5%."'* %*B c((,3.'$- ===================================================== bN
W,+2/%."'* %*B c((,3.- ======================================================== ZU
+##.$0 +,,(#&$<
1%.7'+,*0%--'3"%.,B <'/,32/%$ 1%..,$*- ================ ZT
M0(3"8<$0 P&7%.$&"#
!,2?'3&., EB7,-"'* %*B <"+$%."'* =========================== ZX
G.$1"5"7&8.5 +,,(#0 P081.#&),)
.#6 D"50%.#80
_&8,$-,*-"."5".& W,%3."'*- =============================================== ZZ
@*B23."'* %*B 1$,-,$5%."'* '( 9'/,$%*3, ================ ZN
<,37%*"-6- '( E2.'"662*".& `@a =============================== YU
<,37%*"-6- '( E2.'"662*".& `@@a ============================= YT
F-"-$")&)
E8'8.'-"- ===================================================================================== YX
!055(5.% +,,(#&$<
),// @-'/%."'* 9,37*"d2,- ================================================== NN
9,-.- '( 90),// C2*3."'* ===================================================== MU
E*."+,*0-8,3"("3 9,-.- ========================================================= MT
E--%& 1$'3,B2$,- ('$ )7%$%3.,$"K"*+
E*."+,*0-8,3"("3 9 ),//- ===================================================== MX
Q(,"%.5 +,,(#&$<
9,-.- '( A0),// C2*3."'* ==================================================== MZ
P"508(5.% C&"5"7&8.5 P0$1"6)
E*%/&."3%/ 9,37*"d2,- ========================================================= MN
7 84%*)%*1

8+.%./'+ !(($%4+495
+,,(#"602&8&0#8&0) 1%.7'+,*,-"- '( W7,26%.'"B E$.7$"."- `@a ============ LYU
_26'$%/ @662*'B,("3",*3",- =================================== LUU 1%.7'+,*,-"- '( W7,26%.'"B E$.7$"."- `@@a ========== LYT
),//2/%$ @662*'B,("3",*3",- ====================================== LUT G25,*"/, )7$'*"3 E$.7$"."- ============================================== LYX
D$%*2/'3&."3 4,("3",*3",- ============================================== LUX )/"*"3%/ C,%.2$,- '( J8'*B&/%$.7$"."- ======================= LYZ
)'68/,6,*. 4,("3",*3",- %*B 4,(,3.- ================= LUZ 1%.7'+,*,-"- '( J8'*B&/%$.7$"."- ============================= LYN
_@F J.$23.2$, %*B W,8/"3%."'* =================================== LUN D'2.; 1'/&37'*B$"."- %*B A,73j,.R- J&*B$'6, == LNU
)'2$-, '( _@F @*(,3."'* =================================================== LLU
F($".#$&'"6&0)
4"%+*'-"- %*B 9$,%.6,*. '( _@F @*(,3."'* ========= LLT
E2.'%*."#'B& 1%..,$*- ==================================================== LNT
Q0,"5<$&8 N&)0.)0) .#6 !<$"-0#&.)
!"##08$&;0 D&))(0 N&)0.)0
EAQ A/''B D$'28 J&-.,6 ============================================== LLX
.#6 T.)8(5&$&)
W7,-2- %*B Q.7,$ A/''B D$'28 J&-.,6- ============ LLZ
)/"*"3%/ C,%.2$,- '( J!c ================================================== LNX
<,37%*"-6- '( _,6'/&-"-
1%.7'+,*,-"- '( J!c ========================================================== LNZ
%*B E*."#'B& 4,.,3."'* ================================================== LLN
J3/,$'B,$6% %*B <">,B )'**,3."5,
E2.'"662*, _,6'/&-"- 42, .'
9"--2, 4"-,%-, ====================================================================== LNN
I%$6 E*."#'B",- =============================================================== LTU
Ji'H+$,*R- J&*B$'6, ========================================================== LMU
E2.'"662*, _,6'/&-"- 42, .'
<&'-"."3 4"-,%-,- =============================================================== LMT
)'/B E*."#'B",- =================================================================== LTT
D,*,$%/ )/%--"("3%."'* '( F%-32/"."- ========================= LMX
4$2+0"*B23,B _,6'/&-"-
@662*, F%-32/"."B,-
%*B 9$%*-(2-"'* W,%3."'*- =========================================== LTX
%*B 1'/&%$.,$"."- S'B'-% =============================================== LMZ
E2.'"662*, S,2.$'8,*"%- %*B
D"%*. ),// E$.,$"."- ============================================================= LMN
Q.7,$ )&.'8,*"%- ================================================================ LTZ
K3&# N&)0.)0)
Q0,.$"5"7&8.5 N&)0.)0)
:$."3%$"% ==================================================================================== TUU
E32., !,2?,6"%- ================================================================= LTN
)'*.%3. E//,$+",- ================================================================= TUT
Q5,$5",\ '( !&687'6% )/%--"("3%."'*- =============== LVU
E.'8"3 4,$6%."."-
_'B+?"*R- 4"-,%-, ============================================================== LVT
%*B !,2?'3&.'3/%-."3 F%-32/"."- ================================= TUX
90),// !&687'6%- ============================================================= LVX
1-'$"%-"- %*B A2//'2- J?"* 4"-,%-,- ======================= TUZ
A0),// !&687'6%- ============================================================ LVN
1/%-6% ),// 4&-3$%-"%- ==================================================== LXT ?.)$%"&#$0)$&#.5 N&)0.)0)
<2/."8/, <&,/'6% ============================================================= LXX E.$'87"3 D%-.$"."-; I7"88/,R- 4"-,%-,
)$&'+/'#2/"*,6"% =============================================================== LXZ %*B J8$2, ================================================================================ TUN
E6&/'"B'-"- ============================================================================ LXN )7$'*"3 @*(/%66%.'$& A'\,/ 4"-,%-,- ================ TLU
E2.'"662*, !"5,$ 4"-,%-,- ======================================== TLT
D(,"% +,,(#"5"7<
4,.,3."'* %*B @B,*."("3%."'* A0)-&%.$"%< N&)0.)0)
'( 926'$ E*."+,*- ============================================================ LbU A$'*37"%/ E-.76% %*B E//,$+"3 W7"*"."- ================ TLX
@662*, c-3%8, <,37%*"-6- '( 926'$ J%$3'"B'-"- %*B @B"'8%.7"3
E*."+,*- =================================================================================== LbT 12/6'*%$& C"#$'-"- ============================================================ TLZ
@662*'.7,$%8,2."3 J.$%.,+",- `@a =========================== LbX c>.$"*-"3 E//,$+"3 E/5,'/"."- =========================================== TLN
@662*'.7,$%8,2."3 J.$%.,+",- `@@a ========================== LbZ 92#,$32/'-"- =========================================================================== TTU
D%.#)-5.#$.$&"# "2 F($"5"7"()
A0#.5 N&)0.)0)
A'*, <%$$'\[_,6%.'8'",."3 J.,6 ),//- =========== LbN
@662*'/'+"3%/ <,37%*"-6- ======================================= TTT
9$%*-8/%*.%."'* '( E//'+,*"3
D/'6,$2/'*,87$"."."- `@a ================================================= TTX
A'*, <%$$'\[_,6%.'8'",."3 J.,6 ),//- =========== LZU
D/'6,$2/'*,87$"."- `@@a %*B
)/"*"3%/ E-8,3.- '( Q$+%* 9$%*-8/%*.%."'* ========= LZT
@*.,$-."."%/ S,87$"."- ========================================================= TTZ
@662*'/'+"3%/ E-8,3.- '( Q$+%*
9$%*-8/%*.%."'* ==================================================================== LZX P0$.'"5&8 N&)0.)0)
E2.'"662*, 97&$'"B 4"-,%-,- ================================= TTN
P()8(5")3050$.5 N&)0.)0)
4"%#,.,- <,//".2- %*B
)/"*"3%/ C,%.2$,- '( W7,26%.'"B E$.7$"."- ========== LZZ
E2.'"662*, 1'/&+/%*B2/%$ J&*B$'6, =============== TVU
J&*'5"%/ )7%*+,- "* W7,26%.'"B E$.7$"."- ======= LZN
 84%*)%*1 7!

Q0.%$ N&)0.)0 A0-%"6(8$&"# +,,(#"5"7<

W7,26%."3 C,5,$; <&'3%$B"."-; W,8$'B23."'* @662*'/'+& =========================================== TXN
%*B 1'-."*(%$3."'* J&*B$'6, ====================================== TVT
T.88&#.$&"#)
/0(%"5"7&8.5 N&)0.)0) Q5,$5",\ ================================================================================== TbU
<2/."8/, J3/,$'-"- ================================================================ TVX S,\ F%33"*,- ========================================================================= TbT
E2.'%*."#'B&06,B"%.,B 4"-,%-,- ============================= TVZ
+,,(#0 G1.%,.8"5"7<
<&%-.7,*"% D$%5"- %*B
S'*-.,$'"B%/ E*."0"*(/%66%.'$& 4$2+-
!%6#,$.kc%.'* J&*B$'6, ============================================= TVN
%*B D/23'3'$."3'"B- =========================================================== TbX
L-1$1.5,&8 N&)0.)0) E*."6,.%#'/".,-; )&3/'87'-87%6"B,;
E*%.'6& %*B 1%.7'+,*,-"- ========================================== TXU J2/(%-%/%K"*,; %*B D'/B =================================================== TbZ
c>.$%'32/%$ @*(/%66%."'*- ============================================ TXT )&3/'-8'$"* E; <&3'87,*'/%.,;
:5,"."- `@a ================================================================================== TXX %*B !,(/2*'6"B, ================================================================== TbN
:5,"."- `@@a %*B Q32/%$ <%*"(,-.%."'*- <'*'3/'*%/ %*B 1'/&3/'*%/ E*."#'B",- ================ TZU
'( J&-.,6"3 4"-,%-, =========================================================== TXZ

600)%&.:
9%#/,- ========================================================================================== TZT C2$.7,$ W,%B"*+ ==================================================================== VUZ
D/'--%$& ===================================================================================== VUU @*B,> ============================================================================================ VUN
7!!
%47-"8#25.+2-&(
97, %2.7'$- .7%*? 1$'(,--'$ C%/? _",8,; 4$=
J2-%**, 1$",6; 4$= A$2*' J.27/62H//,$; %*B 4$=
A,$*7%$B 97",/,; 4,8%$.6,*. '( <,B"3"*,; W7,20
6%.'/'+& %*B )/"*"3%/ @662*'/'+&; )7%$".,e _'-8"0
.%/; ('$ .7,"$ 7,/8 "* 8$,8%$"*+ .7, /%#'$%.'$& -,30
."'*= Q2$ -8,3"%/ .7%*?- +' .' 1$'(,--'$ _%*-0
c#,$7%$B F'H/?,$ %*B 1$'(,--'$ _,$$6%** P$%-.,/;
4,8%$.6,*. '( Q87.7%/6'/'+&; :*"5,$-".& '(
_,"B,/#,$+; ('$ .7,"$ 7,/8(2/ -2++,-."'*- %*B ('$
-288/&"*+ -/"B,- '* "662*'/'+"3%/ B"-,%-,- '(
.7, ,&,; %*B .' 1$'(,--'$ I'/(+%*+ J37*,"B,$;
_,%B '( .7, 1%.7'/'+"3%/ @*-.".2.,; P$%*?,*7%2-
A,$/"* A237; ('$ 7"- 3'*-.$23."5, 3'66,*.- %*B %
*26#,$ '( 87'.'+$%87- '* "662*'/'+"3%/ B"-,%-,-
'( .7, ?"B*,&=
F%/2%#/, 87'.'+$%87- %*B -/"B,- \,$, %/-' 8$'0
5"B,B #& 4$= E*B$,%- A$,".#%$.; 4,8%$.6,*. '(
_,6%.'/'+&; :*"5,$-".& '( :/6; 4$= :\, 1/,&,$;
4,8%$.6,*. '( Q87.7%/6'/'+&; )7%$".,e _'-8".%/;
1$'(,--'$ _,"B$2* <'//; ),*.,$ ('$ @*(,3."'* W,0
-,%$37; :*"5,$-".& '( I2H$K#2$+; 1$'(,--'$ 1,.,$
<'H//,$; 4"$,3.'$ '( .7, @*-.".2., '( 1%.7'/'+&; :*"0
5,$-".& '( :/6; 1$'(,--'$ <"37%,/ _2H(*,$; <,B"3%/
4,8%$.6,*. %*B 1'/"3/"*"3; :*"5,$-".& '( D'H.."*0
+,*; 1$'(,--'$ _,$\%$. Q..'; 4"$,3.'$ '( .7,
@*-.".2., '( 1%.7'/'+&; :*"5,$-".& '( _,"B,/#,$+;
4$= _%*- W= D,/B,$#/'6; W'#,$. P'37 @*-.".2.,;
A,$/"*; 1$'(,--'$ _%*-0<"37%,/ <,"*3?; 4,8%$.0
6,*. '( S,2$'/'+&; :*"5,$-".& '( _,"B,/#,$+; %*B
4$= 97'6%- I'/(,*-#,$+,$; _'l8".%/ G2/,- D'*"*;
!%2-%**,=
 7!!!

96(& ") %00$2:6'&6"-(

EE %6"*' %3"B 49 B"87.7,$"%; .,.%*2- `5%33"*%."'*a

E# %*."#'B& 49_ B,/%&,B0.&8, 7&8,$-,*-"."5".&
E)c %*+"'.,*-"*03'*5,$."*+ ,*K&6, cEc ,>8,$"6,*.%/ %2.'"662*, ,*3,87%/"."-
E)7 %3,.&/37'/"*, cE: ,>8,$"6,*.%/ %2.'"662*, 25,'$,."*"."-
E4)) %*."#'B&0B,8,*B,*. 3,//06,B"%.,B cAF c8-.,"*kA%$$ 5"$2-
3&.'.'>"3".& c) ,*B'.7,/"%/ 3,//
E+ %*."+,* c)1 ,'-"*'87"/ 3%."'*"3 8$'.,"*
E@4J %3d2"$,B "662*'B,("3",*3& -&*B$'6, cDC ,8".7,/"%/ +$'\.7 (%3.'$
E@_E %2.'"662*, 7,6'/&."3 %*,6"% c!@JE ,*K&6,0/"*?,B "662*'-'$#,*. %--%&
E@!4 %*+"'"662*'#/%-."3 /&687%B,*'8%.7& c<E ,8".7,/"%/ 6,6#$%*, %*."+,*
\".7 B&-8$'.,"*,6"% cSE ,>.$%3.%#/, *23/,%$ %*."+,*
E!)! %*%8/%-."3 /%$+,03,// /&687'6% cW ,*B'8/%-6"3 $,."32/26
E!! %32., /&687'#/%-."3 /,2?,6"% cJW ,$&.7$'3&., -,B"6,*.%."'* $%.,
E!9 %/%*"*, %6"*'.$%*-(,$%-, CE)J (/2'$,-3,*3,0%3."5%."*+ 3,// -'$.,$
E<E %*."6".'37'*B$"%/ %*."#'B& C3`!k"aW C3 $,3,8.'$- ('$ !; #; $; %; %*B " "6620
E<! %32., 6&,/'"B /,2?,6"% *'+/'#2/"*-
ESE %*."*23/,%$ %*."#'B& C4) ('//"32/%$ B,*B$"."3 3,//
ES)E %*."*,2.$'87"/ 3&.'8/%-6"3 %*."#'B& CD_ ("#$'#/%-. +$'\.7 (%3.'$
E1 %/?%/"*, 87'-87%.%-, C@J_ (/2'$,-3,*3, "* -".2 7&#$"B"K%."'*
E1) %*."+,*08$,-,*."*+ 3,// C@9) (/2'$,-3,"* "-'.7"'3&%*%.,
EW) E@4J0$,/%.,B 3'68/,> DE4 +/2.%6%., B,3%$#'>&/%-,
EJ9 %-8%$.%., %6"*'.$%*-(,$%-, DE!9 +2.0%--'3"%.,B /&687'"B ."--2,
AE! #$'*37'%/5,'/%$ /%5%+, DA< +/'6,$2/%$ #%-%/ 6,6#$%*,
AE!9 #$'*372-0%--'3"%.,B /&687'"B ."--2, D)4) +,$6"*%/ 3,*.,$ B,*B$"."3 3,//
A)D #%3"//2- )%/6,..,kD2,e$"* D0)JC +$%*2/'3&., 3'/'*&0-."62/%."*+ (%3.'$
A)W A03,// $,3,8.'$ D<0)JC +$%*2/'3&.,06%3$'87%+,
)( 3'68/,6,*. (%3.'$ ( 3'/'*&0-."62/%."*+ (%3.'$
)E!!E 3'66'* %32., /&687'#/%-."3 DS +/'6,$2/'*,87$"."-
/,2?,6"%0%--'3"%.,B %*."+,* D1@ +/&3'-&/%.,B 87'-87%."B&/"*'-".'/
)AW 3'68/,6,*.0#"*B"*+ $,%3."'* DF_4 +$%(.05,$-2-07'-. B"-,%-,
)4 3/2-.,$ '( B"((,$,*."%."'* DF! +$%(.05,$-2-0/,2?,6"% `,((,3.a
)4W 3'68/,6,*.%$".&0B,.,$6"*"*+ $,+"'* _E<E 726%* %*."62$"*, %*."#'B&
)C: 3'/'*&0('$6"*+ 2*". _)F 7,8%."."- ) 5"$2-
)!! 37$'*"3 /&687%."3 /,2?,6"% _4 _'B+?"*R- B"-,%-,
)<F 3&.'6,+%/'5"$2- _cF 7"+7 ,*B'.7,/"%/ 5,*2/,-
)Qm 3&3/''>&+,*%-, _@F 726%* "662*'B,("3",*3& 5"$2-
)W 3'68/,6,*. $,3,8.'$ _!E 726%* /,2?'3&., %*."+,*
)W1 )0$,%3."5, 8$'.,"* 7-8 7,%.0-7'3? 8$'.,"*
)JC 3'/'*&0-."62/%."*+ (%3.'$ _JF 7,$8,- -"68/,> 5"$2-
)9! 3&.'.'>"3 9 /&687'3&., _9!F 726%* 90/&687'.$'8"3 5"$2-
)F@4 3'66'* 5%$"%#/, "662*, B,("3",*3& @) "662*, 3'68/,>
3&. "*.$%3&.'8/%-6"3 @)E< "*.,$3,//2/%$ %B7,-"'* 6'/,32/,
4% B%/.'* @)c "*.,$/,2?"*0L&03'*5,$."*+ ,*K&6,
4EC B,3%&0%33,/,$%."*+ (%3.'$ @4) "*.,$B"+".%."*+ 3,//
4) B,*B$"."3 3,// @44< "*-2/"*0B,8,*B,*. B"%#,.,- 6,//".2-
B,/ 37$'6'-'6%/ B,/,."'* @CS "*.,$(,$'*
419 B"87.7,$"%; 8,$.2--"-; .,.%*2- @+ "662*'+/'#2/"*
7!"

@! "*.,$/,2?"* S1<0E!P *23/,'87'-8%6"*, %*%8/%-."3

@!9 @+0/"?, .$%*-3$"8. /&687'6% ?"*%-,
"*5 37$'6'-'6%/ "*5,$-"'* SJE@4 *'*-.,$'"B%/ %*."0"*(/%66%.'$& B$2+-
@WEP @!0L $,3,8.'$0%--'3"%.,B ?"*%-, 1EC 8/%.,/,.0%3."5%."*+ (%3.'$
@WA1 "*.,$87'.'$,3,8.'$ $,."*'"B0#"*B"*+ 1E!J 8,$"%$.,$"'/%$ /&687'3&., -7,%.7
8$'.,"* 1E<1 8%.7'+,*0%--'3"%.,B 6'/,32/%$ 8%..,$*
@9E< "662*'$,3,8.'$ .&$'-"*,0#%-,B 1A) 8$"6%$& #"/"%$& 3"$$7'-"-
%3."5%."'* 6'."( 1)W 8'/&6,$%-, 37%"* $,%3."'*
@9@< "662*'$,3,8.'$ .&$'-"*,0#%-,B 14DC 8/%.,/,.0B,$"5,B +$'\.7 (%3.'$
"*7"#"."*+ 6'."( 1c 87&3',$&.7$"*
@91 "B"'8%.7"3 .7$'6#'3&.'8,*"3 82$82$% 1cD 8'/&,.7&/,*, +/&3'/
@F@D "*.$%5,*'2- "662*'+/'#2/"* .7,$%8& 1C) 8/%d2,0('$6"*+ 3,//
G)E i25,*"/, 37$'*"3 %$.7$"."- 1@AC 8$'+,-.,$'*,0"*B23,B #/'3?"*+ (%3.'$
GWE i25,*"/, $7,26%.'"B %$.7$"."- 1!1 8$'.,'/"8"B 8$'.,"*
?4% ?"/'B%/.'* 1<S 8'/&6'$87'*23/,%$ *,2.$'87"/ +$%*20
P@W ?"//,$ 3,// @+0/"?, $,3,8.'$ /'3&.,
! /"+%*B 1<W 8'/&6&%/+"% $7,26%."3%
!E< /"8'%$%#"*'6%**%*, 8'/&0@+W 8'/&6,$"3 "662*'+/'#2/"* $,3,8.'$
!A! /&687'#/%-."3 /&687'6% 1Qm 8,$'>"B%-,
!) !%*+,$7%*- 3,// 1WW 8%..,$* $,3'+*"."'* $,3,8.'$-
!)C /&687'3&., 37,6'.%3."3 (%3.'$ 1J) 8$"6%$& -3/,$'-"*+ 37'/%*+"."-
!CE /&687'3&., (2*3."'*0%--'3"%.,B %*."+,* WE $7,26%.'"B %$.7$"."-
!D! /%$+, +$%*2/%$ /&687'3&., WcE! $,5"-,B c2$'8,%*0E6,$"3%*
!@W /,2?'3&., @+0/"?, $,3,8.'$ /&687'6% 3/%--"("3%."'*
!P< /"5,$0?"B*,& 6"3$'-'6%/ %*."#'B& WC $7,26%.'"B (%3.'$
!1J /"8'8'/&-%337%$"B, W7 $7,-2-
!9W /'*+ .,$6"*%/ $,8,%.- W@4 $%B"%/ "662*'B"((2-"'*
<E# 6'*'3/'*%/ %*."#'B& W1DS $%8"B/& 8$'+$,--"5, +/'6,$2/'*,87$"."-
<ED 6&,/"*0%--'3"%.,B +/&3'8$'.,"* WW $,/%."5, $"-?
<E!9 623'-%0%--'3"%.,B /&687'"B ."--2, WJ W,,BkJ.,$*#,$+
<EJ1 6%**%*0#"*B"*+ /,3."*0%--'3"%.,B J J5,B#,$+ 2*".
-,$"*, 8$'.,%-, JEE -,$26 %6&/'"B E
<A1 6%i'$ #%-"3 8$'.,"* JE1 -,$26 %6&/'"B 1
<)1 6'*'3&., 37,6'%..$%3.%*. 8$'.,"* J)@4 -,5,$, 3'6#"*,B "662*, B,("3",*3&
<0)JC 6'*'3&., 3'/'*&0-."62/%."*+ (%3.'$ J!c -&-.,6"3 /282- ,$&.7,6%.'-2-
<)94 6">,B 3'**,3."5, ."--2, B"-,%-, . `(O(a 37$'6'-'6%/ .$%*-/'3%."'* ($'6
<D:J 6'*'3/'*%/ +%66'8%.7& '( 2*?*'\* 37$'6'-'6, ( .' (
-"+*"("3%*3, 9E1 .$%*-8'$.,$ %--'3"%.,B \".7
<_) 6%i'$ 7"-.'3'68%."#"/".& 3'68/,> 8$,-,*.%."'*
<@C 6"+$%."'* "*7"#"."'* (%3.'$ 9A@@ 9J_0#"*B"*+ "*7"#"."*+ "662*'+/'#2/"*
<@W! 6,6#$%*, "*7"#".'$ '( $,%3."5, /&-"- 9)W 903,// $,3,8.'$
<QD 6&,/"* '/"+'B,*B$'3&., +/&3'8$'.,"* 9B9 .,$6"*%/ B,-'>&$"#'*23/,'.$%*-(,$%-,
<1DS 6,6#$%*'8$'/"(,$%."5, +/'6,$20 9D .7&$'+/'#2/"*
/'*,87$"."- 9DC .$%*-('$6"*+ +$'\.7 (%3.'$
<1Q 6&,/'8,$'>"B%-, 9@! .26'$0"*("/.$%."*+ /&687'3&.,
<1J 6'*'*23/,%$ 87%+'3&."3 -&-.,6 9SC .26'$ *,3$'-"- (%3.'$
SC *23/,%$ (%3.'$ 91Q .7&$'"B%/ 8,$'>"B%-,
SCE9 *23/,%$ (%3.'$0%3."5%.,B 9 3,// 9JA@ .7&$'"B -."62/%."'*0#/'3?"*+ "662*'0
SDC *,$5, +$'\.7 (%3.'$ +/'#2/"*
S_! *'*0_'B+?"*R- /&687'6% 9J_ .7&$'"B0-."62/%."*+ 7'$6'*,
SP *%.2$%/ ?"//,$ `3,//a 9J@ .7&$'"B0-."62/%."*+ "662*'+/'#2/"*
F)E< 5%-32/%$ 3,// %B7,-"'* 6'/,32/,
... Key to Symbols

Membrane,
phospholipid
Antigens layer

Receptors Thymus

Lymph node
TCR

Class I MHC Cellular tissue

molecule

Bacteria and
Class II MHC viruses
molecule

Arrows denoting
Cytokine receptor transportation,
effect, and
direction

Positive effect
Antibody (Ab)

Negative effect

Auto-Ab Inhibition

Blockade

Complement Signal
... Key to Symbols

Stem cell Plasma cell

Antigen-
presenting cell
B cell (APC)

Natural killer cell

(NK cell)
T cell

Erythrocyte Macrophage

Monocyte Megakaryocyte

Neutrophil
granulocyte Thrombocytes

Basophil ,
granulocyte Langerhans cell

Eosinophil Interdigitating
granulocyte dendritic cell

Basophil mast cell Mature

dendritic cell
!"# $%%&'# ()*+#%
!" "##$ %#&' "()* +,, %-..-#* /')&0 #1 '2#.3"-#*
1#& #3& -%%3*' 0/0"'% "# 4'2'.#5 -*"# "('
(-6(./ 7#%5.'8 )*4 )4)5")9.' 4'1'*0' %'7()*:
-0% "()" -" -0 "#4)/; !"0 5&-%)&/ ")0$ -0 "# 5&#"'7"
30 1&#% 1#&'-6* )*4 ()&%13. 0390")*7'0< %-7&#:
#&6)*-0%0< "#8-*0< )*4 %).-6*)*" 7'..0; =*./
"(&#36( "(' 7#*"-*3#30 4'2'.#5%'*" #1 "(' -%:
%3*' 0/0"'% >)0 -" 5#00-9.' "# 5&#"'7" .-2-*6 #&:
6)*-0%0 )6)-*0" 7#*0")*" )"")7$0 1&#% 9#"( "('
'8"'&*). )*4 -*"'&*). '*2-&#*%'*"0; !* "(' 5&#:
7'00< "(' -%%3*' 0/0"'% ()0 .')&*'4 "# -*)7"-:
2)"' 4'0"&37"-2' &'05#*0'0 "# '*4#6'*#30 039:
0")*7'0 )*4 "# 5&'2'*" -&&'5)&)9.' 4)%)6' "#
"(' 03&&#3*4-*6 "-003'; ?#0" -%%3*#.#6-7). &':
05#*0'0 )&' #1 .-%-"'4 43&)"-#* )*4 )&' &':
0"&-7"'4 9/ &'63.)"#&/ %'7()*-0%0 "# 5&'2'*"
#2'&&')7"-#*0;
@* '00'*"-). ")0$ #1 "(' -%%3*' 0/0"'% -0 "#
4-0"-*63-0( 4)*6'&#30 1&#% ()&%.'00; !*1-."&):
"-#* >-"( %-7&##&6)*-0%0 #& 9)7"'&-). "#8-*0<
1#& '8)%5.'< -0 ) 4)*6'&#30 )"")7$ #* )* #&6)*:
-0%< >('&')0 "(' -*().)"-#* #1 5#..'* #& "(' -*:
1-."&)"-#* #1 1##4 )*"-6'*0 1&#% "(' 0"#%)7( -*"#
"(' 9.##4 0/0"'% -0 ()&%.'00; A(' 4'0"&37"-#* #1
%).-6*)*" 7'..0 #& 1#&'-6* 7'.. %)"'&-). -0 4'0-&:
)9.' B';6;< -* 5)&)0-"' -*1'0")"-#*C< 93" 4-&'7" )":
")7$0 )6)-*0" "(' (#0" "-003' )&' 3*4'0-&)9.'
B';6;< -* )3"#-%%3*' 4-0')0'C; A(' 5&#7'00'0
9/ >(-7( "(' -%%3*' 0/0"'% )2#-40 "(' 4'2'.:
#5%'*" #1 4'0"&37"-2' 0'.1:&')7"-2-"/ )&' 7#..'7:
"-2'./ &'1'&&'4 "# )0 !"#$%&'($; A(' .)&6' %)D#&-"/
#1 ./%5(#7/"'0 4-&'7"'4 )6)-*0" 0'.1:)*"-6'*0
5&'0'*" "(&#36(#3" "(' 5&-%)&/ ./%5(#-4 #&:
6)*0 )&' 4'0"&#/'4 -* ) 5&#7'00 $*#>* )0 ($'!%&#
!"#$%&'($; )$%*+,$%&# !"#$%&'($ -0 0"-.. )*#"('&
%'7()*-0% "()" #773&0 -* .'00 7#%%#* '*4#:
6'*#30 0"&37"3&'0 #& -* "(#0' 5&'0'*" #*./ -*
7'&")-* &'6-#*0 #1 "(' 9#4/;
!"#$%&'()(' *++,#& -.$/&+
A(' (-0"#&-7)../ #.4'& 7#*6'*-"). 4'1'*0' %':
7()*-0%0 )&' 4'1-*'4 )0 *#*05'7-1-7 9'7)30'
"('/ 9'7#%' )7"-2' -*4'5'*4'*"./ #1 "(' -*2)4:
-*6 5)"(#6'*; A('/ )&' ).0# 7)..'4 '"'(#"'&# -$.
/$'0$ 1$(,&'*010 9'7)30' *# -*4-2-43). 7'..
7.#*' -0 &'E3-&'4 1#& "('-& 05'7-1-7 4'2'.#5%'*";
F#%' '8)%5.'0 -*7.34' "(' )7-4 .)/'& #1 "('
0$-*< "(' -*")7" '5-4'&%-0< "(' 7#%5.'%'*" 0/0:
"'%< )*"-%-7&#9-). '*G/%' 0/0"'%0< )*4 *#*:
05'7-1-7 %'4-)"#&0 037( )0 -*"'&1'&#*0 )*4 -*"'&:
.'3$-*0; H8)%5.'0 #* "(' 7'..3.)& .'2'. -*7.34'
01& *++,#& -.$/&+
6&)*3.#7/"'0< "(' %#*#7/"'I%)7&#5()6' 0/0:
"'%< )*4 *)"3&). $-..'& BJKC 7'..0; A(' .)""'& &':
!
5&'0'*" )* -*"'&1)7' 9'">''* "(' 05'7-1-7 )*4
*#*05'7-1-7 -%%3*' 0/0"'%0;
A(' -*1.)%%)"#&/ &'05#*0' 5'&%-"0 )* #*:
"(':0-"' 7#*7'*"&)"-#* #1 4'1'*0-2' 1#&7'0 2-)
"(' 7#%5.'8 -*"'&5.)/ #1 0#.39.' )*4 7'..3.)&
7#%5#*'*"0L "(-0 -0 )* -%5#&")*" *#*05'7-1-7
4'1'*0' %'7()*-0%; A(' 1-&0" 0"'5 -* "(-0 5&#:
7'00 -0 "(' &'.')0' #1 %'4-)"#&0 "()" 4-.)"' "('
9.##4 2'00'.0 )*4 %)$' "(' 7)5-..)&/ >)..0
%#&' 5'&%')9.'; A(' 0-"' #1 -*1'7"-#* -0 "('* 5':
*'"&)"'4 9/ 6&)*3.#7/"'0< >(-7( )&' &'5.)7'4 9/
%)7&#5()6'0 -* "(' .)"'& 7#3&0' #1 "(' &')7"-#*;
2,#34+&#/45 67(#'(%5&$
A(' 6&)*3.#7/"'0 7)&&/ #3" "(' M1-&0" .-*' #1 4':
1'*0'N -* >(-7( "(' %)D#&-"/ #1 -*2)4-*6 5)"(#:
6'*0 )&' 4'0"&#/'4; A(' &'%)-*-*6 5)"(#6'*-7
#&6)*-0%0 )*4 >)0"' 5&#437"0 #1 "(-0 1-&0":
.-*' 4'1'*0' )&' 5()6#7/"#0'4 9/ %)7&#5()6'0;
-%&'()(' *++,#& -.$/&+
A(' 5&#7'00 #1 037( )* -%%3*' &'05#*0' 5)2'0
"(' >)/ 1#& "(' 05'7-1-7 -%%3*' &'05#*0'; !* )
05'7-1-7 7/"#$-*' '*2-&#*%'*"< "(' 9#4/ 7)* 4':
"
7-4' >('"('& "# 5&#7''4 "# ) %#&' (3%#&). .-*'
#1 4'1'*0' #& ) %#&' 7'..3.)& .-*' #1 4'1'*0'; A('
%-6&)"-#* #1 )*"-6'*:5&'0'*"-*6 7'..0 B@OPC "#
"(' ./%5(#-4 #&6)*0 1-&0" "&-66'&0 ) 0/0"'%-7
-%%3*' &'05#*0'< "('* ) 1$1"%2 %$0+"'0$;
A(' 05'7-1-7 -%%3*' 0/0"'% 7#*0-0"-*6 #1 A
)*4 Q ./%5(#7/"'0 -0 &'05#*0-9.' 1#& "(-0; A('0'
7'.. 0/0"'%0 7)* 5&#437' (-6(./ 05'7-1-7 &')7:
"-#*0 "# "('-& &'05'7"-2' )*"-6'*0 )*4 3*4'&6#
7.#*). '85)*0-#*< "(30 )7(-'2-*6 ) (-6(./ '11'7:
"-2' &'05#*0' "# )*4 %'%#&/ 1#& "(#0' )*"-6'*0;
!
8
"
! #$%&%' () *+,,- () ./+ 0112'+ 34-.+1
!" #$%&%' () *+,,- () ./+ 0112'+ 34-.+1
!"" #$%&$'(')* $+ ),( -"$$./ 0'#"1.0'2 ),( #(""*
$+ ),( 0%%1'( *3*)(%/ $4020'5)( +4$% &"140&$6
)(') ,(%5)$&$0()0# *)(% #(""* $+ ),( -$'( %546
4$78 90), ),( 50. $+ *$"1-"( %(.05)$4* :#3)$6
;0'(*< 5'. #$')5#) *02'5"* (%0))(. -3 *)4$%5"
#(""*/ ),(*( ,02,"3 1'.0++(4(')05)(. &4$2('0)$4
#(""* #5' 20=( 40*( )$ ),( .0++(4(') -"$$. #(""*
:!<8 >,(*( #(""* 54( 5%$'2 ),( +(7 -$.3 #(""*
#5&5-"( $+ *("+64('(75"8 ?('#(/ ),(3 #5' .0=0.(
70),$1) .0++(4(')05)0'2/ ),(4(-3 &4$.1#0'2 5'
1'"0%0)(. *1&&"3 $+ -"$$. #(""*8 >,( -$'( %546
4$7 &4$.1#(* @8AB!@C@@ (43),4$#3)(* :4(.
;2'<91+'.9, :$%'8%=,+-
-"$$. #(""*< 5'. A!@C@C "(1;$#3)(* :7,0)( -"$$.
#(""*< (5#, .53 5'. ,5* ),( #5&5#0)3 )$ 0'#4(5*(
),0* &4$.1#)0$' 1& )$ *(=(45"+$". 0+ '((.(.8 D'
=0)4$/ ),(*( *$6#5""(. &4$2('0)$4 #(""* #5'
+$4% #$"$'0(* $+ .0++(4(')05)(. #(""*8 E3("$0.
&4$2('0)$4 #(""* #5' .0++(4(')05)( 0')$ ),( +$"6
"$70'2 )3&(* $+ #(""*F !"#$%$&'()'*"+/ =(43
"542( %1")0'1#"(5)(. #(""* ),5) -4(5; 1& 0')$
*%5"" &54)0#"(* 7,0#, #$'*)0)1)( ),( &"5)("()*
:),4$%-$#3)(*< $+ ),( -"$$.G "&'*,&(-.$+*+/
7,0#, +14),(4 %1")0&"3 5'. .0++(4(')05)( 0')$
#04#1"5)0'2 (43),4$#3)(* :4(. -"$$. #(""*<G !'"/
"
.(-.$+*+0 7,0#, #5' .0++(4(')05)( 0')$ '(1)4$6
&,0"*/ ($*0'$&,0"*/ 5'. -5*$&,0"* :),(3 5""
,5=( 5 *(2%(')(. '1#"(1* 5'. 54( ),(4(+$4(
#5""(. &$"3%$4&,$'1#"(54 "(1;$#3)(* 0' $4.(4
)$ .0*)0'210*, ),(% +4$% ),( $),(4 %$'$'1#6
"(54 #(""*<G !(1(-.$+*+ :%$'$#3)( &4(#14*$4*<G
5'. 2"12&3*3) )"..+8 H45'1"$#3)(*/ %$'$#3)(*/
5'. .('.40)0# #(""* ,5=( ),( 5-0"0)3 )$ 0'2(*) &546
)0#"(*/ %0#4$$425'0*%* 5'. +"10.* 5'. 54( ),(4(6
+$4( #5""(. 4,$#()'*"+ :+4$% ),( H4((; 7$4.
I&,52$J K I(5)J<8
D' 4(*&$'*( )$ *$"1-"( %(.05)$4* #5""(. ),"/
!(%31"+/ ),( "(1;$#3)(* %0245)( +4$% ),( -"$$.
0')$ ),( )0**1(/ 7,(4( ),(3 4(&504 .5%52(. )0*6
*1( 5'. 4(%$=( -5#)(405/ &545*0)(*/ 5'. .(5.
#(""* ),5) 0'.1#( 0'+"5%%5)0$'8 !+)(4 %0245)0$'
0')$ ),( )0**1(/ ),( -"$$. %$'$#3)(* .0++(4(')06
5)( 0')$ %5#4$&,52(*8
>,( %$*) 0%&$4)5') #(""* $+ ),( 0%%1'( *3*6
)(% 54( ),( "3%&,$#3)(*/ 7,0#, $4020'5)( +4$%
5 #$%%$' &4$2('0)$4 #("" 0' ),( -$'( %544$78
>7$ )3&(* $+ "3%&,$#3)(* #5' -( .0*)0'6
210*,(.F > "3%&,$#3)(*/ 7,0#, 54( 4(*&$'*0-"(
! >
+$4 ),( #(""1"54 0%%1'( 4(&$'*(/ 5'. L "3%6
&,$#3)(*/ 7,0#, &4$.1#( 5')0-$.0(* :,1%$45"
0%%1'( 4(*&$'*(<8 M(""* $+ 5 ),04. )3&(/ ),(
'5)145" ;0""(4 #(""*/ 54( 5"*$ &54) $+ ),( "3%&,5)0#
*3*)(%8 >,(*( #(""* 54( 4("5)(. )$ > "3%&,$6
#3)(*/ -1) ),(04 $4020' 0* *)0"" 5 %5))(4 $+ .(-5)(
*0'#( ),(3 5"*$ (N&4(** *$%( +(5)14(* $+ %3(6
"$0. #(""*8
5" 6+)+'-+ 7+8/9'%-1- 9&9%'-. 0')+8.%('-
>,( &40%543 +1'#)0$' $+ ),( 0%%1'( *3*)(% 0*
),( &4$)(#)0$' $+ ),( $425'0*% 5250'*) 0'+(#6
)0$'8 511$*" 3!!613*' 0* 5 %$4( 5'#0(') "0'(
$+ .(+('*(/ 7,0#, 0* ,02,"3 #$'*(4=(. -()7(('
),( .0++(4(') *&(#0(*8 D) #$'*0*)* %50'"3 $+ &,56
2$#3)0# #(""*/ -"$$. &4$)(0'*/ 5'. '5)145" ;0""(4
#(""*8 !"" $+ 0)* *)45)(20(* 54( -5*(. $' ),( 4(#$26
'0)0$' $+ )3&0#5" %$"(#1"54 *)41#)14(* ),5) 54(
*,54(. 5%$'2 .0++(4(') &5),$2('*8 >,( %(6
#,5'0*%* $+ 0''5)( 0%%1'0)3 54( .(&"$3(.
*,$4)"3 5+)(4 ),( -$.3 ,5* -((' 0'=5.(. -3 5
&5),$2('O1*15""3 70),0' ,$14*8
P,52$#3)$*0* 0* ),( %50' %(#,5'0*%* $+ 0'6
'5)( 0%%1'0)38 D' ),0* &4$#(**/ ),( %0#4$$425'6
0*% 0* #$5)(. 70), -"$$. #$%&$'(')* *1#, 5*
#$%&"(%(')/ 7,0#, 0'.1#(* "3*0* $+ ),( 0'=5.(4
$4 ),( 4("(5*( $+ #3)$)$N0# "3)0# ('Q3%(* +4$%
;0""(4 #(""*8
72$4*38" 3!!613*'/ ),( &,3"$2('()0#5""3
%$.(4' %(#,5'0*%/ 0* -5*(. $' ),( &4(*('#(
$+ 4(#(&)$4* ),5) 54( ,02,"3 *&(#0+0# +$4 #(4)50'
4(20$'* :(&0)$&(*< $+ ),( &5),$2('*8 >,(*( 4(6
#(&)$4* 54( (0),(4 #(""6-$1'. :> "3%&,$#3)(*
5'. *$%( L "3%&,$#3)(*< $4 *(#4()(. :5')0-$6
.0(* &4$.1#(. -3 L "3%&,$#3)(*<8 ! *0'2"( > $4
L "3%&,$#3)( &4$"0+(45)(* 5'. &4$.1#(* "542(
R15')0)0(* $+ 0.(')0#5" .512,)(4 #(""* :#"$'5" (N6
&5'*0$'<8 >,0* *&(#0+0# 4(*&$'*( &4$#(** )5;(*
.53* )$ 7((;*8
*" :,9-.%8%.4 () 3.+1 *+,,-
9,(' &4(*(') 0' *&(#05"0Q(. )0**1(/ ,(%5)$6
&$0()0# &4$2('0)$4 #(""* #5' .0++(4(')05)( 0')$
=540$1* .0++(4(') -"$$. #(""* $4 )0**1(6*&(#0+0#
#(""*/ *1#, 5* ,(&5)$#3)(*/ '(14$'*/ %1*#"(
#(""*/ $4 ('.$),("05" #(""*8 >,( *02'5"* ),5) 4(26
1"5)( ),(04 .0++(4(')05)0$' 0')$ *&(#05"0Q(. #(""*
54( *)0"" "542("3 1';'$7'8 ?(%5)$&$0()0# *)(%
#(""* #04#1"5)( 0' *%5"" '1%-(4* 0' ),( &(406
&,(45" -"$$.8 >,(3 54( %$4&,$"$20#5""3 0'.0*6
)0'210*,5-"( +4$% *%5"" "3%&,$#3)(*8
 CD34+ Pluripotent stem cell
#?+$?%+@
!
Myeloid Lymphoid
progenitor progenitor

T-cell B-cell
Mega- pre- Thymus pre-
karyocyte Myeloblast Monoblast cursor cursor

Erythroblast

;2'<91+'.9, :$%'8%=,+-
Platelets
B
P lympho-
h cytes
Erythrocytes a
g o e s
c y t
T lympho-
cytes

"
Basophils

Eosinophils Dendritic Natural

Neutrophils Monocytes cells killer cells
A. Origin of cells of the immune system

Innate immunity Adaptive immunity

Infectious
Phagocytes agents

Generation of
Natural killer cells specific receptors

Blood
components

Hours Days, weeks

B. Defense mechanisms against infections

Hematopoietic
CD34+ stem cell

!
Hepatocytes
Cardio-
Neurons myocytes
Smooth Endothelial Skeletal
muscle cells cells muscle cells
C. Plasticity of stem cells
A
! 7%8062 )* $+( ,-./+0$1' #-2$(.

!" #$%&'$&%( )* $+( ,-./+0$1' #-2$(.

!"" #"$$% &'""( %')'"$* +,$- &$--$./ *"0,1*$2
3'.3 #$.' -4,,$5 (3'- &'""(6 78'9 &4. #' %'2
./+*-010--*+20",3 %&'()*23
4.56!7 1( 4 &$""'&31$. $+ "9-*8431& &'""( 1.
38' (0#-0&$(4" 31((0' $+ 38' <4(3,$1.3'(31.4"
"2--/,

>QJ? 3,4&3/ #,$.&814" 3,4&3/ 0,1.4,9 3,4&3/ 4.% "42

3'&3'% 1. 38' +'34" "1)',/ 581&8 84( 8'-43$*$1'2
&,1-4" <"4.%(6 R,<4.1E'% "9-*8$1% 31((0' >'6<6/
31& *,$*',31'(/ +,$- 38' :38 5''; $+ <'(3431$.
3$.(1"( $, S'9',T( *43&8'(? 4.% 4 "4,<' .0-#',
0.31" (8$,3"9 #'+$,' #1,386 78' (3'- &'""( <1)'
$+ "9-*8431& &'""( "$$('"9 %1(3,1#03'% 38,$0<82
,1(' 3$ 38' *,'&0,($, &'""( $+ 38' "9-*8431&
$03 38' *',1&4*1""4,9 4.% *',1'.%$38'"14" 31((0'
4.% -9'"$*$1'31& (9(3'-(6 =,938,$&93'(/ <,4.02
&4. #' +$0.% 38','6
"$&93'(/ 4.% 38,$-#$&93'( 84)' &$--$. *,'2
&0,($, (34<'( >*,$<'.13$, &'""(?/ 58','4( "9-2 3" ,-./+0$1' 4('1%'&50$1)6
*8431& &'""( %')'"$* '4,"9 1.3$ ('*4,43' &'""
"1.'(6 @34,31.< +,$- 38' AB38 5''; $+ <'(3431$./ 78' &'""( $+ 38' "9-*8431& (9(3'- &1,&0"43' &$.2
($-' (3'- &'""( -1<,43' 3$ 38' 389-0( 4.% 31.0$0("9 4.% ,'4&8 4"" *4,3( $+ 38' #$%9 5138 4
+'5 'U&'*31$.( >'6<6/ )13,'$0( #$%9/ #,41./ 3'(312
9&6:0.(6$05 ;%16'1/5(2

#$.' -4,,$5/ 581&8 4,' ,'+',,'% 3$ 4( 38' !"#$

%&"' ('%!)*#+ *",&-.6 78','/ 38' &'""( &$.31.0'
3$ *,$"1+',43' 4.% %1++','.3143'6 ! "9-*8$&93'(
,'C01,' *4((4<' 38,$0<8 38' "89-0( 3$ &$-2
*"'3' 38'1, -430,431$./ 58','4( # "9-*8$&93'(
&$-*"'3' 38'1, -430,431$. 1. 38' #$.' -4,,$5
>'C01)4"'.3 3$ 38' $0,(4 $+ D4#,1&10( 1. #1,%(?6
@*'&14"1E'% ,'&'*3$,( 4,' "$&43'% $. 38' (0,2
+4&' $+ 7 4.% F "9-*8$&93'( >4.31<'. ,'&'*3$,(
-4%' $+ 35$ <"9&$*,$3'1. &841.(?6 78' (3,0&30,'
$+ 38' ,'&'*3$,( )4,1'( +,$- $.' &'"" 3$ 4.$38',6
=4&8 ,'&'*3$, ,'&$<.1E'( 4.% #1.%( 5138 $."9
&"'(?6 78'9 ,'4&8 38' "9-*8 .$%'(/ (;1./ 4.% 1.2
3'(31.' )14 4 (*'&14"1E'% '.%$38'"10- $+ *$(3&42
*1""4,9 )'.0"'(/ 38' ($2&4""'% )1<8 ,.%$38'"14"
8'.0"'( >9:;?6 78' &'""( $+ 381( '.%$38'"10-
4,' -0&8 81<8', 384. .$,-4" '.%$38'"14" &'""(6
78'9 'U*,'(( 81<8 "')'"( $+ 4%8'(1$. -$"'&0"'(
3843 (',)' 4( 8$-1.< ,'&'*3$,( +$, "9-*8$2
&93'(6 J. ,'(*$.(' 3$ &',341. &8'-$34&31& +4&2
3$,(/ "9-*8$&93'( -1<,43' 3$ 38' 0.%',"91.< 31(2
(0' >%14*'%'(1(?6 78' "9-*8431& &'""( ,''.3',
38' &1,&0"431$. 38,$0<8 '++','.3 "9-*8 )'(('"(

"
$.' (*'&1+1& 4.31<'. >G"$&;24.%2;'9H *,1.&1*"'?6 3843 -',<' 1.3$ 38' 38$,4&1& %0&36 78' "9-*8$2
I."1;' 7 "9-*8$&93'(/ F "9-*8$&93'( &4. -42 &93'( '.3', 38' (*"''. )14 4,3',1$"'( 4.% (1.02
30,' 1.3$ *"4(-4 &'""(/ *,$%0&' "4,<' C04.3131'( ($1%( 4.% 'U13 38' $,<4. )14 38' (*"'.1& )'1.6
$+ ,'&'*3$,( 1. -$%1+1'% +$,-/ 4.% '.3', 38'
#"$$%(3,'4- 4( &1,&0"431.< 4.31#$%1'(6
J--430,' 7 "9-*8$&93'( -4;' &$.34&3 5138
(*'&14"1E'% '*138'"14" &'""(/ %'.%,131& &'""(/ 4.%
-4&,$*84<'( 1. 38' 389-0(/ 581&8 *,$)1%'(
4. $**$,30.139 +$, 38' ('"'&31$. 4.% %1++','.2
31431$. $+ 7 &'""( 0('+0" 3$ 38' 1--0.' (9(3'-6
K93$;1.'( >($"0#"' ,'<0"43$,9 +4&3$,( $, G-'(2
('.<',(H +$, 38' 1--0.' (9(3'-?/ (0&8 4( 1.3',2
"'0;1.( A/ L/ M/ 4.% N/ 4"($ *"49 4. 1-*$,34.3 ,$"'6
! "4,<' .0-#', $+ "9-*8$&93'(/ '(*'&14""9
38$(' 581&8 ,'&$<.1E' ('"+2&$-*$.'.3( $+
38' #$%9/ 4,' %'(3,$9'% %0,1.< 381( *,$&'(( $+
('"'&31$.6
# %&'()*+&",- (34,3 3$ %')'"$* +,$- (3'-
&'""( 1. 38' #$.' -4,,$5 4,$0.% 38' AO38
5''; $+ <'(3431$.6 K$.34&3 5138 (3,$-4" &'""(
$+ 38' #$.' -4,,$5 4.% &93$;1.'( 1( 1-*$,34.3
+$, 38' %1++','.31431$. $+ F &'""(6 J.3',"'0;1.( A/
M/ 4.% N 4,' 38' -$(3 1-*$,34.3 &93$;1.'( 1.

! <
381( *,$&'((6 78' #$.' -4,,$5 1( 38' "1+'31-'
*,$%0&31$. (13' $+ F "9-*8$&93'(6
P430,' 7 4.% F "9-*8$&93'( "'4)' 38'1, %1+2
+','.31431$. (13'( 4.% -1<,43' 3$ *',1*8',4" $,
./0*-+&"' ('%!)*#+ *",&-. >'6<6/ (*"''./ "9-*8
.$%'(/ 4.% -0&$(424(($&143'% "9-*8$1% 31((0'?6
Ontogenesis Primary lymphoid organs Secondary
7=(%=1(>
!
lymphoid organs
Progenitor cell
Medulla
Epithelium
IL-1
IL-2
Dendritic IL-6 Spleen
cells IL-7

Cortex Macro-
phages T lymphocytes

Fetal liver

9&6:0.(6$05 ;%16'1/5(2
Thymus T lymphocytes

Myelopoietic
progenitor cell
Pluripotent
stem cell
?

"
Bone marrow B lymphocytes Lymph nodes
Lymphatic
progenitor cell
Progenitor cell

Sinus
IL-1
IL-6
IL-7
Erythron Stroma

Mucosa-associated
B lymphocyte
lymphoid tissue
A. Structure of the lymphoid system

Liver

Lung Spleen

Skin

B. Lymphatic recirculation
Mesenteric
lymph nodes
Peyer´s
patches

Efferent lymphatics
Peripheral
lymph nodes

!
?
! 456$#3 &/ %0+ 7('.0$%89 :(3%+'

!"# $"%&'( )( $"# *#+$,-. /,0-+ 1/, $"# 2)11#,3

#+$)-$)/+ -+2 1'+*$)/+-. &-$',-$)/+ /1 ! .%&3
4"/*%$#(5 6)7# $"# 8/+# &-,,/9 -+2 8',(- /1
:-8,)*)'( ;)+ 8),2(<= )$ )( /+# /1 $"# 4,)&-,%
.%&4"/)2 /,0-+( -+2 )( 2)($)+0')("#2 1,/&
(#*/+2-,% .%&4"/)2 /,0-+(= ('*" -( $"# (4.##+=
.%&4" +/2#(= -+2 &'*/(-3-((/*)-$#2 .%&3
4"/)2 $)(('#5
!" !#$%&'( $#) *+,+-&.'+#% &/ %0+
10('23
! >+ $"# /+$/0#+)* (#+(#= $"# $"%&'( 2#?#./4(
-( -+ /'$0,/9$" /1 $"# $"),2 8,-+*")-. 4/'*"
-+2 .-$#, &)0,-$#( $",/'0" $"# -+$#,)/, &#23
;2#)$'+#%$- <58#98.-+3
)+ $"# #-,.% ($-0#( /1 2#?#./4&#+$ ;)&4/,$-+$
1/, &-$',-$)/+ ($'2)#(<= 8'$ -( $"# 4,/*#(( /1
2)11#,#+$)-$)/+ */+$)+'#(= $"#% 8#*/&# &/,#
-+2 &/,# */,$)(/+#3,#()($-+$5 !"# */,$)(/+#3
(#+()$)?#= )&&-$',# $"%&/*%$#( -,# ./*-$#2
&-)+.% )+ $"# */,$#A= -+2 $"# */,$)(/+#3)+3
(#+()$)?# /+#( -,# &-)+.% ./*-.)B#2 )+ $"#
&#2'..-5
% F4-,$ 1,/& .%&4"/*%$#( -+2 J-((-..K(
8/2)#(= $"# $"%&'( -.(/ */+$-)+( #4)$"#.)-. *#..(
9)$" - .-,0# *%$/4.-(& -+2 2#+2,)$)* *#..( -+2
&-*,/4"-0#( ;$"# .-$$#, *#.. 0,/'4( -,# +/$
("/9+ )+ $"# )..'($,-$)/+<5 N/,#/?#,= $"#
$"%&'( */+$-)+( - .-,0# +'&8#, /1 8.//2 ?#(3

)-($)+'& $/ )$( 1)+-. 2#($)+-$)/+ 8#$9##+ $"# (#.( -+2 #11#,#+$ .%&4"/)2 $)(('#( $"-$ 2,-)+
($#,+'& -+2 $"# &-@/, ?#((#. $,'+7(5 >$ */+()($( )+$/ $"# &#2)-($)+-. .%&4" +/2#(5
/1 $9/ ./8#( $"-$ '+)$# *,-+)-..% $/ 1/,& $"#
"/,+( /1 $"# $"%&'(= 9")*" (/&#$)&#( #A$#+2
$/ $"# $"%,/)2 0.-+25
" !"# ()B# /1 $"# $"%&'( )( -0#32#4#+2#+$5
>$ ,#-*"#( - &-A)&'& 9#)0"$ /1 -,/'+2 CD 0
-,/'+2 $"# ED$" %#-, /1 .)1# -+2 $"#+ '+2#,0/#(
- */+$)+'/'( 4,/*#(( /1 )+?/.'$)/+5 F( - ,#('.$=
$"# 4-,#+*"%&- /1 $"# $"%&'( */+()($( -.&/($
#+$),#.% /1 1-$ -+2 1)8,/'( $)(('# )+ /.2 -0#5 G+.%

"
- 1#9 *.'($#,( /1 4-,#+*"%&- -+2 .%&4"/*%$#(
,#&-)+ )+$-*$ ;(## -.(/ 4-,-0,-4"( # -+2 $<5
>+ &-+% *-(#(= )$ )( +/$ 4/(()8.# $/ ,#.)-8.%
2)11#,#+$)-$# 8#$9##+ $"# )+?/.'$#2 /,0-+
-+2 $"# (',,/'+2)+0 &#2)-($)+-. 1-$ 8% &-*,/3
(*/4)* &#-+(5
#= $ H-*" ./8# /1 $"# $"%&'( )( ('82)?)2#2
8% 1)8,/'( (#4$- ;$,-8#*'.-#< )+$/ (&-..#, ./8#(=
#-*" /1 9")*" */+()($( /1 -+ /'$#, .-%#, ;*/,$#A<
-+2 -+ )++#, .-%#, ;&#2'..-<5 !"# */,$#A */+3
$-)+( - 2#+(# *.'($#, /1 .%&4"/*%$#(I $"# -83
'+2-+*# /1 &)$/(#( )( )+2)*-$)?# /1 #A$#+()?#
4,/.)1#,-$)/+5 !"# &#2'..-= /+ $"# /$"#, "-+2=
"-( - &'*" (&-..#, 4/4'.-$)/+ /1 .%&4"-$)*
*#..(5 >$ -.(/ */+$-)+( ($,'*$',#( 7+/9+ -(
J-((-..K( 8/2)#( $"-$ -,# &-2# /1 2#+(#.%
4-*7#2 *#.. .-%#,(5 !"#(# ($,'*$',#( &-% 8#
$"# ,#&+-+$( /1 2#0#+#,-$#2 #4)$"#.)-.
*#..(5 F+ )+$,-$"%&)* 8-,,)#, ()&).-, $/ $"#
8.//2L8,-)+ 8-,,)#, 2)?)2#( $"# */,$#A 1,/&
$"# *),*'.-$)+0 8.//25 M/ ('*" 8-,,)#, #A)($(
1/, $"# &-,,/95
!"# .%&4"/*%$#( $"-$ &-$',# )+$/ ! *#..( )+

!
$"# $"%&'( -,# /1$#+ *-..#2 !"#$%&#!'(
1/, 1'+*$)/+-. -+2 -+-$/&)*-. ,#-(/+(5 !"#
(4#*)1)* */&8)+-$)/+ /1 )&4/,$-+$ (',1-*#
&-,7#,( 4#,&)$( )&&'+/4"#+/$%4)* 2)11#,#+3
$)-$)/+ 8#$9##+ $"%&/*%$#( -+2 &-$',# ! *#..(5
= !"%&/*%$#( -,# #A$,#&#.% */,$)(/+#3(#+()$)?#
Thyroid gland
Large
10('23
!
vessels 40

Lung 30

Weight (g)
Heart 20 Cortex Fat and
connective tissue

10

Medulla
0
Diaphragm 0 5 10 10 20 30 40 90

;2#)$'+#%$- <58#98.-+3
Age/months Age/years
1. Position of the thymus 2. Growth curve

Hassall’s
body Fat
Hassall’s
body

Inter- Thymic
lobular

"
parenchyma
connective
tissue
(trabecula) Inter-
lobular
connective
tissue

Cortex

Medulla

3. Thymus of a newborn 4. Thymus of an adult

Thymo-
Thymo- cytes
cytes Cortex Medulla
Epithelial
cells

Epithelial
cells

Inter-

!
lobular
connective
tissue
Hassall’s Hassall’s
5. Histology body body
A. Anatomy and development of the thymus
>

"
! >%?8.5 )* $+( 012,+8$:' #15$(2

!" #$%&'$&%( )* $+( #,-((.

!"# $%&##' ($ )"# &*+,#$) &-.%"/(0 /+,*' 1$(2#
*3/4) 56!7!8 9.: ;#(,") *3/4) 6<< ,=> ?) 9/'@
*'0 9#')+/3&*$)$= *'0 * .*')&# 2/'# .*0# /A
$.*&& &-.%"/9-)#$>

6" 7&')589855)':8$(4 012,+):4 ;:55&(

$($)$ /A );/ )-%#$ /A )($$4#B +#0 %4&% *'0 ;"()#
%4&%> !"# !"#$% &'(& 9/'$($)$ /A &-.%"/9-)#$>
!"# )%* &'(& +#$#.3&#$ * $%/',# .*0# /A #+-@
)"+/9-)#$C () ($ )"# $()# /A #&(.('*)(/' /A /&0 *'0D
/+ 0*.*,#0 #+-)"+/9-)#$> !"# $%&##' ($ $4+@
+/4'0#0 3- * 9*%$4&# /A 9/&&*,#' A(3#+$> E/&@
&*,#' $#%)* 1)+*3#94&*#= *99/.%*'(#0 3- *+)#+@
(/&#$ +*0(*)# A+/. )"# 9*%$4&# (')/ )"# $%&#'(9
%*+#'9"-.*: ;"#+# )"# ;"()# %4&% ($ &/9*)#0>
! &-.%"/9-)#$ *+# .*('&- &/9*)#0 (' )"# %#+(*+@
@&.482(.$8- A%:.':,-(5
<7!0;=
H//$#&- /+,*'(2#0 &-.%"/(0 )($$4#$ ;()" $.*&&
*,,+#,*)#$ /A ! 9#&&$: J 9#&&$: *'0 %&*$.* 9#&&$
1.*('&- /A )"# ?,G )-%#= *+# &/9*)#0 (' )"# $43@
.49/$* /A )"# ,*$)+/(')#$)('*& )+*9): +#$%(+*)/+-
)+*9): &*9+(.*& ,&*'0$: *'0 4+('*+- )+*9)>
!"# ,*$)+/(')#$)('*& )+*9) *&$/ 9/')*('$ 9/.@
%&#M $)+49)4+#$: $49" *$ )"# )/'$(&$ *'0 F#-#+R$
%*)9"#$> !"# )/'$(&&*+ *+9"()#9)4+# ($ $(.(&*+ )/
)"*) /A &-.%" '/0#$>

)#+(/&*+ +#,(/': )"4$ A/+.(', )"# %#+(*+)#+(/&*+

&-.%"/9-)# $"#*)" 1FGHI=> !"#- *+# $4+@
+/4'0#0 3- J &-.%"/9-)#$ )"*) A/+. )"# $/@
9*&&#0 +,)-#.,( /0.%> I.*&& 9&4$)#+$ /A J &-.@
%"/9-)#$ 1&)#+,)1 20((#3(%4= 9*' *&;*-$ 3# A/4'0
(' )"# .*+,('*& 2/'# /A )"# FGHI> K4+(', *' (.@
.4'# +#$%/'$#: )"# %+(.*+- A/&&(9&#$ 0#L#&/%
(')/ )+4# A/&&(9&#$ 14%30.*,)1 20((#3(%4= ;()" *
,#+.('*& 9#')#+ *'0 A/&&(94&*+ 9/+)#M>
J 9#&&$ #$9*%# A+/. )"# 3&//0$)+#*. (')/ )"#
!@9#&&@+(9" %#+(*+)#+(/&*+ +#,(/' *'0 9/')('4#
/' )/ )"# A/&&(9&#> !"#- )"#' %*$$ )"# .*+,('*&
?' )"# )#+.('*& (&#4.: F#-#+R$ %*)9"#$ 9/'$($)
/A A/&&(9&#$ ;()" ,#+.('*& 9#')#+$ *'0 .*')&#
2/'#$> G &*+,# '4.3#+ /A *')(,#'@%+#$#')(',
9#&&$ 9*' 3# A/4'0 (' )"# +#,(/' 3#);##' )"#
A/&&(9&# *'0 )"# A/&&(9&#@*$$/9(*)#0 (')#$)('*&
#%()"#&(4. 1S0/.# +#,(/'T=> !"# 0/.# #%()"#@
&(4. ($ 9"*+*9)#+(2#0 3- )"# %+#$#'9# /A $/@
9*&&#0 +#3)020(* 3%((4 1U 9#&&$=: ;"(9" "*L# '4@
.#+/4$ .(9+/A/&0$ 1'/) .(9+/L(&&(= /' )"#
#%()"#&(*& $(0# *'0 *+# $%#9(*&(2#0 )+*'$%/+)#+$
/A *')(,#'$> !"# *%(9*& $4+A*9# /A )"#$# 9#&&$

"
2/'# *'0 L#'/4$ $('4$/(0*& L#$$#&$ (' )"# +#@ )"#+#A/+# 9/')*('$ $%#9(A(9 /&(,/$*99"*+(0#$ ('@
,(/' /A )"# ;"()# %4&%: ;"#+# )"#- 4&)(.*)#&- $)#*0 /A )"# 4$4*& ,&-9/9*&-9#$> U 9#&&$ 9*' *&$/
+##')#+ )"# 9(+94&*)(/' 1J@9#&& +#9(+94&*)(/'C 3+(', (' &-.%"/9-)#$ *'0 ./'/9-)#$: ;"(9"
$## *&$/ %%> 66 *'0 68=> 9*' %(9N 4% *')(,#'$ #L#' ;()"(' )"# U 9#&&$>
! &-.%"/9-)#$ *+# .*('&- &//$#&- 0($)+(34)#0
/" #$%&'$&%( )* $+( 012,+ 3)4(5 )"+/4,"/4) )"# (')#+A/&&(94&*+ )($$4#B $/.# *+#
*&$/ A/4'0 (' )"# (')+*#%()"#&(*& +#,(/'> !"#
H-.%" '/0#$ *+# $()4*)#0 *&/', )"# &-.%"*)(9
'4.3#+ /A (')+*#%()"#&(*& &-.%"/9-)#$ *'0
L#$$#&$C )"#- A/+. * 9/.%&#M '#);/+N )"*)
%&*$.* 9#&&$ ('9+#*$#$ 0+*.*)(9*&&- ;"#' ('@
0+*('$ )"# $N(' *'0 )"# (')#+'*& /+,*'$> H(N#
A&*..*)(/' /994+$>
)"# $%&##': )"# &-.%" '/0#$ *+# ('L#$)#0 (' *
9*%$4&# /A 9/&&*,#' A(3#+$> O/+.*& &-.%" '/0#$
*+# +/4'0 )/ N(0'#-@$"*%#0 $)+49)4+#$ )"*) *+#
5P5Q .. (' 0(*.#)#+> !"# &-.%"*)(9$ %#'#@
)+*)# )"# 9*%$4&# *'0 A/+. )"# +,)-#.,( 4#.'4%4
(' )"# $439*%$4&*+ +#,(/' *'0 )"# #.$%)20((#3'(,)
4#.'4%4 (' )"# 0##%#+ 2/'#$ 0/;' )/ )"# 9#')#+
/A )"# &-.%" '/0#> G) )"# 9#')#+ /A )"# '/0#:
)"# $('4$#$ .#+,# )/ A/+. 9#')+*& +%*'((,)1 4#5
.'4#$> H-.%" &#*L#$ )"# &-.%" '/0# L(* * $('@
,&# #AA#+#') &-.%"*)(9 ;"(9" +4'$ *&/', )"#
3&//0 L#$$#&$>
!"# #M)#+'*& 9/+)#M /A )"# &-.%" '/0#

!
9/')*('$ .*('&- J &-.%"/9-)#$: ;"#+#*$ )"#
! &-.%"/9-)#$ *+# .*('&- &/9*&(2#0 (' )"#
4'0#+&-(', %*+*9/+)(9*& +#,(/'> GA)#+ *')(,#'
$)(.4&*)(/': &//$# 9&4$)#+$ /A J 9#&&$ (' )"# 9/+@
)#M 1&)#+,)1 20((#3(%4= ,(L# +($# )/ )"# $/@9*&&#0
B 4%30.*,)1 20((#3(%4: ;"(9" 9/')*(' * ,#+.('*&
9#')#+ .*0# /A 3&*$)(9 #&#.#')$ 19#')+/9-)#$
 Red pulp Germinal center White pulp Sinus
A(%:,+(%8- >%?8.5
!
Lymphoid
follicle
Arteriole
Follicular mantle Marginal zone
Mantle zone Marginal zone
B
B
B
T T
Periarterial B T
lymphatic sheath Germinal center T

@&.482(.$8- A%:.':,-(5
1. Anatomic structure 2. Cross-section through arteriole and
follicle; lymphocyte circulation
A. Structure of the spleen

Capsule Secondary follicle

Marginal sinus Paracortex

"
Inter-
follicular
sinus
Afferent
Medullary sinus lymphatic

Primary follicle Efferent lymphatic

1. Inactive lymph node 2. Active lymph node

B. Structure of the lymph node

Follicle center M cells Follicle-associated

epithelial cells
Mantle zone Dome region

T-cell zone

Postcapillary venule

Muscular mucosa

1. GALT: Gut-associated1.
Efferent lymphatic

lymphoid tissue; Peyer’s patch

C. Mucosa-associated lymphoid tissue
2. BALT: Bronchus-associated
2. lymphoid tissue
!
C

"
! ,:;4583)-4%. 6.7./)85.*% $*< 6(++.'.*%($%()*

!" #$%&'$%()* )+ , -.//0

!"#$%&'()*'%#+ !"# $"#%&"'("' () *+# , %#--'
., -/0$+(%/*#'12 *+#/ 0!*&"# 34 *+# 5(4# 0!"6
"(7 !48 )#*!- -39#": ;4 *+# #05"/(4!- '*!<#'= *+#
*+/0&' !"3'#' )"(0 *+# >"8 5"!4%+3!- $(&%+
!48 34%(034< $"#%&"'(" %#--'2 *+# 5"!4%+3!-
$(&%+ *+#"#5/ )("0' *+# #$3*+#-3!- %(0$(4#4*
!48 *+# $"#%&"'(" %#--' *+# -/0$+!*3% %(0$(6
4#4* () *+# *+/0&': ,+# *+/03% #$3*+#-3!- %#--'
$"(938# +("0(4#' 30$("*!4* )(" *+# 8#9#-($6
0#4* () *+# $"#6*+/0(%/*#': ;4 *+# *+/0&'
*+# $"#%&"'(" %#--' 0!*&"# 34*( *+/0(%/*#'
!48 !"# &-*30!*#-/ "#-#!'#8 !' 0!*&"# , %#--'
=&*<$5.*%$/ 2'(*-(8/.0
9" 6.7./)85.*% )+ #$%&'. , 9.//0
Q)*#" 5#34< "#-#!'#8 34*( *+# %3"%&-!*3(4= *+#
0!*&"# , %#--' &48#"<( )&"*+#" 83))#"#4*3!*3(4
34 *+# 5-((8 !48 -/0$+!*3% '/'*#0: ,+#'# ,-./#
0 *#11+ %3"%&-!*# &4*3- !4*3<#4 %(4*!%* +!' 5##4
#'*!5-3'+#8 (&*'38# *+# -/0$+(38 ("<!4':
,+#/ 5#!" *+# AGLWBQ '&")!%# !4*3<#4: ,+3'
!4*3<#4 %(4*!%* -#!8' *( *+# 8#9#-($0#4* ()
0#0("/ , %#--' *+!* !"# %+!"!%*#"3D#8 5/ *+#
$"#'#4%# () *+# AGLWBF !48 AGHT !4*3<#4':
AGLWBF 3' ! 9!"3!4* () %(00(4 -#&@(%/*# !4*36
<#4 .'## !-'( $: JI1= ! %#-- '&")!%# $+('$+!*!'#:
AGHT= (4 *+# (*+#" +!48= 3' ! )35"(4#%*34 "#%#$6

34*( *+# %3"%&-!*3(4: *(" 30$("*!4* )(" *+# !8+#'3(4 () , %#--' !48 )("
*+#3" 03<"!*3(4 34 *3''&#:
1" 23$0.0 )+ ,345)-4%. 6.7./)85.*%
?"#6*+/0(%/*# 8#9#-($0#4* *!@#' $-!%# 34 *+#
)#*!- -39#" !48 5(4# 0!""(7= 7+#"# *+# "#!""!46
<#0#4* () ,6%#-- "#%#$*("' .,AB1 !48 *+# %+!4<#
34 <#4#*3% 34)("0!*3(4 "#C&3"#8 )(" <!00!
%+!34' !-'( (%%&": ,+#'# $"#%&"'(" %#--' !"#
%+!"!%*#"3D#8 5/ *+# $"#'#4%# () *#"034!- 8#(E6
/4&%-#(*38/- *"!4')#"!'# .,8,1 #4D/0#: F4%#
*+#/ #4*#" *+# *+/0&'= *+# %#--' 83))#"#4*3!*#
34*( #!"-/ *+/0(%/*#' 83'*34<&3'+#8 5/ '&")!%#

" #E$"#''3(4 () AGH !48 AGI !4*3<#4' .'*!<# J

() ,6%#-- 83))#"#4*3!*3(41: ,"!4'%"3$*3(4 () *+#
,6%#-- "#%#$*("K' <!00! %+!34 !48 "#!""!4<#6
0#4* () *+# 5#*! %+!34 !-'( (%%&"' 34 *+# *+/6
0&': ,+#'# %#--' !"# 8#'%"35#8 !' 8(&5-# 4#<!6
*39# '34%# *+#/ %(4*!34 4#3*+#" *+# AGL 4(" *+#
AGM !4*3<#4:
;4 *+# 4#E* '*!<# () 0!*&"!*3(4 .'*!<# H1= *+#
%(00(4 *+/0(%/*# %(4*!34' %+!"!%*#"3'*3%
AGJ !4*3<#4' !' 7#-- !' AGL !48 AGM '&")!%#
!4*3<#4' .8(&5-# $('3*39#1: NE$"#''3(4 () *+#
,AB (4 *+# %#-- '&")!%# (%%&"' 34 %(4O&4%*3(4
73*+ *+# )("0!*3(4 () !-$+! !48 5#*! %+!34':
P(-#%&-#' () *+# AG> !4*3<#4 "#%#$*(" %(0$-#E
!-'( !$$#!" (4 *+# %#-- '&")!%#:
Q 8#%3'39# '*#$ *(7!"8 *+# 0!*&"!*3(4 () *+#
!%*&!- , %#--' 4(7 (%%&"' .'*!<# >1: ,+# AGJ
!4*3<#4 3' -('*= !48 *+# %#--' 83938# *( )("0
*7( ,6%#-- $($&-!*3(4' *+!* 5#!" #3*+#" *+#
AGL !4*3<#4 (" *+# AGM !4*3<#4: ,+# AGL !4*36
<#4 3' %+!"!%*#"3'*3% () *+# ,6+#-$#" ., R1 %#-- $(6
$&-!*3(4= !48 *+# AGM !4*3<#4 3' %+!"!%*#"3'*3%

!
() *+# %/*(*(E3% , %#-- $($&-!*3(4 .,A= A,S1: ,+#
%#--' !"# 4(7 '!38 *( 5# '34<-# $('3*39#: F9#"
TT U () !-- 0!*&"# , %#--' 5#!" ,AB!V" (4 *+# '&"6
)!%#2 *+# "#'* +!9# ,AB#V$: ,+# ,6%#-- "#%#$*("'
!"# 83'*34<&3'+#8 )&4%*3(4!--/ 34 *+#3" !53-3*/ *(
>? "#%(<43D# !4*3<#4':
 3. Branchial pouch Thymus
,:9.// 6.7./)85.*%

Thymic epithelial cell

!
1. Epithelial
– thymulin
component
Thymic – thymosin "1
2. hormone – thymopoietin
– etc.

3.

Circulation
4.

Progenitor cell (pre-thymocytes)

Thymocytes Mature T cells
(bone marrow, fetal liver)

A. Maturation of T cells

=&*<$5.*%$/ 2'(*-(8/.0
Location

Fetal liver
Thymus
Bone marrow
Pre- Early General Mature thymocyte
thymocytes thymocyte thymocyte CD4
CD4 CD8 TCR
CD2 CD2
TCR CD3
CD5 CD7
Cell

CD3
CD8

"
CD7
CD1 CD7
TCR
(CD1) CD2 CD5 CD2 CD3
CD5 CD7
Rearrangement Transcription Cell surface Mainly expression
of TCR! of TCR! expression of TCR",#
TCR

rearrangement of TCR!,", #
of TCR#
TdT enzyme TdT, CD2, CD7 TdT, CD1, CD2, CD3, TH: CD2, CD5,
CD5, CD4 and CD8 CD7, CD3, CD4
Marker

(CD1) TC: CD2, CD5,

CD7, CD3, CD8
Double negative Double positive Single positive
B. Phases of thymocyte development

CD3
CD8 CD3
CD4 Naive
Cytotoxic T cell
CD45RA
T cell
CD2, 5, 7, TCR",# CD2, 5, 7, TCR",#
CD3
CD4
CD3
CD4 Memory

!
CD45RO T cell
T-helper cell
CD29
CD2, 5, 7, TCR",# CD2, 5, 7, TCR",#
Thymus
(see B) Mature T cell in blood and lymphoid system
C. Development of mature T cells
>>

"
! ./64+7&,%43$ 8$9$1,7+$(3 '(: 8)--$;$(3)'3),(

!"# $"%&'( #)('*#( $"+$ &,($ ! -#..( $"+$ +*#

*#.#+(#/ 0)$, $"# -0*-'.+$0,) 1')-$0,) 0) -,)2
3')-$0,) 40$" $"# -,**#(5,)/0)6 !"#$% &'()$*
+$!,")'-'.')/ +$!,.01 789:; 6#)#( ,1 $"#
<,/%=( 0&&')# (%($#& <'$ /, ),$ 0/#)$01% #)2
/,6#),'( ('<($+)-#( +( 1,*#06) &+$#*0+.>
!" #$%&'()*+* ,- ./0$11 2$1$%3),(
)( 3&$ .&4+5*
?1$#* 5*#2$"%&,-%$#( &06*+$# $, $"# $"%&'(@
$"#% -,&# 0)$, -,)$+-$ 40$" $"%&0- #50$"#.0+.
-#..(> !2-#.. *#-#5$,*( $"#) /#A#.,5 +)/ 0)$#*+-$
40$" 89: &,.#-'.#( ,) #50$"#.0+. -#..(> B)# ,1
$"# 1,..,40)6 #A#)$( &+% ,--'* 0) $"# 5*,-#((>
<5(:'+$(3'1 =;)(%)71$*
7(## +.(, 5> KP?;> ! -#..( $"+$ *#+-$ 40$" ,)#
,1 $"#(# +'$,+)$06#)( 40.. ),$ *#-#0A# + .01#2(+A2
0)6 (06)+. +)/ 40.. +.(, <# /#($*,%#/ 7-+(# :;>
B).% $",(# -#..( $"+$ *#-,6)0F# $"# &+$-"0)6
89: &,.#-'.#@ 1,*& + &,/#*+$#.% ($*,)6 <,)/
40$" 0$@ +)/ +*# ),$ /0*#-$#/ +6+0)($ +)% +'$,2
+)$06#)( 40.. <# +..,4#/ $, 1'..% &+$'*# +)/
5+(( +( 1'..% 1')-$0,)+. ! -#..( 0)$, $"# -0*-'.+2
$0,) 7-+(# O;>
:,)(0/#*0)6 $"0( ($*0-$ 5*,-#(( ,1 (#.#-$0,)@
PQ R ,1 $"# $"%&,-%$#( $"+$ &06*+$# 0)$, $"#
$"%&'( 40.. 5#*0("> ?5+*$ 1*,& $"#(# (#.#-$0A#
&#-"+)0(&(@ -#*$+0) 5#*05"#*+. (+1#$% &#-"+)2
0(&( +.(, 4,*H $, ('55*#(( +'$,+66*#((0A#

! -#..(> !"0( 5*,A0/#( +) +//0$0,)+. /#6*## ,1

!"# $"%&,-%$#( &+% <# ')+<.# $, <0)/ 40$"
(+1#$% 4"#) $"# +'$,+66*#((0A# -#..( +*# ),$
89: &,.#-'.#( A0+ $"# !2-#.. *#-#5$,* 7-+(# ?;>
#.0&0)+$#/ 0) $"# 10*($ 5*,-#(( ,1 (#.#-$0,)
!"0( 0( )#-#((+*%@ ",4#A#*@ 1,* /#($*'-$0,) ,1
7(## +.(, 5> KP!;>
A0*'(20)1#-$#/ -#..( $"+$ 5*#(#)$ $"# A0*+. +)$02
6#) $, ! -#..( ,) $"# -,**#(5,)/0)6 89: &,.#2
-'.#(> C1 $"# D5+*$)#*E ,1 $"# 0)1#-$#/ -#.. 4#*#
+ ! -#.. 0)-+5+<.# ,1 1,*&0)6 ('-" + <,)/@ $"#
! -#.. 4,'./ ),$ <# +<.# $, *#-,6)0F# $"# +)$02
6#)> ?( + *#('.$@ $"# 0)1#-$#/ -#.. 4,'./ ),$ <#
/#($*,%#/> G'-" D&0(5*,6*+&&#/E ! -#..( +*#
,1 ), '(# $, $"# 0&&')# (%($#& +)/ +*# #.0&02

"
)+$#/ *06"$ +4+%> !"0( 0( ),$ /,)# <% +-$0A#.%
H0..0)6 $"# -#..(@ <'$ <% +) #)/,6#),'( D('0-0/#
5*,6*+&E *#1#**#/ $, +( ,%$2%"!!03 +0.. 30")&
,* ",$,)$('(> !"#(# -#..( /, ),$ *#-#0A# + 5,(02
$0A#@ .01#2(+A0)6 (06)+. $, $#*&0)+$# $"# 5*,-#((
,1 5*,6*+&&#/ -#.. /#+$"I (## +.(, 5> JK>
!"# ! -#..( &+% <# +<.# $, -,,5#*+$# 40$" $"#
-,**#-$.% &+$-"0)6 89: &,.#-'.#> !"# !2-#..
*#-#5$,* 0( +<.# $, 1,*& + <,)/ 40$" + $"%&'(
#50$"#.0+. -#.. A0+ $"# 89: &,.#-'.#@ +)/ $"#
! -#.. *#-#0A#( + (06)+. $, +<,*$ $"# ('0-0/# 5*,2
6*+&@ $"'( (+A0)6 0$( .01#> !"# -#.. 0( +..,4#/ $,
-,)$0)'# $, &+$'*# +)/ &+% '.$0&+$#.% <# *#2
.#+(#/ 0)$, $"# -0*-'.+$0,)> ?),$"#* 0&5,*$+)$
5*,$#-$0A# &#-"+)0(& /#$#*&0)#( 4"#$"#*
$"0( ,--'*(> C1 $"# <,)/ <#$4##) $"# !2-#..
*#-#5$,* +)/ $"# 89: &,.#-'.# 0( $,, ($*,)6@
+ -%$,$,L0- *#(5,)(# $, $"# <,/%=( ,4) +)$02
6#)25*#(#)$0)6 -#..( &+% .+$#* ,--'*> C) $"0(
-+(# +.(,@ $"# ! -#.. 40.. <# /#($*,%#/ 7-+(# M;>
C) (,&# -+(#(@ $"# !2-#.. *#-#5$,* +)/ $"#
89: +)$06#) &+% &+$-" <'$ $"# *#-#5$,* *#2
-,6)0F#( +) #)/,6#),'( +)$06#)> N#(5,)(#(

! >?
<% ('-" D+'$,0&&')#E ! -#..( -,'./ '.$0&+$#.%
/#($*,% $"# ,*6+)0(&> 9#)-#@ $"0( $%5# ,1 -#.. 0(
+.(, D(,*$#/ ,'$E 0) + 5*,-#(( $"+$ 0( 5*,<+<.%
&#/0+$#/ <% /#)/*0$0- -#..( $"+$ &06*+$# $,
$"# $"%&'(> O#)/*0$0- -#..( 5,((#(( &,($@ <'$
),$ +..@ ('*1+-# +'$,+)$06#)( H),4) $, #L0($
Pre-
./0$11 2$1$%3),(
!
thymocytes

<5(:'+$(3'1 =;)(%)71$*
Thymic
epithelial cells
MHC molecule

TCR

A B

Dendritic

C
cell

D
"
(No
Autoantigen binding)

Thymus with
maturing thymic cells

Thymocyte Self-MHC Autoantigen Fate

(type) binding recognition

Missing or _
A Cell death
weak

B Strong _ Cell death

!
C Moderate Yes Cell death
Mature
Complete
immuno-
D Moderate No
maturation competent
T cell

A. Mechanisms of T-cell selection in the thymus

>@

"
! #$@A2*9,)A+& :&B&',*2&/+ 1/? :377&-&/+31+3,/

!" #$%&'' (&)&*+,- .&/& 0123'3&4

!"#$% &!' %() *+,% &"' -$%.(/ %0+ ,$+ 12/,
-2112("3 +4#0+//+) 567 8+(+/9 567#:$ ./ +4;
J( -2(,0%/, ,2 ,$+ ! %() " -$%.(/@ ,$+ # %() $
-$%.(/ %0+ "2-%,+) 2("3 2( 5 -+""/ ,$%, +4#0+//
6GS *<, (2, !:" 0+-+#,20/9 5$+ /,0<-,<0+ 2= #
%() $ -$%.(/ ./ /.1."%0 ,2 ,$%, 2= ,$+ ! %() "
#0+//+) 2( .11%,<0+ 5 -+""/ %() 2( % 1.(20.,3
-$%.(/9 5$+ %1.(2 %-.) /+I<+(-+ 2= ,$+ # -$%.(
2= 5-+""/ .( ,$+ #+0.#$+0%" *"22)9 !"#$% %() *+,%
D+03 -"2/+"3 0+/+1*"+/ ,$%, 2= ,$+ " -$%.(@ %()
-$%.(/ %0+ "2-%,+) 2( -$0212/21+ >?@ A$+0+%/
,$+ /+I<+(-+ 2= ,$+ $ -$%.( -200+/#2()/ ,2 ,$%,
)+",% %() 8%11% -$%.(/ %0+ /.,<%,+) 2( -$02;
2= ,$+ ! -$%.(9
12/21+ B9 C.1."%0"3 ,2 ,$+ .11<(28"2*<".(/@
,$+ D%0.%*"+ 0+8.2(/ 2= ,$+ 5;-+"" 0+-+#,20 %0+ :" #$%&'' (&)&*+,- %,2;3/1+3,/ <,+&/+31'
"2-%,+) 2( D%0.2</ +42(/@ A$.-$ %0+ <",.1%,+"3
".(E+) A.,$ ,$+ -2(/,%(, 0+8.2(/ 2= ,$+ 0+-+#,20 !/ .( ,$+ .11<(28"2*<".(/@ ,$+ ).==+0+(, #2//.;
*3 /#".-.(89 5$./ +(/<0+/ % D+03 $.8$ )+80++ 2= *.".,.+/ =20 -21*.(.(8 P@ G@ %() F 8+(+/ %()
0+-+#,20 D%0.%*.".,3@ A$.-$ ./ =<0,$+0 +($%(-+) 2,$+0 1+-$%(./1/ -0+%,+ %( +(2012</ ).D+0;
/.,3 0+/<",.(8 .( % -21*.(%,.2( #2,+(,.%" 2=
08/?12&/+1' <-3/)3*'&4

*3 ,$+ D%0.%*"+ /+"+-,.2( 2= F +"+1+(,/ &! %() "

-$%.(/' %() G /+81+(,/ &" -$%.(/'9 >K>N =20 5;-+"" 0+-+#,20/9

5" #$%&'' (&)&*+,- (&1--1/6&2&/+
5$+ 0+-21*.(%,.2( #02-+// ,$%, 2--<0/ A$."+
,$+ .(=201%,.2( (++)+) =20 ,$+ 5;-+"" 0+-+#,20
-$%.( =201%,.2( ./ *+.(8 208%(.H+) 0+/<",/ .(
!"#" $"%$$%#!"&"#'@ % #02-+// .( A$.-$ % #%0,.;
-<"%0 8+(+ +"+1+(, 20 +"+1+(,/ 1%3 *+ )+"+,+)
20 %",+0+) .( %( <(*%"%(-+) -$0212/21+ +4;
-$%(8+9 (#)"$*+,# ./ % #02-+// -$%0%-,+0.H+)
*3 ,$+ =201%,.2( 2= "22#/@ /<*/+I<+(, -$0212;
=" :34+-3;8+3,/ ,7 !>" 1/? #>$ # %&''4
5$+ "%08+ 1%V20.,3 2= 1%,<0+ 5 -+""/ .( ,$+ *"22)
&%()@ #0+/<1%*"3@ %"/2 ,$2/+ .( ,.//<+' +4#0+//
567!:"9 5$./ .(-"<)+/ ,$+ -%9 MM W 6G?;#2/.,.D+
%() -%9 SS W 6GT;#2/.,.D+ 5;-+""/ &%D+0%8+ =.8;
<0+/'9 567!:" -+""/ %0+ /+")21 )2<*"+ (+8%,.D+
20 )2<*"+ #2/.,.D+ &/++ #9 R!'9 J( -2(,0%/,@ ,$+
1%V20.,3 2= #:$ 5 -+""/ %0+ )2<*"+ (+8%,.D+9
C21+ %0+ )2<*"+ #2/.,.D+@ %() 2("3 % =+A +4;

" /21+ -"+%D%8+@ %() 0+-2((+-,.2( ,2 .(D+0/.2(/9

J( 2,$+0 A20)/@ ,$+ ,0%(/-0.#,.2( 20)+0 2= ,$+
20.8.(%" 8+(+,.- .(=201%,.2( ./ 0+D+0/+)9

%" %,/7368-1+3,/ ,7 +9& #$%&'' (&)&*+,-

5$+ ! -$%.( 2= ,$+ 5;-+"" 0+-+#,20 ./ % ?KLMK EG%
#0+// ,$+ 6G? %(,.8+(9
5$+ =<(-,.2( 2= ,$+ 567#:$;#2/.,.D+ -+""/ ./
/,."" <(E(2A(9 5$+3 %0+ ,$2<8$, ,2 #"%3 %( .1;
#20,%(, 02"+ .( ,$+ )+=+(/+ %8%.(/, 13-2*%-,+0;
.% %() .( ,$+.0 0+/#2(/+ ,2 /<#+0%(,.8+(/9

8"3-2#02,+.(@ A$+0+%/ ,$+ " -$%.( $%/ % 12"+;

-<"%0 A+.8$, 2= ?KLNK EG%9 O.E+ ,$+ .11<(2;
8"2*<".(/@ 5;-+"" 0+-+#,20 -$%.(/ $%D+ )%$+%-."
$"!+,#* %() /,#*'%#' $"!+,#*9 J( ,$+ " -$%.(@
,$+ 6;,+01.(%" +()/ 2= ,$+ P 0+8.2( &".(E *+;
,A++( ,$+ P %() 6 0+8.2(/' %0+ +(-2)+) *3
F %() G 8+(+/9 5$+ P 0+8.2(/ 2= ,$+ ! %() "
-$%.(/ $%D+ >KQL>>R %1.(2 %-.)/ %() -2(,%.(
,A2 -3/,+.(+ -21#2<()/ ,$%, #+01., ,$+ =20;
1%,.2( 2= % )./<"=.)+ *0.)8+9
5$+ 6 0+8.2(/ 2= ,$+ ! %() " -$%.(/ -2(,%.(
>STL>BR %1.(2 %-.)/ %() $%D+ =2<0 =<(-,.2(%"
)21%.(/@ A$.-$ %0+ (201%""3 +(-2)+) *3 ).=;
=+0+(, +42(/9
5$+ %1.(2;,+01.(%" 6 )21%.( -2(,%.(/ ,A2
-3/,+.(+ -21#2<()/ A.,$ )./<"=.)+ *0.)8+/

!
A.,$.( ,$+ -$%.(U $+(-+@ ,$+ ,+0,.%03 /,0<-,<0+
#0+/<1%*"3 -200+/#2()/ ,2 ,$%, 2= ,$+ -2(/,%(,
0+8.2( 2= ,$+ .11<(28"2*<".( 12"+-<"+9 5$+
,0%(/1+1*0%(+ )21%.( -21#0./+/ QKLQ? #0.;
1%0."3 $3)02#$2*.- %1.(2 %-.)/9
CD
!, " (Chromosome 14)
#$%&'' (&)&*+,-4
!
V!1 V!2 V!n V"n D" J C" V J! segments C!
"

# (Chromosome 7q)
V#1 V#2 V#3 V#n D#1 J#1 C#1 D#2 C#2 V#14

$ (Chromosome 7p)
V$I V$II V$III V$IV Jp1 Jp J1 C$1 C$2

V1.1 V1.3 V1.5 V1.6 V1.8 VA VB VII

V1.2 V1.4 V1.5P V1.7

08/?12&/+1' <-3/)3*'&4
Pseudogene (Reversed direction of transcription)

A. T-cell receptor gene families

I
II

II

Deletion
B. T-cell receptor rearrangement
I
II
Unequal chromosome switch Inversion
"
! (") # ($) Gene segments !-chain #-chain
V 100 100
Extra- V! S S
V D 0 2
cellular S S
region J 100 13
CHO
V x D x J-combinations 104 2 x103
C! S S
C N-sequences 104 104
S S
SS Total number
Trans- of !/# combinations 1015
membrane
region D. Possible combinations of the T-cell
Cyto- receptor (!/#)
plasmic-
!/# $/"
region Total:
248 282 95 % 5%

Marker: CD4+ CD8– 66 % <1%

! chain = V - J - C
# chain= V - D - J - C
" chain = V - D - J - C
$ chain = V - J - C
C. Configuration of the T-cell receptor
CD4–
CD4–
CD4+
CD8+
CD8–
CD8+
33 %
<1 %
<1 %

E. Distribution of !/# and $/" T cells

25 %
70 %
<12 %
Weak

!
CE

"
! ()67%892471+ -+:+,28%+'1 &'; -.//+0+'1.&1.2'

!" #$$%&%'" &' &() *+,)-- .),)/&'.0 "12).'13

()-/). 2'-),1-)3 #.) #-3' "))$)$ 4'. &()
$)5)-'/2)"&0 $%44).)"&%#&%'"0 #,&%5#&%'"0 #"$
#"&%6)" .),'6"%&%'" '4 * ,)--37 *()3) 2'-),1-)3
/-#8 #" %2/'.&#"& .'-) %" &() 9%"$%"6 '4 * ,)--3
:%&( #"&%6)"+/.)3)"&%"6 ,)--3 ;#,,)33'.8 2'-)+
,1-)3<7 ='2) '4 &()3) 2'-),1-)30 31,( #3 &()
>?@ #"&%6)"30 ',,1. )A,-13%5)-8 '" ,)--3 '4 &()
*+,)-- -%")0 :().)#3 '&().3 ',,1. '" B ,)--3 #"$
#,,)33'.8 ,)--37 *()3) 2'-),1-)3 ,#" 9) .),'6+
"%C)$ #"$ #"#-8C)$ :%&( &() ()-/ '4 2'"',-'+
"#- #"&%9'$%)37 *(%3 2)&('$ (#3 "'& '"-8 6.)#&-8
%",.)#3)$ &() 1"$).3&#"$%"6 '4 -82/(#&%, ,)--
41",&%'"0 91& %& %3 #-3' '") '4 &() 2'3& %2/'.+
<$';&%+'1&, =0.'4.8,+5
%" ,-#33 !! KL> 2'-),1-) 9%"$%"6 #"$ %"&).#,&3
:%&( /NV-,J &8.'3%") J%"#3)7 !& #-3' 3).5)3 #3 &()
9%"$%"6 /.'&)%" 4'. &() (12#" %221"'$)4%+
,%)",8 5%.13 ;L!W<7 *() >?U #"&%6)" ,'..)+
3/'"$3 &' &() >?O 2'-),1-)0 :(%,( ,'"3%3&3
'4 &:' ,(#%"3 #"$ %3 ,(#.#,&).%3&%, '4 ,8&'&'A%,
* ,)--37 !& %3 #-3' -',#&)$ '" %22#&1.) &(82'+
,8&)3 #"$ %3 :)#J-8 ,(#.#,&).%3&%, '4 "#&1.#- J%--+
). ,)--37 !& %3 .)3/'"3%9-) 4'. 9%"$%"6 &' ,-#33 !
KL> 2'-),1-)3 #"$ %"&).#,&3 :%&( /NV-,J &8.'+
3%") J%"#3)7
*() >?N #"&%6)" #"$ >?T #"&%6)" #.) #-3'
,(#.#,&).%3&%, '4 * ,)--37 >?N %3 %"5'-5)$ %" 3%6"#-
&.#"3$1,&%'" #"$ ,)--+&'+,)-- %"&).#,&%'"37 *()

&#"& #$5#",)3 %" %221"'-'6%,#- $%#6"'3&%,37
!& %3 &() 2)&('$ 13)$ &' $)&).2%") &()
%221") 3&#&13 #"$ &() &8/) ,#&)6'.8
'4 2#-%6"#"& -82/(#&%, &12'.37 D& ,'"3)"313
,'"4).)",)30 #"&%6)"3 %$)"&%4%)$ 13%"6 2'"'+
,-'"#- #"&%9'$%)3 (#5) 9))" ;#"$ :%-- ,'"&%"1)
&' 9)< 6%5)" %"&)."#&%'"#--8 5#-%$ $)3%6"#&%'"3
3&#.&%"6 :%&( E>?F ;,-13&). '4 $%44).)"&%#&%'"<
#"$ # ,'..)3/'"$%"6 "129).7
!" #$%&' ()*+,, -.//+0+'1.&1.2' 32,+4$,+5
>?T #"&%6)" ,#" 9) $)3,.%9)$ #3 &() )#.-%)3&
*+,)-- 2#.J).X %&3 2'$) '4 #,&%'" %3 3&%-- -#.6)-8
1"J"':"7 *() >?N #"&%6)" %3 #-3' )A/.)33)$ %"
# 319/'/1-#&%'" '4 B -82/(',8&)37
>?MO #"$ >?GNM ;>*ID+U< 2'-),1-)3 %"&).+
#,& :%&( >?OY #"$ >?OV 2'-),1-)3 '" #"&%+
6)"+/.)3)"&%"6 ,)--37 !"&).#,&%'" 9)&:))"
>?MO #"$ >?OYZ>?OV 6)").#&)3 #" %2/'.&#"&
,'+3&%21-#&'.8 3%6"#- 4'. *+,)-- #,&%5#&%'" #"$
/.'-%4).#&%'"7 *() 9%"$%"6 '4 >*ID+U &' &(%3 2'+
-),1-)0 '" &() '&(). (#"$0 .)/.)3)"&3 # ")6#&%5)
3%6"#- 4'. &() * ,)--7

"
*() >?G #"&%6)" (#3 4%5) %3'4'.23 ;#0 90 ,0 $0 )<
#"$ %3 )A/.)33)$ '" ,'.&%,#- &(82',8&)3 #"$
$)"$.%&%, ,)--37 >?G 2'-),1-)3 #.) 3&.1,&1.#--8
3%2%-#. &' ,-#33 ! 2#H'. (%3&','2/#&%9%-%&8 #"&%+
6)"37 I%J) &() KL> #"&%6)"30 &()8 4'.2 ,'2+
/-)A)3 :%&( !M+2%,.'6-'91-%"7 >?G #"&%6)"3
#.) &('16(& &' 9) %"5'-5)$ %" &() /.)3)"&#&%'"
'4 -%/%$+,'"&#%"%"6 #"&%6)"3 &' * ,)--37 K8,'9#,+
&).%#- -%/%$%, #"&%6)"3 #.) #-3' /.)3)"&)$ 98 >?G7
*() >?M 2'-),1-) 3).5)3 #3 # .),)/&'. 4'.
&() >?NO #"&%6)"0 )7670 &() -82/(',8&) 41",+
&%'"#- #"&%6)" ;IPD<+G7 >?M %3 #" %2/'.&#"& 4#,+
&'. %" #-&)."#&%5) *+,)-- #,&%5#&%'"7 !& %3 #" )#.-8
*+,)-- 2#.J). &(#& %3 )",'$)$ 98 #-- * -82/('+
,8&)3 #"$ "#&1.#- J%--). ;QR< ,)--37
*() >?@ ,-13&). ,'"3%3&3 '4 # "129). '4 %2+
/'.&#"& 2)29.#")+9#3)$ 2'-),1-)3 &(#& #.)
,-'3)-8 #33',%#&)$ :%&( *+,)-- .),)/&'.37 *()3)
2'-),1-)30 )3/),%#--8 &()%. C)&# ;"< #"$ )&#
;#< ,(#%"30 #.) .)S1%.)$ 4'. 3%6"#- &.#"3$1,&%'"
'",) ,'"&#,& :%&( KL> 2'-),1-)3 (#3 9))" )3+
&#9-%3()$7 KL> 2'-),1-)3 #.) $%.),&-8 .)3/'"+
3%9-) 4'. *+,)-- #,&%5#&%'"7 D" )A#,& $)3,.%/&%'"

!
'4 (': &()3) 2'-),1-)3 41",&%'" ,#" 9) 4'1"$
'" /7 GT7
*() >?U 2'-),1-) %3 ,(#.#,&).%3&%, '4 *+()-/+
). ,)--37 D/#.& 4.'2 %22#&1.) &(82',8&)30 %& %3
#-3' )A/.)33)$ 98 #,,)33'.8 ,)--3 #"$ )'3%"'+
>? /(%-%, 6.#"1-',8&)37 !& /-#83 #" %2/'.&#"& .'-)
 Molecule Molecular
weight (kDa)
Gene
locus
Cell expression
()*+,, !'1.@+'5

Function
!
# 43 – 49 1q22-23 Thymocytes, Antigen-
dendritic cells, presentation
CD1a few B cells (CD1c) (glycolipids)
$ 2m b,c,d,e

50 1p13 Thymocytes, Receptor for CD58

all T cells, (LFA-1), T-cell acti-
CD2 NK cells vation

%
CD3g 25 11q23 Maturing Signal-
& CD3d 20 11q23 thymocytes, transduction
!/" CD3e 20 11q23 T cells after MHC-TCR

<$';&%+'1&, =0.'4.8,+5
#(&)
!-chain 16 1q22 contact
"-chain 22 1q22
$(%)
'
CD3/TCR

55 12p12 Thymocytes, Binding to

T-helper cells, mono- MHC class II
cytes/macrophages, MHC
dendritic cells,
eosinophilic
CD4 granulocytes

CD5
67

40
11q13

17q25
Thymocytes,
all maturing T cells,
few B cells

All cells of
T-cell lineage
Signal transduction

Not known
"
CD7

# CD8# 33 2p12 Thymocytes, cyto- Binding

$ CD8$ 33 2p1 toxic T-cells, NK to class I MHC
cells (weak, CD8a) molecules
CD8

33 Xq26.3- CD4+ T cells Binds to CD40,

27.1 (after activation), activates B cells
CD8+ T cells and dendritic
(subpopulation), cells
CD154
basophils
(CD40L)

40 2q33 Thymocytes Ligand for CD80,

CD4+T cells, CD86 (“co-stimula-
„
CD8+T cells, tory signal )
CD28 (subpopulation)

!
33 2q33 Activated T cells Ligand for CD80,
CD86 (negative
regulator of
CD152
T-cell activation)
(CTLA–4)

A. Human T-cell differentiation molecules

>A

"
! #$>?8=7-(?)& @&+&'-=8&.) ,./ @*99&2&.)*,)*-.

!" #$%&'' !()*+,)*-. ,./ 0*1.,'

#2,.3/4()*-.
!"#$ %& '() *$$" *+,"- *. /01 ! ("- "
2+3$#,3$) 4)$$ 56 789: &'$ ("&%;$"%# 5$5&%-$ %)
5<$)$"&$- &+ &'$ )5$#%=%# > #$33: ?'%#' =%<)&
=+<2) ( *+"- ?%&' ! ("- " #'(%") &+ =+<2 ( &<%@
2+3$#,3(< #+253$A 4)$$ 56 B796 >'$ *+"- %) )&(@
*%3%C$- *. &'$ 1DEF1DG 2+3$#,3$6 >'$ (#&,(3
)%;"(3 &<(")-,#&%+" 5<+#$)) =%"(33. &(H$) 53(#$
2(%"3. I%( &'$ # ("- $ 2+3$#,3$) += &'$ 1DB
#+253$A6 1DE ("- 1DG 4! #'(%"9 #$33) (<$ %"@
I+3I$- %" )%;"(3 &<(")-,#&%+" I%( 57J3#H &.<+)%"$
H%"()$: *,& &'$ 1DE7 ("&%;$" 53(.) ( I$<.
A4./,8&.),' B2*.(*='&3
> #$33) 4YZT>9 =<+2 &'$ 5<$$A%)&%"; =+<2 &+ &'$
(#&%I$ =+<2 *. ?(. += 5'+)5'+<.3(&%+" 53(.) (
-$#%)%I$ <+3$ %" &'$ 5<+#$))6 YZT> 2%;<(&$) &+
&'$ ",#3$,): *%"-) &+ &'$ )5$#%=%# UX@M 5<+2+&$<
<$;%+": ("- #++5$<(&$) ?%&' ("+&'$< ",#3$(<
*%"-%"; =(#&+< 4TN@8 #+253$A9 %" )&(<&%"; UX@M
;$"$ &<(")#<%5&%+" I%( KYT 5+3.2$<()$ UU6
5" #$%&'' !()*+,)*-.6 #7& #*8& %-423&
-9 :&.& ;<=2&33*-.
T -%)&%"#&%+" %) 2(-$ *$&?$$" %22$-%(&$:
$(<3.: ("- 3(&$ >@#$33 (#&%I(&%+" 5<+#$))$)6 N<+@
&+@+"#+;$"$) 4#@1&0 ("- #@'*#9: ",#3$(< *%"-@
%"; 5<+&$%") 4)$$ )$#&%+" !9: ("- #.&+H%"$ ;$"$)

%25+<&("& <+3$6 >'$ 3(&&$< +##,<) %" )$I$<(3

%)+2$<%# =+<2) ("- $A'%*%&) %"&<(#$33,3(< &.<+@ *$#+2$ %"I+3I$- %" &'%) +<-$< += ),##$))%+"6
)%"$ 5'+)5'(&()$ (#&%I%&.6 0$"#$: 5'+)5'+<.3(@ >'$ %"#<$()$- $A5<$))%+" += /01 -$&$<2%"("&)
&%+" (#&%I%&. 2$-%(&$- *. 5'+)5'+&.<+)%"$ H%@ 4+" #$<&(%" #$33 ).)&$2)9 ("- (-'$)%+" 2+3$@
"()$ %) &'$ =%<)& )&$5 &+?(<- >@#$33 (#&%I(&%+" #,3$) +##,<) +"3. )$I$<(3 -(.) 3(&$<6
(=&$< &'$ 3%;("- *%"-) &+ &'$ >1K 2+3$#,3$6
>'%) 5<+#$)) 5$<2%&) +&'$< 5<+&$%") ?%&' )5$#%@
=%# &.<+)%"$@*%"-%"; 5<+5$<&%$) &+ #+2*%"$ ?%&'
5'+)5'+<.3(&$- 5<+&$%")6 >'$)$ )&<,#&,<(33.
5<$)$<I$- *%"-%"; 2+&%=) (<$ <$=$<<$- &+ ()
!"#$%&'&(&)*$+ ,&'-./0 4L0M -+2(%")9 *$@
#(,)$ &'$. ?$<$ =%<)& %-$"&%=%$- %" &'$ L<# 5<+@

"
&$%"6
N'+)5'+<.3(&%+" += &.<+)%"$ (2%"+ (#%-) +"
&'$ #.&+53()2%# 5(<& += ( 2$2*<("$@*()$- 5<+@
&$%" 3$(-) &+ &'$ *%"-%"; += L0M@#+"&(%"%"; 5<+@
&$%") (& &'%) *%"-%"; )%&$6 O$)%-$) 1DE7: 57P=.":
("- 57J3#H: C$&(@())+#%(&$- 5<+&$%" 4QR HD(9 ("-
C$&(@())+#%(&$- 5<+&$%" H%"()$) 4STN H%"()$9
(3)+ 53(. (" %25+<&("& <+3$6
N'+)5'(&%-.3%"+)%&+3 5'+)5'+3%5()$ 4NUN9
$"C.2$ %) )&%2,3(&$- -,<%"; &'$ (#&%I(&%+" 5<+@
#$))6 >'%) &<%;;$<) +&'$< 5<+#$))$) &'(& ,3&%@
2(&$3. 3$(- &+ (" %"#<$()$ %" &'$ #+"#$"&<(&%+")
+= %"+)%&+3 &<%)5'+)5'(&$ 4UNB9 ("- -%(#.3;3.#$<@
+3 4DTV9 %" #.&+53()26 >'%): %" &,<": #(,)$) (
#+")%-$<(*3$ %"#<$()$ %" #$33,3(< #(3#%,2 3$I$3)
-,$ &+ &'$ 2+*%3%C(&%+" += 2$2*<("$@*()$-
%"&<(#$33,3(< #(3#%,2 -$5+)%&)6 >'%) %"=3,A +=
DTV ("- #(3#%,2 =%<)& (#&%I(&$) 5<+&$%" H%"()$
1 4NW19: ( )$<%"$F&'<$+"%"$ 5'+)5'+H%"()$:
&'$" &'$ 5<+&+@+"#+;$"$ 5<+-,#& K()6 >'%) %"@
%&%(&$) ( )5$#%=%# )%;"(3 &<(")-,#&%+" #()#(-$
&'(& 3$(-) &+ &'$ (#&%I(&%+" += &<(")#<%5&%+" (#@
&%I(&+<): ),#' () TNF8 4)$$ *$3+?96 1(32+-,3%"

! CD
("- #(3#%"$,<%" (<$ (3)+ %"I+3I$- %" &'%) (#&%I%&.6
>'$)$ $I$"&) ,3&%2(&$3. 3$(- &+ ;$"$ (#&%I(@
&%+" ("- &'$ <$;,3(&%+" += ;$"$ &<(")#<%5&%+"6
>'$ %"%&%(&%+" += %"&$<3$,H%"@M 4UX@M9 ;$"$ &<("@
)#<%5&%+" %) ( H$. =(#&+< %" >@#$33 (#&%I(&%+"6 >'$
&<(")=+<2(&%+" += &'$ ",#3$(< =(#&+< += (#&%I(&$-
APC MHC
#$%&'' !()*+,)*-.
!
$ # CD4(CD8)

CD3 Ag
CD45 $ #
% '
! !(") & %
! !

PIP2
PLC

A4./,8&.),' B2*.(*='&3
DAG
TCR
IP3
p56Ick PKC
p59fyn

Ca2+
Tyrosine kinases
T cell Ca-dependent
kinases

"
Phosphorylated proteins
Cytoplasm

Gene activation
Nucleus regulation of transcription Phosphorylated
proteins
A. T-cell activation: Signal transduction
Immediate

Proto-oncogenes c-fos c-myc

Nuclear binding proteins NFAT-1 NF(B
Minutes 15 30

Cytokines IFN-' TGF-# IL-4 GM-CSF

IL-2 IL-3 IL-5
IL-6
Receptors Insulin-R IL-2R Transferrin-R
Activating CD69
Early antigens
Enzymes,
intracellular ODC Actin Cyclin Transferrin Histones
proteins
Hours 1 2 3 4 5 6 12 18 24 48

!
MHC HLA-DR
Late Cytokines Rantes
Adhesion proteins VLA-4 VLA-1
Days 2 4 6 8 10
B. T-cell activation: Time course of gene expression
CE

"
! ,=><?@A+1<)& #&B&2+@?&() *(/ #$%%&'&()$*)$+(

!" #$%%&'&()$*)$+( $()+ ,-. *(/ ,-0 1&223

!"#$%&"#'( ) *"((+ *', -$.."#",/$'/" $,/0 ,'$1" )
*"((+ ',- 2"20#3 ) *"((+ 4+"" %'5" 6!78 9./"#
+:%%#"++$0,8 )&" *&'#'*/"#$+/$* *3/0>$,"+; 0,
/&" 0/&"# &',-; &'1" ' %0+$/$1"; $,/",+$.3$,5 ".B
."*/ 0, /&" #"+%"*/$1" +:=%0%:('/$0,8 GHBA; .0#
"N'2%("; '*/+ 0, )?@ *"((+ ',- GHBX 0, )?A *"((+8
.:#/&"# ',/$5", *0,/'*/; /&"3 .0#2 /<0 -$+/$,*/
\" 2:+/ +/#"++; &0<"1"#; /&'/ /&"#" '#" 0./",
+:=%0%:('/$0,+ >,0<, '+ /&" )?@ ',- )?A +:=B
,0 +/#$*/ ($,"+ ="/<"", /&" +:=%0%:('/$0,+ $,
5#0:%+8
/&" &:2', -".",+" +3+/"28 ], /&" *0,/#'#3;
9./"# /&" $,$/$'( *0,/'*/ <$/& 1'#$0:+ ',/$B
$/ $+ %0++$=(" /0 &'1" +200/&; %'/&05",B-"%",B
5",+ 4"858; ='*/"#$'; .:,5$; %#0/0C0',+; 5#'++ %0(B
-",/ /#',+$/$0,+ ="/<"", /&" +:=%0%:('/$0,+8
(",+7; 20+/ )? *"((+ ",*0:,/"# "("2",/+ 0. /&"
,0,+%"*$.$* $22:," +3+/"2; "+%"*$'((3 2'*#0B 4" 5&672*)$+( +% 869 :'+/71)$+(
%&'5"+; ,'/:#'( >$(("# *"((+; ',- 2'+/ *"((+8 )&"
"+/'=($+&2",/ 0. +:*& *0,/'*/ ',- /&" *0##"B )&" )?A *"(( %('3+ ', "++",/$'( #0(" $, /&" #"5B
+%0,-$,5 ',/$5", #"+%0,+" '#" +:=D"*/ /0 /&" :('/$0, 0. G5^ %#0-:*/$0,8 9*/$1'/$0, 0. /&" O
*"(( /'>"+ %('*" 2'$,(3 1$' /&" FRXTQFRXT ($B
C7(/*?&()*2 :'$(1$@2&3

5","/$* +:+*"%/$=$($/3 4%#"-$+%0+$/$0,7 0. /&"

&0+/; <&$*& $+ -"/"#2$,"- =3 E?F *02%0B
,",/+; )B*"(( #"*"%/0#+; ',- 0/&"# +/$(( :,>,0<,
.'*/0#+8
9,/$5", %#0*"++$,5 =3 ,0,+%"*$.$* -".",+"
*"((+ %#0-:*"+ ' *3/0>$," 2$($": /&'/ &'+ ' -"B
*$+$1" ".."*/ 0, /&" .:#/&"# *0:#+" 0. /&" $2B
2:," #"+%0,+"8 G,/"#(":>$, 4GH7B@A; <&$*& $+ +"B
*#"/"- =3 2'*#0%&'5"+; '(+0 %('3+ ', $2%0#/',/
#0("8 I:#/&"# ',/$5", %#"+",/'/$0, $+ *'##$"- 0:/
=3 J%#0."++$0,'(K ',/$5",B%#"+",/$,5 *"((+
42'$,(3 -",-#$/$* *"((+78 )&" /#$20("*:('#
5',- +3+/"28 )&"#" 0**:#+ ' #"("'+" 0. GHBX;
GHB@Z ',-Q0# +0(:=(" #"*"%/0#+ 0. GHBX 4GHBXBL7
/&'/ '(+0 *0,/#$=:/" /0 G5^ %#0-:*/$0,8 GHBX
("'-+ /0 /&" -$.."#",/$'/$0, 0. O *"((+ $, G5V@
',- G5^B%#0-:*$,5 %('+2' *"((+; <&"#"'+ GHB
@Z $,-:*"+ /&" .0#2'/$0, 0. G5VX ',- G5V^ ',/$B
=0-$"+8
;" 5&672*)+'< , 1&223
L"5:('/0#3 ) *"((+ &'1" ' +:%%#"++0# .:,*/$0,8
)&"3 #"%#"+",/ ' 2$,0#$/3 0. FRX! ) *"((+

"
)FLM',/$5",$* %"%/$-"ME?F *02%("N ',- /&" /&'/ *0B"N%#"++ FRAY "1", $, /&" '=+",*" 0.
=0,- ="/<"", /&" OPQ@ 4FRST7 ',- FRAS 20B '*/$1'/$0,8 FRX! FRAY! #"5:('/0#3 ) *"((+
("*:("+ '#" '(+0 $2%0#/',/8 R:" /0 /&" %#"-02$B &'1" ="", +&0<, /0 %#"+",/ ':/0$22:,$/3;
,',/(3 *3/0>$," 2$($": ',- /&" -$.."#",/ 2',B '+ /&"$# -"%("/$0, %#020/"+ -"1"(0%2",/ 0.
,"#+ 0. ',/$5", %#"+",/'/$0,; /&" 0#$5$,'((3 1'#$0:+ ':/0$22:," -$+"'+"+ $, 2$*"8 )&"3
:,-"/"#2$,"- )B&"(%"# ,:(( *"(( 4)?T7 /#',+B '(+0 +""2 /0 %('3 ' #0(" $, %#"1",/$,5 ".."*/$1"
.0#2+ $,/0 "$/&"# ' )?@ 0# )?A *"((8 $22:,0+:#1"$((',*" $, %'/$",/+ <$/& *',*"#
)?@ ) *"((+ 2'$,(3 +"*#"/" GHBA; GIUB!; )UIB"; 4+"" %8 @YA78
',- VEBFWI8 )&"3 ("'- 1$' 2'*#0%&'5" '*/$1'B
/$0, /0 "N/",+$1" $,.('22'/0#3 %#0*"++"+ /&'/
'(+0 ",'=(" /&" >$(($,5 0. $,/#'*"((:('# %'/&0B
5",+8
)?A *"((+ 2'$,(3 .0#2 GHBX ',- GHBY 4',- '(+0
GHBZ; GHB[; GHBP; GHBS; GHB6; GHB@T; ',- GHB@X7 ',-
'*/$1'/" O *"((+ .0# %#0-:*/$0, 0. ',/$=0-$"+8
)&" ,'/:#" 0. /&"+" %#0*"++"+ $, !"#$%&'(#'
$,."*/$0, &'+ ="", +/:-$"- $, ', "N"2%('#3
.'+&$0,8 R$.."#",/ 20:+" +/#'$,+ #"'*/ -$.."#B
",/(3 /0 /&" $,."*/$0, -"%",-$,5 0, /&" *3/0B
>$," %'//"#,8 9 )?@ *3/0>$," %'//"#, ",+:#"+
/&" +:#1$1'( 0. /&" ('=0#'/0#3 ',$2'(+ './"# *0,B
/'*/ <$/& /&" %'/&05",; <&"#"'+ /&" %#"-02$B
,',*" 0. )?A *"((+ ("'-+ /0 ' ("/&'( *0:#+" 0. $,B

! 0D
."*/$0,8
O0/& )B&"(%"# *"(( 5#0:%+ '#" '=(" /0 $,&$=$/
/&" '*/$1'/$0, 0. /&" 0/&"# 5#0:% :+$,5 /&"$#
0<, *3/0>$,"+8 ?",*"; GIUB! ("'-+ /0 $,&$=$/$0,
0. )?A *"((+; <&"#"'+ GHB@T $2%"-"+ 2'*#0B
%&'5" '*/$1'/$0, ',- ("'-+ /0 2'#>"- $22:,0B
 Antigens
,-. *(/ ,-0 ;&223
!
Protozoans
Bacteria Fungi (e.g. helminths) Pollen

Genetic susceptibility (e.g. MHC, TCR etc.)

C7(/*?&()*2 :'$(1$@2&3
NK cell !/" T cell Basophils, ?
Macrophage mast cell
IL-12 IFN-! IL-4

Cytokine milieu
IL-12 IFN-! IL-4

Dendritic
cell
MHC II

B7-1
(CD80)
TCR

CD28

TH0
TCR

CD28
MHC II

B7-1
(CD80)
Dendritic
cell
"
IFN-! IL-4

IL-2 TH1 TH2

IFN-! 0 IL-5
IFN- IL-1
Intracellular TNF-# ! IL-4 IL-4 Antibody
killing

Macro-
phage B cell

A. Differentiation into TH1 and TH2 cells

IL-13 IL-4R
IL-10 IL-4 Ag

IL-4R IL-4R sIgM

!
IL-4
TCR MHC + Ag
IgE
CD40 CD40
TH2 ligand B cell
B. Regulation of IgE production
0.

"
! -6./)(0'1/+$ #$%$&'()$*+ 7*8 #9,,$:$*+97+9'*

!" #$%$&'()$*+ ', - ./)(0'1/+$2

! "#$%&'(#)*+ ,*-*"'% ./ )&* 0'/* $122'3
42'$ %"52.%')*/) +)*$ (*""+ ./ 2*1().'/ )' +.67
./1" $1)521).'/ '4 ! (*""+ ./)' %"1+$1 (*""+ )&*/
'((52+ ./ )&* 0'/* $122'3 '2 ./ )&* $5('+1 '4
)&* 61+)2'./)*+)./1" )21()=
S'$* '4 )&* 1/).6*/7+).$5"1)*, ! (*""+ $.7
/1"+ 42'$ +)2'$1" (*""+ 8+'"50"* (#)'9./*+:
621)* )' )&* $126./1" ?'/* '4 )&* %*2.%&*21" '27
(*"";(*"" ('/)1()<=
61/+ 1/, ,.44*2*/).1)* ./)' J6C7/*61).-*P BCID7
>&* %2'6*/.)'2 ! (*"" 8%2'7! (*""< .+ )&* 4.2+)
/*61).-*P 1/, BCDH7%'+.).-* (*""+ 8*A)214'"".(57
2*('6/.?10"* +)16* '4 !7(*"" ,*-*"'%$*/)= @2'7!
"12 ! (*""+<= J/ ('/)21+) )' $'+) ')&*2 ! (*""+P
(*""+ 12* +*"472*%"*/.+&./6 (*""+ )&1) *A%2*++
)&*+* (*""+ (1/ 1"+' 2*1() )' (120'&#,21)* 1/).7
+)*$ (*""71++'(.1)*, 1/).6*/+ 8BCDE 1/,
6*/+ 8>7(*""7./,*%*/,*/) 2*+%'/+*<P 05) '/"#
BCFFG< 1/, !7(*"" "./*7+%*(.4.( 1/).6*/+ BCFH
6*/*21)* J6L 1/).0',.*+ '4 "'3 144./.)#=
1/, BCII 8)&* "1))*2 .+ *A%2*++*, '/"# ./ (#)'7
%"1+$<= -" 3#45 - 3$&&2
J$$5/'6"'05"./ +#/)&*+.+ 0*6./+ ./ )&*
Q +$1"" 421().'/ '4 ! (*""+ .+ ,.+)./65.+&*, 0# )&*
;<*87)$*+7& =:9*19(&$2

452)&*2 +)16* '4 ,*-*"'%$*/)= K*1-# (&1./+

'4 )&* J6L .$$5/'6"'05"./+ 8! (&1./+< (1/
0* ,*)*()*, ./ )&* (#)'%"1+$ '4 %2*7! (*""+=
>&* /*A) +)16* '4 ,.44*2*/).1).'/ .+ (1""*, )&*
M-.26./ ! (*""N 0*(15+* )&* (*""+ &1-* /') #*)
('$* ./)' ('/)1() 3.)& 4'2*.6/ 1/).6*/+= B'$7
%"*)* J6L .$$5/'6"'05"./+ 12* *A%2*++*, '/
)&* +5241(* '4 )&* -.26./ (*""+= >&* 452)&*2
('52+* '4 ,.44*2*/).1).'/ .+ 1/).6*/765.,*,=
>&* .$$1)52* ! (*""+ 12* 9.""*, 0# 1%'%)'+.+
.4 )&*.2 .$$5/'6"'05"./+ 12* 0'5/, 0# 15)'1/7
).6*/+ %2*+5$10"# %2*+*/)*, )' )&*$ 0# +)2'7
*A%2*++.'/ '4 )&* >7(*""71++'(.1)*, ,.44*2*/).17
).'/ 1/).6*/ BCT 8U#F 1/).6*/ ./ )&* $'5+*<=
>&*+* ! (*""+ 8!FV !7(*"" 421().'/< 12* 0*".*-*,
)' 0*"'/6 )' 1 +50%'%5"1).'/ )&1) ,.-*26*+ 42'$
)&* /'2$1" !7(*"" "./* *12"# '/ ./ )&* ('52+* '4
'/)'6*/*+.+ 1/, ('"'/.?*+ )&* %"*521" 1/, %*2.7
)'/*1" (1-.).*+= K'3*-*2P )&* *A.+)*/(* '4 )&.+
!7(*"" %'%5"1).'/ &1+ '/"# 0**/ ('/4.2$*, ./
)&* $'5+*= BCTV ! (*""+ 12* "'/67".-*,P +*"472*7
%"*/.+&./6P 1/, +*(2*)* "'37144./.)#P %'"#2*1(7
).-* 15)'1/).0',.*+ '4 )&* J6L ("1++= >&*.2

"
$1" (*""+ ./ )&* 0'/* $122'3 8("'/1" ,*"*).'/O ,.44*2*/).1).'/ ./ )&* %"*521" 1/, %*2.)'/*1"
("'/1" 1/*26#<= >&* ')&*2+ "*1-* )&* 0'/* $127 (1-.).*+ $.6&) *A%"1./ )&* 15)'2*1().-.)# '4
2'3 1) )&.+ +)16* '4 $1)521).'/ 1/, )&*/ $.7 )&*+* (*""+ 810+*/(* '4 ("'/1" ,*"*).'/ ,5* )'
621)* )' )&* >7(*""72.(& ?'/*+ '4 )&* %*2.%&*21" ('/)1() 3.)& +)2'$1" (*""+ '4 )&* 0'/* $122'3<=
"#$%&'., '261/+P 3&*2* 1 %2'(*++ '4 +*"*().'/
'((52+ '/(* $'2*= Q"" (*""+ )&1) &1-*
/') 2*(*.-*, 1 M+52-.-1" +.6/1"N 42'$ )&*
> (*""+ ,.* ,5* )' 1%'%)'+.+= >&* 2*$1././6 !
(*""+ $.621)* )' )&* "#$%&1).( 4'"".("*+= R/
)&* +5241(*P )&*# *A%2*++ J6C .$$5/'6"'05"./+
1/, )&* (*"" ,.44*2*/).1).'/ 1/).6*/+ BCIFP
BCIIP BCIDP 1/, BCDG= Q+ (.2(5"1)./6 4'"".(5"12
! (*""+P )&*# ('/)./5'5+"# 2*(.2(5"1)* 0*)3**/
)&* 0'/* $122'3 1/, )&* +*('/,12# "#$%&'.,
'261/+ 5/)." )&*# $**) 1 $1)(&./6 1/).6*/= >&.+
5+51""# )19*+ %"1(* )&* ./ >7(*""72.(& ?'/* '4 )&*
"#$%& /',*+ '2 ./ $5('+171++'(.1)*, "#$7
%&'., ).++5*P 3&*2* )&* ! (*""+ ,*-*"'% ./)'
J6L7%2',5(./6 %"1+$1 (*""+ 8%2.$12# !7(*""
2*+%'/+*<= >&*+* J6L 1/).0',.*+ &1-* '/"# 1
"'3 144./.)# 4'2 )&* 1/).6*/= >' %2',5(* M0*))*2N
1/).0',.*+P )&* ! (*""+ 5/,*26' 1 +%*(.1" %2'(*++
'4 ,*-*"'%$*/) ./ )&* "#$%&1).( 4'"".("*+

! >>
86*2$./1" (*/)*2 2*1().'/: +** %= IE< 3&*/
)&*# */('5/)*2 .$$5/* ('$%"*A*+ 0'5/, )'
4'"".(5"12 ,*/,2.).( (*""+= >&* 6*2$./1" (*/)*2
2*1().'/ 1""'3+ )&* ! (*""+ )' ,*-*"'% )&* 10.".)#
)' %2',5(* 1/).0',.*+ '4 ')&*2 ("1++*+ 8.$$57
/'6"'05"./ +3.)(&< 1/, '4 &.6&*2 144./.)#= >*2$7
 CD34 CD19 CD38
-63$&& ?*+'@$*$292

CD19 CD20 CD38

!
CD10
CD117

CD22 CD10
Pro-B Plasma cell Intestinal Pro-plasma cell
submucosa

Follicle Marginal
zone
Pro-PC

;<*87)$*+7& =:9*19(&$2
Pro-B Plasma cell
Antigens

Circulating
follicular
Circulating B cell
follicular Extra-
T-cell zone follicular
B cell
B cell

Apoptosis
Pre-B

Bone marrow : primary

B-cell production

CD20
CD19
CD22
CD19
CD20
„Virgin”-B

Peripheral blood

CD21
CD22 CD19
CD20 CD21
Virgin-B

Secondary lymphatic organs:

antigen-induced B-cell proliferation

CD22 CD19
CD20 CD21
CD22
"
CD23
CD37 CD39
cyt-µ
slgM slgM slgM
slgD CD11c
Circulating Extra-
Pre-B Virgin-B follicular B cell follicular B cell

A. Development of B lymphocytes

Pleural space CD5+ B cells

– T-independent
– Secrete low-affinity
lgM-autoantibodies
Bone marrow – Can renew themselves
CD5+
– No hypermutations
slgM+

CD5 CD45R
CD20

Early ontogenesis
B. CD5+ B cells
Peritoneal cavity slgM
CD11a

!
>A

"
! #$@<3?0-(<)& 8&+&'-?3&.) ,./ 8*77&2&.)*,)*-.

!" #$%&'' !()*+,)*-. ,./ )0& 1&23*.,'

%&.)&2 4&,()*-.
!"#$%&'()$*+ ,*#$%"- (.&/0)$%1 23((%1(*# #'10 )#
$03#* %" 2*$)( (.&/0 "3+*# 13"#%#$ 32 ) "*$43,5
32 23((%1'(), +*"+,%$%1 1*((# 6789#: %" (33#* 13";
$)1$ 4%$0 #&)(( 23((%1'(), < 1*((# $0)$ *=0%>%$ #',;
2)1* *=/,*##%3" 32 ?-@ )"+ ?-8A B"1* )"$%-*"
13"$)1$ $)5*# /()1*C #*13"+),. (.&/03%+ 23((%;
1(*# 4%$0 /,3&%"*"$ -*,&%")( 1*"$*,# +*D*(3/A
E0* *=/3"*"$%)( -,34$0 32 < 1*((# $)5*# /()1* %"
$0* -*,&%")( 1*"$*, 32 $0* 23((%1(* 3"(. FGH +).#
)2$*, $0* %"%$%)( )"$%-*" 13"$)1$A E0* < 1*((# 2%,#$
+*D*(3/ %"$3 (),-* 1*((# 4%$0 (),-* )&3'"$# 32
A9./,3&.),' 62*.(*?'&>
$,)"#23,& %"$3 &*&3,. < 1*((# 3, /()#&)>()#$#C
40%10 $0*" +%22*,*"$%)$* %"$3 /()#&) 1*((# %" $0*
>3"* &),,34 3, %" $0* &'13#)( (%"%"- 32 $0*
-)#$,3%"$*#$%")( $,)1$A
%" :&'&()*-. -7 ;*50$!77*.*)< !.)*=-/*&> =<
;<?&239),)*-. *. )0& 1&23*.,' %&.)&2
9*"$,3>()#$# )10%*D* )" *=$,*&*(. 0%-0
&'$)$%3" ,)$* %" %&&'"3-(3>'(%" -*"*# 6#3;
&)$%1 0./*,&'$)$%3": %" 3,+*, $3 -*"*,)$* )"$%;
>3+%*# 32 +%22*,*"$ )22%"%$.A K# 1*"$,31.$*#C $0*.
&%-,)$* $3 $0* (%-0$ N3"* 32 $0* -*,&%")( 1*"$*,A
B"1* $0*,*C 3"(. #$,3"- >%"+%"- $3 )"$%-*";/,*;
#*"$%"- 23((%1'(), +*"+,%$%1 1*((# 1)" /,*D*"$

1.$3/()#& 6/,%&),. < >()#$#: )"+ #&)((C I,*#$;

%"-J 1*((# )(3"- $0* 23((%1'(), &),-%"A K 2*4
+).# ()$*,C $0* >()#$# ),* 13"1*"$,)$*+ /,%&),%(.
%" $0* >)#)( ,*-%3" 32 $0* 23((%1(* 6!"#$ %&'( 32
$0* -*,&%")( 1*"$*,:C 40*,* $0* >,)"10%"- 1.;
$3/()#&%1 /,31*##*# 32 $0* 789# 23,& ) 2%"*C
(33#* "*$43,5A E0* >()#$# 61*"$,3>()#$#: 0)D*
) +3'>(%"- $%&* 32 ),3'"+ #*D*" 03',#A L3"*;
$0*(*##C $0*. +3 "3$ %"1,*)#* %" "'&>*, #%"1*
$0*. M'%15(. $,)"#23,& %"$3 #&)(( 1*((# 4%$0 (3>;
'(), "'1(*% 61*"$,31.$*#: $0)$ &%-,)$* )4).
2,3& $0* +),5 N3"*A E0*#* 1*"$,31.$*# $0*"
$0*& 2,3& '"+*,-3%"- )/3/$3#%#A E0* 1*"$,3;
1.$*# ,*1*%D* ) 2',$0*, #',D%D)( #%-")( D%)
98HS 2,3& 98HS (%-)"+;/3#%$%D* E (.&/03;
1.N*# %" $0* (%-0$ N3"*A E0*. $0*" &%-,)$*
>)15 $3 $0* +),5 N3"* )"+ >*-%" ) "*4 /,31*##
32 1*(( +%D%#%3" )# 1*"$,3>()#$#A E0* )22%"%$. 32
$0* #',2)1* %&&'"3-(3>'(%"# 23, $0* )"$%-*"
1)" %"1,*)#* +'* $3 /3%"$ &'$)$%3"A T'>#$%$';
$%3" 32 ) #%"-(* )&%"3 )1%+C 23, *=)&/(*C 1)" %";
1,*)#* $0* )22%"%$. 32 $0* %&&'"3-(3>'(%" $*";
23(+A E0%# &*10)"%#& 0*(/# $3 #*(*1$ < 1*((# $0)$

"
23,& $0* #3;1)((*+ )*+,- %&'( 32 $0* -*,&%")( /,3+'1* 0%-0;)22%"%$. )"$%-*";)+)/$*+ )"$%>3;
1*"$*,C 40*,* $0*. 13&* %"$3 1(3#* 13"$)1$ +%*#A E0* I+*&)"+J 23, $0*#* )"$%>3+%*# +*$*,;
4%$0 ) D*,. +*"#* "*$43,5 32 +*"+,%$%1 1*((#A &%"*# 40*$0*, ) < 1*(( 4%(( >* )>(* $3 #',D%D*
K (),-* 2,)1$%3" 32 1*"$,31.$*# +%* +'* $3 )/3/; )"+ /,3+'1* )"$%>3+%*# 32 $0* +*#%,*+ )22%"%$.
$3#%#C *#/*1%)((. "*), $0* >3'"+),. >*$4**" $0* )"+ #/*1%2%1%$.A
(%-0$ )"+ +),5 N3"*#C 40*,* "'&*,3'# &)1,3;
/0)-*# 4%$0 /0)-31.$3#*+ )/3/$3$%1 "'1(*%
6-*'+*.)( .&!*(/: ),* (31)$*+A E0* -*,&%")( 1*";
$*, ,*)1$%3" ()#$# 23, )>3'$ $0,** 4**5#A B"(. )
2*4 <;1*(( >()#$# 6#*13"+),. <;>()#$#: 1)" >*
23'"+ %" $0* 1*"$*, 32 ) I>',"$;3'$J 23((%1(* )2$*,
OGF &3"$0#A

#" #$%&'' !.)*5&. 62-7*'& 892*.5 )0&

1&23*.,' %&.)&2 4&,()*-.
9*"$,3>()#$# )"+ 1*"$,31.$*# 0)D* ) 0%-0 (*D*(
32 98FP )"$%-*" *=/,*##%3"A ?" 13"$,)#$ $3 23(;
(%1'(), )"+ *=$,)23((%1'(), < 1*((#C $0*. 0)D* (3#$
$0* 98OF )"+ 98FQ )"$%-*"#A 9*"$,3>()#$# )(#3
*=/,*## ) 0%-0 +*"#%$. 32 98RRA
<*1)'#* $0* $,)"#1,%/$%3" 32 %&&'"3;
-(3>'(%" -*"*# %# $*&/3,),%(. 0)($*+ 40%(* I#3;

!
&)$%1 0./*,&'$)$%3"J $)5*# /()1* %"
1*"$,3>()#$#C $0* 1*"$,3>()#$# ),* ?-;"*-)$%D*A
9*"$,31.$*# 0)D* ,*"*4*+ *=/,*##%3" 32 %&;
&'"3-(3>'(%"C 40%10 /*,&%$# $0*& $3 ,*)1$
4%$0 )"$%-*" /,*#*"$*+ >. 789#A E0*. &). +%2;
BC 2*,*"$%)$* )-)%" %"$3 1*"$,3>()#$#C >'$ &). )(#3
 = Follicular
dendritic
Follicle
mantle
1&23*.,' %&.)&2 4&,()*-.
!
cells (FDC)
Primary
B-blasts Phase 1
of follicle
Primary lymphoid reaction
follicle (3-4 days)
Follicle
Follicle mantle
mantle – Centrocytes
– FDC Light zone
Secondary
– T-helper cells
B-blasts
– Macrophages
Phase 3 Phase 2
of follicle of follicle
reaction reaction

A9./,3&.),' 62*.(*?'&>
(months) – Centroblasts Dark zone (3 weeks)

A. B-cell activation: the germinal center reaction

Follicular Primary Centroblast Centrocyte

B cell B-blast
– CD19 – CD19 – CD19 – CD10
– CD20 – CD20 – CD20 – CD19 Circulating Apoptosis
– CD21 – CD22 – CD22 – CD20 memory cell

"
Antigen – CD22 – CD40 – CD38 – CD22 Plasmablast
profile – CD23 – slgM – CD77 – CD37
– CD39 – CD40 – CD38
– CD40 – slg± – CD40
– CD76 – slgM/A/G/E Intestinal Bone
– slgM/D mucosa- marrow
plasma cell plasma cell
B. Antigen profile of B cells during germinal center reaction

Antigen-specific B cell FDC FDC

Apoptosis

Apoptosis

Repeated cycles
Dark zone Light zone
of germinal center of germinal center
– Proliferation Mutated immunoglobulin with higher affinity
– Point mutation in binds antigen-presenting FDC and survives
– V-region of H/L-chains

A A C T G C

T T G A C G
A A C C G C

T T G G C G
= Amino acid switch = 10-fold increase in affinity

C. Selection of high-affinity antibodies through hypermutation in the germinal center

!
BD

"
! 1>?6$3@'/6-0 90;0)'3$0&- 5&A 9+440.0&-+5-+'&
!" #$$%&'()'*%)+& ,-.%/-%.0
!"#$%% &'()*$' +$#$,(-+. &+$ )//0'-*%-10%)'.
$2,+$..$3 -' (4$ .0+5&#$ -5 /&(0+$ ! #$%%.6
74$ +$#$,(-+. &+$ ,+-30#$3 18 ($+/)'&%%8 3)5"
5$+$'()&($3 ! #$%%. 9,%&./& #$%%.: &'3 .$#+$($3
&. &'()1-3)$. )'(- (4$ 1%--36 ;//0'-*%-10%)'.
&+$ *%8#-,+-($)'. #-/,-.$3 -5 (<- )3$'()#&%
4$&=8 9>: #4&)'. &'3 (<- )3$'()#&% %)*4( 9?:
#4&)'.6 74$)+ /-%$#0%&+ <$)*4(. &+$ )' (4$
+&'*$ @A AAABCA AAA D& &'3 E@ AAA D&F +$.,$#"
()=$%86 74$+$ &+$ (<- (8,$. -5 %)*4( #4&)'.F 3$"
'-($3 G&,,& 9!: &'3 %&/13& 9":6
H8.($)'$ +$.)30$. 5-+/ 1+)3*$. 1$(<$$' (4$
B%&A5$0&-5) C.+&/+3)0=
)'3)=)30&% #4&)'. -5 &' )//0'-*%-10%)' /-%$"
#0%$6 I' $'J8/$ 9,&,&)': .$,&+&($. (<- )3$'"
()#&% &'()*$'"1)'3)'* 5+&*/$'(. 9K&1 5+&*"
/$'(.: 5+-/ & '-'"&'()*$'"1)'3)'* 5+&*/$'(
G'-<' &. (4$ K# 9#+8.(&%%)J&1%$: 5+&*/$'(6 K#
5+&*/$'(. ,-..$.. 1)'3)'* .)($. 5-+ #-/,%$"
/$'( 5&#(-+ HLM 9.$$ ,6 @N:6
?)*4( #4&)'. #-'.).( -5 (<- %&+*$ +$*)-'. -5
&,,+-2)/&($%8 $M0&% .)J$6 74$ #-'.(&'( +$*)-'
9H?: =&+)$. %)((%$ 5+-/ -'$ )//0'-*%-10%)' (-
&'-(4$+6 74$ &/)'- &#)3 .$M0$'#$ -5 (4$ =&+)"
&1%$ +$*)-' 9O?:F -' (4$ -(4$+ 4&'3F $24)1)(. &'
"
$'-+/-0. 3$*+$$ -5 =&+)&1)%)(86 !-(4 (4$ #-'"
.(&'( &'3 (4$ =&+)&1%$ 3-/&)'. #-'.).( -5 &1-0(
LLA &/)'- &#)3. 9II:6 >$&=8 #4&)'. #-'.).( -5
-'$ =&+)&1%$ 9O>: 3-/&)' <)(4 &+-0'3 LLA II
&'3 (4+$$ #-'.(&'( 9H>: 3-/&)'.F $2#$,( )'
(4$ #&.$ -5 ;*P &'3 ;*QF <4)#4 4&=$ 5-0+ #-'"
.(&'( 3-/&)'.6 74$ 3)55$+$'( 3-/&)'. -5 & *)=$'
)//0'-*%-10%)' /-%$#0%$ 4&=$ & .)/)%&+ *%-1"
0%&+ .(+0#(0+$ #4&+&#($+)J$3 18 (4$ ,+$.$'#$ -5
/0%(),%$ #",%$&($3 .4$$(. &'3 3).0%5)3$ 1-'3.6
1" #$$%&'()'*%)+& 2,%30.45$+)67
R%-10%&+ 3-/&)'. -5 .)/)%&+ .(+0#(0+$ &+$ #4&+"
&#($+).()# -5 &' $'()+$ .$+)$. -5 /-%$#0%$. -5 (4$
)//0'$ .8.($/ +$5$++$3 (- &. &' )//0'-*%-"
10%)' .0,$+5&/)%86 74$ .0,$+5&/)%8 #-/,+).$.
)//0'-*%-10%)'. &. <$%% &. 7"#$%% +$#$,(-+.
97HS:F #%&.. ; &'3 #%&.. ;; /&T-+ 4).(-#-/,&()1)%"
)(8 #-/,%$2 9P>H: /-%$#0%$.F & %&+*$ '0/1$+
-5 P>H"+$#-*')()-' &'()*$'. ,+$.$'( -' '&(0+"
&% G)%%$+ #$%%.F /-%$#0%$. )'=-%=$3 )' #$%%"(-"#$%%
)'($+&#()-'. 9$6*6F HDUF HDNF HDLVF &'3 HDEE
!
&'()*$'.:F &34$.)-' /-%$#0%$. 9$6*6F HD@W:F
&'3 ,-%8/$+)# )//0'-*%-10%)' +$#$,(-+.
9,-%8";*S:6 X-%8";*S ). +$.,-'.)1%$ 5-+ (4$ ,&."
.&*$ -5 ;*I &'3 ;*P (4+-0*4 $,)(4$%)&% #$%%.6
74$ .0,$+5&/)%8 &%.- )'#%03$. /&'8 -(4$+ &'()"
DE *$'. <4-.$ 50'#()-' 4&. '-( 8$( 1$$' #4&+&#"
($+)J$36
8" 90-0.$+&5-+'& '4 !&-+(0& ,30/+4+/+-6
*6 :630.;5.+5*)0 <0(+'&=
74$ =&+)&1%$ 3-/&)'. -5 4$&=8 &'3 %)*4( #4&)'.
#-'(&)' +$*)-'. <)(4 $2(+$/$%8 =&+)&1%$ &/)'-
&#)3 .$M0$'#$.6 >$'#$ (4$ '&/$ Y48,$+=&+)&1%$
+$*)-'.6Z
>8,$+=&+)&1%$ +$*)-'. #-'.).( -5 WBN &/)'-
&#)3. &+-0'3 ,-.)()-'. [AF @AF &'3 V[ -5 %)*4(
#4&)'. &'3 &+-0'3 ,-.)()-'. [EF @@F &'3 VN -5
4$&=8 #4&)'.6 74$8 3$($+/)'$ (4$ .,$#)5)#)(8
-5 &'()*$' 1)'3)'* &'3 &+$ +$5$++$3 (- &. !"#$
%&'#'()*+,)-$.')'+#,(,(/ +'/,"(0 9HDS:\ .$$
.$#()-' !6 74$ .01.()(0()-' -5 & .)'*%$ &/)'-
&#)3 )' (4). +$*)-' ). #+0#)&% 5-+ (4$ 1)'3)'* -5
& ,&+()#0%&+ &'()*$'6
74$ $55$#(-+ 50'#()-' -5 & *)=$' )//0'-*%-"
10%)' ). 3$($+/)'$3 18 (4$ #-'.(&'( +$*)-'6 ;'
-(4$+ <-+3.F (4$ #-'.(&'( +$*)-' 3$($+/)'$.
(4$ 3$*+$$ -5 #-/,%$/$'( 1)'3)'*F )'($+&#()-'
<)(4 .,$#)5)# +$#$,(-+. 9K# +$#$,(-+.: -5 =&+)-0.
#$%%.F &'3 (+&'.,%&#$'(&% (+&'.5$+6
;//0'-*%-10%)'. &+$ ,+-($)'. &'3 (4$)+
&/)'- &#)3 .$M0$'#$ #&' 1$ )//0'-*$')#
5-+ 3)55$+$'( )'3)=)30&%. &'3 3)55$+$'( .,$#)$.F
.- (4$8 #&' &#( &. &' &'()*$'6 ;' 5&#(F (4$8
#&' $=$' &#( &. & Y.$%5"&'()*$'Z](4$8 4&=$ ,0"$
)-%,!F *&&")-%,!F &'3 ,.,")-%,! 3$($+/)'&'(.6
10")-%,! .')'+#,(*()0 &+$ +$.,-'.)1%$ 5-+ (4$
3)55$+$'#$. 1$(<$$' (4$ 3)55$+$'( )//0'-*%-"
10%)' #%&..$. &'3 .01#%&..$. &'3 1$(<$$'
4$&=8 &'3 %)*4( #4&)'.6 2&&")-%,! .')'+#,(*()0
&+$ =&+)&()-'. )' (4$ #-'.(&'( +$*)-'. -5 )//0"
'-*%-10%)'. -5 (4$ .&/$ ).-(8,$F -<)'* (-
&%%$%)# =&+)&()-'. )' (4$ *$'$. 5-0'3 &/-'*
3)55$+$'( )'3)=)30&%.6 1.,")-%,! .')'+#,(*()0
&+$ (4$ )'3)=)30&% 3$($+/)'&'(. -5 &'8 *)=$'
&'()1-38 /-%$#0%$ )' &##-+3&'#$ <)(4 (4$
=&+)&1)%)(8 -5 (4$ )//0'-*%-10%)'^. HDS +$*)-'6
CDR Variable Constant Domain
#$$%&'()'*%)+&=
!
C1q binding site
Light chain

S
S
Heavy chain

S S
S S
CH1

SSSS
COOH CH1
CH2 CH3
VH S
S VH CH2 CH3 CH4
COOH
CL CL Only at
NH2 IgE
VL VL and IgM
NH2 Fab Fc Antigen
Antigen binding Effector function binding

B%&A5$0&-5) C.+&/+3)0=
CDR = complementarity-determining region VH = variable domain of heavy chains
Fab = antigen-binding fragment VL = variable domain of light chains
Fc = crystallizable fragment CH/L = constant domain of heavy / light chains
A. Immunoglobulin structure
N N N
N
N
N
N
N N
NN

"
! # #
(") ($) NN

!2m # !

C C CC C CC C C C C C C C
IgG TCR I/II MHC MHC CD4 CD8 Poly-IgR CD19 CD22 N-CAM/
class I class II CD 56
B. Immunglobulin-“superfamily”

CDR
L3 -N-terminal end
90-95
SSSS

CDR
L1
26-32
CDR
L2
49-55
CDR CDR CDR
H3 H1 H2
Variable domain of light chain 95-101 30-35 49-64
with the 3 hypervariable
complementarity determinants

C. Hypervariable regions determine the antigen specificity

CDR
L2
49-55
A n
t i g
e n - E p i t o p
CDR
L1
26-32
e
CDR
L3
90-95 !
DF

"
! 0@A46-.%,4&' 1'B'+%-6')& <)= 1(22'$')&(<&(%)

!" #$%&'() *+',&$%-.%$'/(/

!" #" #$$%&'( '%')*+&) ,&'%(- .'+/0 $+1*'&". .'$#2
+#*' &"*1 ,+#)*&1". )1".&.*&"3 1, #%4/0&"- !52- !62-
"2- #"( #23%14/%&".7 !38 &00/"13%14/%&". 0&2
3+#*' &"*1 *9' #23%14/%&" ,+#)*&1"- :9&%' 1*9'+
&00/"3%14/%&".- $#+*&)/%#+%; !3< #"( !3=-
9#>' # %1:'+ '%')*+1$91+'*&) 014&%&*; #"( #+'
*9'+',1+' ,1/"( 0#&"%; &" *9' "23%14/%&" ,+#)2
*&1"- 4/* '>'" &" *9' !62,+#)*&1"7
0" 1(22'$')& 34-'/ %2 5667)%8+%97+()/
?&+)/%#*&"3 #"*&41(&'. #+' $+1(/)'( #"( .'2
)+'*'( 4; $%#.0# )'%%. &" *9' 41"' 0#++1:-
>7)=<6')&<+ #$(),(-+'/
!3< /./#%%; 1))/+. &" $'"*#0'+&) ,1+0 E012
%')/%#+ :'&39 )#7 SMM MMM =#G7 !* &",+'T/'"*%;
1))/+. #. 1*9'+ $1%;0'+&) )10$%'B'.- #"(
+#+'%; 1))/+. &" 01"10'+&) ,1+07 I9' !3<. +'2
$+'.'"* *9' )%#..&)#% ./+,#)' &00/"13%14/%&".
1" *9' )'%% 0'04+#"' 1, 0#*/+' C )'%%.7 !3<
01%')/%'. 9#>' ,1/+ )1".*#"* (10#&".7 !3<
$'"*#0'+. E%&A' *9' !3@ (&0'+.G #+' ,#.*'"'( *12
3'*9'+ 4; R )9#&".7 !3< 9#. # 9&39 #,,&"&*; ,1+
)10$%'0'"* 4&"(&"37
!3=- %&A' !3<- &. 1"' 1, *9' 01.* )1001"
0'04+#"' &00/"13%14/%&". &" 9/0#" C )'%%.7
!*. ,/")*&1" &" .'+/0 &. /"A"1:"7
U"%; >'+; .0#%% #01/"*. 1, ,+'' !3V #+' ('2

&" 0/)1.#2#..1)&#*'( %;0$91&( *&../' #"( &"
%;0$9 "1('.7 !3@ &00/"13%14/%&". $+'(10&2
"#*' &" *9' .#%&>#- .')+'*&1". ,+10 *9' 4+1")9&#%
#"( /+&"#+; *+#)*.- *'#+ ,%/&(- )1%1.*+/0- #"(
4+'#.* 0&%A- :9'+' *9'; $+1>&(' $+1*')*&1"
#3#&".* 4#)*'+&#7
!00/"13%14/%&". #+' 'B$+'..'( 1" *9' ./+2
,#)' 1, 0#*/+' C )'%%. :9'" *9'; .'+>' #. ./+2
,#)' #"*&3'" +')'$*1+.7 D10' '"(13'"1/. &02
0/"13%14/%&". #+' 41/"( *1 1*9'+ )'%%. E'737-
3+#"/%1);*'.- 0#.* )'%%.- 01"1);*'.F0#)+12
$9#3'.- #"( '$&*9'%&#% )'%%.G- /./#%%; >&# H) +'2
*')*#4%' &" .'+/07 !* /./#%%; 4&"(. *1 4#.1$9&%&)
3+#"/%1);*'. #"( 0#.* )'%%. #"(- &" &"(&>&(/#%.
:&*9 #%%'+3&'.- *1 '$&*9'%&#% )'%%. &" *9' 0/)1.#%
%&"&"3 1, *9' 4+1")9&#% #"( 3#.*+1&"*'.*&"#%
*+#)*.7 !3V $%#;. #" &0$1+*#"* +1%' &" *9' ('2
,'".' #3#&".* $#+#.&*'. #"( &" &00'(&#*' 9;$'+2
.'".&*&>&*; +'#)*&1". E.'' $7 WWG7
1" 3$<)/-%$& %2 58? &.$%78. &.' 5)&'/&()<+
*-(&.'+(76
X':41+". #+' "1* ,/%%; &00/"1)10$'*'"*

" )'$*1+.7 E&00/"13%14/%&" $+1(/)*&1" 4'3&". #* W

:" 5667)%8+%97+() ;&$7,&7$' <)= >'<&7$'/
!38 &00/"13%14/%&". )10$+&.' *9' %#+3'.* $1+2
*&1" 1, .'+/0 &00/"13%14/%&".7 I9'; #+' (&2
>&('( &"*1 ,1/+ ./4)%#..'. E!385- !386- !38J-
#"( !38KG :9&)9 #+' (&.*&"3/&.9'( 4; (&,,'+2
'")'. &" *9'&+ # )9#&".- #. &. ('"1*'( 4; *9' "/2
0'+&)#% ./,,&B'. #5 *1 #K7 I9' 9'#>; )9#&". 9#>'
1"' >#+&#4%' (10#&" #"( *9+'' )1".*#"* (12
0#&".7 I9' 01%')/%#+ :'&39* 1, !38 #01/"*.
*1 # *1*#% 1, )#7 5LM MMM =#7 I9' %&39* )9#&".
E)#7 656 #0&"1 #)&(.G )1"*+&4/*' #+1/"( 6J
MMM =#- #"( *9' 9'#>; )9#&". E)#7 KLM #0&"1
#)&(.G #+1/"( LM MMMNOM MMM =# &" *9' >#+&1/.
./4)%#..'.7 !38J &. 9'#>&'+ *9#" #%% 1*9'+ !38
./4)%#..'. 4')#/.' &* )1"*#&". # %1"3 .'+&'. 1,
(&./%,&(' 41"(. &" *9' .12)#%%'( !"#$% &%$"'#7
!* &. '.$')&#%%; 311( #* 4&"(&"3 )10$%'0'"*7
@%% !38 #"*&41(&'. 1))/+ #. 01"10'+.7
D'+/0 !3@ &00/"13%14/%&". /./#%%; #%.1 1)2
)/+ #. 01"10'+. 4/* )#" #%.1 4' $+'.'"* #. (&2
01"*9.G7 Y9&%' #* 4&+*9 #"*&41(&'. ,+10 *9'
01*9'+ #+' .*&%% $+'.'"* &" *9' 4%11( E!38
)+1..'. *9' $%#)'"*#G- 4+'#..* 0&%A &. # 311(
.1/+)' 1, #"*&41(&'. ,1+ *9' ,&+.* 01"*9. 1,
%&,'7 !38 01%')/%'. ,+10 *9' 4+'#.* 0&%A #+' #42
.1+4'( 4; .$')&#%&Z'( '$&*9'%&#% )'%%. &" *9' &"2
*'.*&"' 1, *9' &",#"* #"( $#..'( 1" *1 *9' 4%11(
>&# # $[ 3+#(&'"*7
*" ;',$'&(%) %2 58!
D')+'*1+; !3@ 01%')/%'. 1))/+ #. (&0'+.
:&*9 #" #((&*&1"#% .')+'*1+; )10$1"'"* E)#7
OM MMM =#G7 I9&. &">1%>'. # )'+*#&" $1+*&1" 1,
*9' 0'04+#"' +')'$*1+ *9#* 4&"(. !3@ 1" *9'
'B*+#%/0&"#% .&(' 1, *9' '$&*9'%&#% )'%%7 I9' +'2
)'$*1+ /"('+31'. )%'#>#3'- #"( *9' $1+*&1" *9#*
:#. 41/"( *1 !3@ &. +'%'#.'( #%1"3 :&*9 *9'
&00/"13%14/%&"7

!
0'+. E#41/* 5L PGQ *9'; +#+'%; 1))/+ #. $1%;2
0'+.7 !3@ (&0'+. #+' 9'%( *13'*9'+ 4; # R
)9#&"7 I9'+' #+' *:1 !3@ ./4)%#..'. E!3@5 #"(
!3@6G *9#* #+' (&.*&"3/&.9'( 4; (&,,'+'")'. &"
*9' (&./%,&(' 41"(. &" *9'&+ 9&"3' +'3&1"7 !3@
CD 01%')/%'. #+' >'+; 9&39 &" )#+419;(+#*'. #"(
(1 "1* 4&"( )10$%'0'"*7
 Albumin Globulins
5667)%8+%97+() :+<//'/

Breast
milk
!
! 1 !2 " #

Fc
receptors

1. Circulating Ig 2. Membrane- 3. Secretory Ig 4. Cell-bound Ig

IgM IgD IgA IgG 2. bound Ig
A. Protein electrophoresis B. Different immunoglobulin types

V IgG IgA IgM IgD IgE

Serum: Serum: lgM Serum: lgD

>7)=<6')&<+ #$(),(-+'/
VL Monomeric lgA
CL
SS
SS

SS

IgG1 65%
SS SS

SS
SS

SS

SS
SS

SS
SS
SS
SS

IgG2 23%

"
Secretory Membrane- Membrane-
lgA; dimer bound lgM bound lgD
SS
SS
SS
SS
Hinge
SS SS
SS SS SS
SS
region SS
SS
SS
SS

J
IgG3 8%
S
S chain SS

SS
SS
SS

Mature Mature Basophil

B lymphocyte B lymphocyte granulocyte
IgG4 4%

Serum lg 80% 13% 6% 0.1% 0.002%

Half-life 23 6 5 3 2.5 days

C. Immunglobulin structure and features

Lumen Fc#R Binding at pH <7.0 Secretory component Lumen

pH 7.4 Release at pH 7.4

D. IgG transport through intestinal epithelium

lgA
E. Secretion of IgA
J chain
!
CE

"
! 8=9A/B:+@A*. <.C.6+B/.'* &', <(00.$.'*(&*(+'
!" #"$#%#$&'( )'" *+,$&)- '. (-'/. 0100 $#22-+-".
'".#3,$#-/4 56#/ 7+-'. $#%-+/#.8 #/ '..+#3&.'3(-
9'#"(8 ., .6- ('+7- "&93-+ ,2 7-"-/ .6'. -":
),$- .6- %'+#'3(- +-7#,"/ ," #99&",7(,3&(#"/4
!" #$%&'()&*(+' &', -.&$$&'%./.'* +0
1 2.'.3 +0 4//5'+%6+756('3
56- 7-"-/ .6'. ),$- 2,+ #99&",7(,3&(#" 6-'%8
;<= )6'#"/ '+- (,)'.-$ ," )6+,9,/,9- 0>4 ?"
.6- 7-+9(#"- ),"2#7&+'.#," ,2 #99'.&+- )-((/@
.6-/- 7-"-/ '+- (,)'.-$ #" 2,&+ +-7#,"/ ;%'+#:
'3(-@ $#%-+/#.8@ A,#"#"7@ ),"/.'".=4 !+,&"$ B1
2&").#,"'((8 ').#%- C 7-"-/ ),$- 2,+ '9#", ')#$/
;!!= 0 ., DB #" .6- %'+#'3(- +-7#,"@ 01EF1 G
D5',&/.'*&6 E$('@(B6.3
7-"-/ ),$- 2,+ !! DH ., 010 #" .6- $#%-+/#.8 +-:
7#,"@ '"$ H I 7-"-/ ),$- 2,+ !! 01J ., 001 #" .6-
A,#"#"7 +-7#,"4 ?" '$$#.#,"@ .6- ),"/.'". +-7#,"
,2 .6- 6-'%8 )6'#" #/ $-.-+9#"-$ 38 D K 7-"-/L !
2,+ ?7M@ "0 2,+ ?7N0@ '"$ "J 2,+ ?7NJ@ -.)4 O')6 C
7-"- #/ 6-'$-$ 38 ' (-'$-+ ;P= /-Q&-")-4 G&+#"7
.6- *+,)-// ,2 9'.&+'.#,"@ ' G 7-"- 3-),9-/
(#"R-$ S#.6 ' I 7-"- ;G:I +-'++'"7-9-".= %#'
$-(-.#," ,2 .6- GT! *,+.#," 3-.S--" .6-94
!" 9UT! 9,(-)&(- #/ .+'"/)+#3-$ 2+,9 .6-
GI /-Q&-")- '"$ .6- 7-"- 2,+ .6- ),"/.'".
"
+-7#," ,2 .6- ?7M 9,(-)&(- ;K!=@ /, ' *+-)&+/,+
GI:K! *+,.-#" #/ /8".6-/#V-$ ;/-- *4 FJ=4 G&+#"7
.6- ),&+/- ,2 2&+.6-+ 9'.&+'.#,"@ .6- C 7-"-
/-Q&-")-/ '+- +-'++'"7-$ #" /&)6 ' S'8 .6'.
' C 7-"- ;.,7-.6-+ S#.6 .6- ),++-/*,"$#"7 P
/-79-".= #/ 3+,&76. "-W. ., .6- +-'++'"7-$
GI 7-"- ;C:GI +-'++'"7-9-".=4 CGI:K! 9UT!
#/ ",S .+'"/)+#3-$ 2+,9 .6#/@ '"$ ' CGI:K! *+,:
.-#" #/ /8".6-/#V-$4 K(-'%'7- ,2 .6- P /-Q&-")-
&(.#9'.-(8 8#-($/ .6- ! 6-'%8 )6'#" ,2 .6-
#99&",7(,3&(#"4 56- .,.'( ,2 )'4 B1 C 7-"-/@
01EF1 G 7-"-/@ '"$ H I 7-"-/ 8#-($/ ' +-),93#:
"'.#," *,.-".#'( ,2 '+,&"$ F!01F ., D!01F 2,+
.6- '9#", ')#$ /-Q&-")-/ ,2 .6- %'+#'3(- +-7#,"
,2 6-'%8 )6'#"/4 56#/ *+,)-// #/ +-2-++-$ ., '/
!"#$%&' ()'"#*&+$%&"+4
8" #$%&'()&*(+' +0 ! 9(%:* ;:&(' 2.'.3
56- 7-"-/ 2,+ # (#76. )6'#"/ '+- (,)'.-$ ," )6+,:
9,/,9- J4 !+,&"$ FBE>1 2&").#,"'((8 ').#%- C
7-"-/ ;.,7-.6-+ S#.6 .6- ),++-/*,"$#"7 P
7-"-/= ),$- 2,+ '9#", ')#$/ 0 ., DB ,2 .6- %'+#:
!
'3(- +-7#," ,2 # (#76. )6'#"/X B I 7-"-/ ),$- 2,+
'9#", ')#$/ DH ., 0014 C 7-"-/ '+- 3+,&76. "-W.
., I 7-"-/ $&+#"7 .6- *+,)-// ,2 GT! +-'++'"7-:
9-".4 ! *+-)&+/,+ 9UT! #/ .+'"/)+#3-$ 2+,9 '
CI /-Q&-")-@ .,7-.6-+ S#.6 .6- /-Q&-")- 2+,9
FG .6- ),"/.'". +-7#," ,2 .6- # (#76. )6'#" ;K#=4 56-
P /-Q&-")- .6-" /*(#./ ,22 2+,9 .6- *+,.-#"4
! .,.'( ,2 FBE>1 C 7-"-/ '"$ B I 7-"-/ )'"
),$- 2,+ '**+,W#9'.-(8 0YBEJ11 $#22-+-". #
(#76. )6'#" /*-)#2#)#.#-/4
;" #$%&'()&*(+' +0 " 9(%:* ;:&(' 2.'.3
56- ,+7'"#V'.#," ,2 $ (#76. )6'#" 7-"-/ ," )6+,:
9,/,9- JJ #/ ",. 2&((8 &"$-+/.,,$4 56-+- '+- '
"&93-+ ,2 7-"-/ 2,+ .6- ),"/.'". +-7#,"@ '"$
.6- I /-Q&-")-/ (#- $#+-).(8 #" 2+,". ,2 .6- K
7-"-/4 56-+- '+- *+-/&9'3(8 A&/. '/ 9'"8
7-"-/ 2,+ .6- $ )6'#" '/ 2,+ .6- # )6'#"4
Z-)'&/- -%-+8 6-'%8 )6'#" #/ (#"R-$ S#.6
' # ,+ $ )6'#"@ .6-+- '+-@ .6-,+-.#)'((8@
B4J!01B ;0YB!F!01F= ., 04[!01H ;J11!D!01F=
$#22-+-". #:3-'+#"7 '".#3,$8 +-),93#"'.#,"/4
56- *+,A-).-$ "&93-+ ,2 $#22-+-". $:3-'+#"7
#99&",7(,3&(#"/ #/ *+,3'3(8 /#9#('+4 56- '):
.&'( "&93-+ ,2 *,//#3(- '".#3,$8 9,(-)&(-/
#/@ 6,S-%-+@ 9&)6 6#76-+4 56#/ #/ '..+#3&.'3(-
., /-%-+'( +-'/,"/@ /&)6 '/L ;0= 9&.'.#,"/ '.
.6- GT! (-%-( $&+#"7 ,".,7-"-/#/X ;J= -++,+/
#" .6- ),&+/- ,2 $-(-.#," '"$ +-),93#"'.#,"
,2 C@ G@ '"$ I 7-"-/@ $&+#"7 .6- ),&+/- ,2 S6#)6
"&)(-,.#$-/ '+- #"/-+.-$ 2+,9 GT! /-Q&-")-/
.6'. '+- ",. ",+9'((8 .+'"/)+#3-$X ;F= .6-
/8".6-/#/ ,2 "-S #99&",7(,3&(#"/ S#.6
-"6'")-$ '22#"#.8 $&- ., .6- /S#.)6#"7 ,2 '9#",
')#$/ %#' *,#". 9&.'.#," $&+#"7 7-+9#"'( )-":
.-+ +-').#,"/ ;/-- *4 J>=4
<" 4//5'+%6+756(' ;6&33=>?(*@:('%
?99&",7(,3&(#"/ ,2 $#22-+-". )('//-/ '+-
/8".6-/#V-$ $&+#"7 '" #99&"- +-/*,"/-4 56-
9'.&+#"7 Z )-((/ 2#+/. *+,$&)- ?7M #99&",7(,:
3&(#"/4 \%-+ .6- ),&+/- ,2 .#9-@ .6- +-'++'"7-$
CGI /-Q&-")-/ '+- *,/#.#,"-$ $#+-).(8 '$A')-".
., ,.6-+ K 7-"-/4 O%-+8 K 7-"- #/ *+-)-$-$ 38 '
/,:)'((-$ /S#.)6#"7 ;]= /-Q&-")- .6'. ),".+,(/
.6- +-'++'"7-9-". *+,)-// 38 +-),93#"#"7
S#.6 ,.6-+ ] /-Q&-")-/ $&- ., .6- 6#76 (-%-(
,2 6,9,(,784 56- K! /-Q&-")-/ (,)'.-$ 3-:
.S--" .6- CGI /-Q&-")-/ '"$ .6- "-S K 7-"-/
'+- $-(-.-$ #" .6- *+,)-//4
 n = ~50
4//5'+%6+756(' 2.'. #$%&'()&*(+'

Chromosome 14
!
✂

✂
VH1 VH2 VH3 Vn

5' 3'
L1 L2 L3 Ln D1 D2 D 3 D 4 Dn J1 J2 J3 J4 J5 J6 Cµ C% C#3 C#1 C&1 C#2 C#4 C' C&2

DJ rearrangement Deletion Germline DNA

VH1 VH2 VH3 Vn C#4

5' 3'
L1 L2 L3 Ln D1 D2 D3 J5 J6 Cµ C% C#3 C#1 C&1 C#2 C' C&2

Deletion Transcription

D5',&/.'*&6 E$('@(B6.3
VDJ-rearrangement DJ-Cµ mRNA DJ-Cµ protein
VH1 VH2
Cleavage
5' 3' of L-coded
L1 L 2 D3 J 5 J6 Cµ C% C#3 C#1 C&1 C#2 C#4 C( C&2 sequence

VDJ-Cµ coding mRNA µ heavy

A. Organization and rearrangement of immunoglobulin H genes chains

"
n = ~35
V$1 V$2 V$3 V$n
5' 3' Chromosome 2
L1 L2 L3 Ln J$1 J$2 J$3 J$4 J$5 C$

B. Organization of ! light chain genes

V"1 V"x V"n

5' 3' Chromosome 22
L1 Lx VpreB Ln J"2 C"2 J"4 C"4 J"x C"x

C. Organization of " light chain genes

C%
µ

#3
C

VDJ
s Cµ C% s C#3 s C#1 Maturation V D J s s C& 1
C# 1

!
mRNA mRNA
µ #1

lgM-expressing B cell lgG1 -expressing B cell

D. Immunoglobulin class-switching
FH

"
! #$:;3<2/1;-& (&=&'/<3&,- .,9 ()**&+&,-).-)/,

!" #$%&'' ()**&+&,-).-)/, 012&3&

!"#$%&' '(")*' %+ ,-.*// 0$++*#*1($"($%1 ."1 2*
0*+$1*0 3$(4 (4* 4*/5 %+ "1($2%0$*' 0$#*.(*0
B#*-,-OO .*//' 4"N* "/#*"0? #*"##"1)*0
!V-9V-WV "10 '?1(4*'$Y* " !9W-8" 5#%(*$1
.%##*'5%10$1) (% " .%=5/*(* " .4"$16 74$' .4"$1
FV"H $' *@5#*''*0 %1 (4* .*// =*=2#"1* (%-
")"$1'( '&#+".* "1($)*1'6 74* "1($)*1' 89:;
)*(4*# 3$(4 (4* !5#*,G!U '&##%)"(* .4"$1A
"10 89<< "#* (4* *"#/$*'( '5*.$+$. ,-.*// ="#-
34$.4 +&1.($%1' "' (4* '$)1"/ (% '("#( #*"##"1-
>*#'6 89<< $' $1$($"//? *@5#*''*0 %1/? $1 .?(%-
)$1) (4* /$)4( .4"$16 O=="(&#* , .*//' "#* 0*-
5/"'= 2&(A "' (4* ="(&#"($%1 5#%.*'' .%1($1&*'A
+$1*0 2? (4* '$=&/("1*%&' *@5#*''$%1 %+ (4*
$( $' "/'% *@5#*''*0 %1 (4* .*// '&#+".*6 B#%)*1$-
" 4*"N? .4"$1' $1 "''%.$"($%1 3$(4 !5#*,G!U
(%# , .*//' "/'% *@5#*'' '(*= .*//-"''%.$"(*0
'&##%)"(* .4"$1' FV"G!5#*,H "10 3$(4 1%#="/
"1($)*1'A '&.4 "' 89CD "10 89::E F.->$(G'(*=
>"55" %# /"=20" /$)4( .4"$1' F.%=5/*(*
.*// )#%3(4 +".(%# #*.*5(%#H "10 89:I6 J$1.*
O)MG# ZV"GL"[ %# O)MG! ZV"GL"[ $==&1%-
89:I 3"' +$#'( 0*(*.(*0 $1 (4* .*//' %+ /*&>*=$"
)/%2&/$1'H6 O+ #*"##"1)*=*1( "( " /$)4( .4"$1
5"($*1('A $( $' #*+*##*0 (% "' .%==%1 ".&(* /?=-
/%.&' $' '&..*''+&/ "10 " /$)4( .4"$1 $' '?1-
>5,9.3&,-.' ?+),1)<'&@

54%2/"'($. /*&>*=$"-"''%.$"(*0 F8KLLKH "1($-

(4*'$Y*0A +&#(4*# #*"##"1)*=*1( "( (4* L /%.$
)*16 M"(&#* .$#.&/"($1) .*//' "#* 89:I-1*)"($N*A
3$// 2* '&55#*''*06 O+ " .*// 4"' &10*#)%1* 5#%-
2&( 89:I $' *@5#*''*0 %1 )*#=$1"/ .*1(*# .*//'6
0&.($N* #*"##"1)*=*1( "( (4* # /%.&'A +%# *@"=-
74* *@5#*''$%1 %+ 89<I '("#(' "55#%@$="(*/? "(
5/*A #*"##"1)*=*1( "( (4* ! /%.&' 3$// 2* '&5-
(4* /*N*/ %+ 5#*-,-OO .*//'6
5#*''*0 "10 N$.* N*#'"6 X*"##"1)*=*1( "( (4* !
89<C F/%3 "++$1$(? P.-O)Q #*.*5(%#H "10 89<:
/%.&' $' '($// 5%''$2/*A 4%3*N*#A $+ #*"##"1)*=*1(
"#* ="#>*#' %+ ="(&#* , .*//'6 89<: $' "/'% " #*-
"( (4* # /%.&' 3"' "2%#(*06 74$' =*.4"1$'=
.*5(%# +%# (4* Q5'(*$1R,"## N$#&' "10 +%# (4*
*1'&#*' (4* 5#%0&.($%1 %+ %1/? %1* (?5* %+ /$)4(
8C0 +#")=*1( %+ .%=5/*=*1(6
.4"$1 2? (4* , .*// F!"#$% &$'"( )*+%)"&%",(H6
#" 4335,/6'/75'), 8/95'.-)/, 95+),6
#$%&'' ()**&+&,-).-)/,

" O==&1%)/%2&/$1' "#* *@5#*''*0 %1 (4* '&#+".*

%+ ="(&#* , .*//' "10 "#* '*.#*(*0 $1 /"#)*
"=%&1(' 2? 5/"'=" .*//'6 74* "=$1% ".$0 '*-
S&*1.*' +%# (4* 0$++*#*1( 5"#(' %+ (4* .%=5/*(*
$==&1%)/%2&/$1 "#* 0*(*#=$1*0 $1 (4* 5#*.&#-
'%# .*//' 0&#$1) (4* .%&#'* %+ ,-.*// %1(%)*1?6
O1 5#%)*1$(%# , .*//' F5#%-, .*//'HA '($// &1=%-
0$+$*0 9TK $' +%&10 "( 4*"N? "10 /$)4( .4"$1 /%.$
$1 (4* '%-."//*0 )*#=/$1* .%1+$)&#"($%16 O1 "0-
0$($%1 (% )*1*' +%# (4* /"=20" /$)4( .4"$1A (3%
%(4*# )*1*' F!5#*, "10 !UH (4"( .%0* +%# (4*
.%##*'5%10$1) /$)4( .4"$1-/$>* 5#%(*$1' F'&##%-
)"(* /$)4( .4"$1'H "#* "/'% /%."(*0 %1 .4#%=%-
'%=* <<6 74* '&##%)"(* /$)4( .4"$1' "#* +$#'( *@-
5#*''*0 %1 (4* .*// =*=2#"1* (%)*(4*# 3$(4 "
:CI >9" )/?.%5#%(*$1 .%=5/*@6 74*? 5#*'&=-
"2/? 2$10 (% .*//&/"# %# '%/&2/* /$)"10' "10
(#"1'5%#( (4* '$)1"/' +%# +&#(4*# ,-.*// 0*N*/%5-
=*1( (% (4* .*// $1(*#$%#6
M%#* 0$++*#*1($"(*0 , .*//' F5#*-,-O .*//'H
4"N* #*"##"1)*0 9V "10 WV )*1*' "( (4* V /%.&'
%+ .4#%=%'%=* :D6 K 9W-8" 5#%(*$1 $' .%0*0

!
0&#$1) (4* 5#%.*'' %+ 9W-8" =XTK (#"1'.#$5($%1
F'** 56 CIH6 74* 5#%(*$1 (#"1'=$(' " 1*)"($N*
+**02".> '$)1"/ (% '(%5 (4* +&#(4*# '?1(4*'$'
%+ 9W-8" 5#%(*$1'6 !5#*,G!U .4"$1' ."1 "''%.$"(*
2%(4 3$(4 5:CI )/?.%5#%(*$1' "' 3*// "' 3$(4
AB 9W-8" 5#%(*$1' %1 (4* .*// =*=2#"1*6
 pro-B pre-B-I pre-B-II
4335,/6'/75'), C&,& ?+/951- DE<+&@@)/,

Immature B Mature B Plasma cell

!
HL A -class II
(HL A -DR)
CD34
CD10
Surface
lg-!/lg-"
Surface
VpreB/#5
cyt-µ slgM/slgD
Immunoglobulins
CD22
CD19
CD20

>5,9.3&,-.' ?+),1)<'&@
CD21
CD23
A. B-cell differentiation scheme Cytoplasmic

CD34 CD19 CD19

IL-7R CD22cyt IL-7R CD22cyt
H L$ H L$
CD10
DJ-rearrangement
L# L#

Pro-B
VpreB/#5

CD19
CD22cyt
pre-B-I

DJ-Cµ
VpreB/#5

transcription
CD19
CD22cyt
"
H L$ H L$
CD10 VDJ-rearrangement CD10

L# L#

Pre-B-II Pre-B-I Prot.

VpreB/#5
DJ-Cµ
Hµ/VpreB/#5

VL-JL- Rearrangement HµL$

Hµ/L$ (slgM) CD19 CD19

CD22cyt CD22s
CD20 CD20

or or

!
CD21
Immature B Mature B CD23
slgM+
Hµ/L#(slgM)
Hµ/VpreB/#5 HµL# (slgM)

B. Immunoglobulin modulation during B-cell differentiation

AA
! !"#$%&'()$*+ ,+-+.(&%+/* 0/1 ,233+4+/*20*2(/

!"# $%&'%&( )* +& +&,%(#& ,) -./*+0# %11.&)2

(3)$.3%&- ,/%((#/- + 0+-0+'# )* $%)0"#1%0+3 -%(2
&+3- 4%,"%& + 5 0#336 7%&0# %11.&)(3)$.3%&-
"+8# )&39 + 8#/9 -")/, %&,/+209,):3+-1%0 ,+%3;
,"#9 +/# '#:#&'#&, )& +00#--)/9 1)3#0.3#-; -%2
1%3+/ ,) ,"# <=> 0)1:3#? )* ,"# !20#33 /#0#:,)/6
@(2! A<=BC+D +&' @(2" A<=BC$D 0"+%&- +--.1#
,"%- *.&0,%)&6 !"#-# 0"+%&- +/# -,/.0,./+339 -%2
1%3+/ ,) !<E #; $; +&' % 0"+%&- +&' ,"#9 *)/1;
,)(#,"#/ 4%," ,"# %11.&)(3)$.3%&-; ,"# 52
0#33 /#0#:,)/ A5<ED 0)1:3#?6
!"#$ %- /#*#//#' ,) +- !"##"$ %!&'(
)*#+,"-)%.'/! )(&0(#/%1%.."!/%'(2 A<FGGFD
%$'/3($ $#0+.-# %, 4+- *%/-, *).&' )& 391:")2
56/10%+/*0. 742/)2&.+8
+.,)0/%&#T:+/+0/%&# 520#33 (/)4," *+0,)/ )00./-
+- + 03#+8+(# :/)'.0, )* <=M>6
!"($ %- 1+%&39 #?:/#--#' $9 5 0#33-; $., +3-)
$9 '#&'/%,%0 0#33- A=<D; *)33%0.3+/ '#&'/%,%0 0#33-
AS=<D; "#1+,):)%#,%0 :/)(#&%,)/ 0#33-; #:%,"#3%+3
0#33-; +&' 0+/0%&)1+ 0#33-6 <=UJ %- + 1#1$#/ )*
,"# !VS /#0#:,)/ *+1%396 F !VS2/#3+,#' (390)2
:/),#%& ,"+, %- 1+%&39 #?:/#--#' )& +0,%8+,#'
<=U ! ! 0#33- A<=UJ 3%(+&'; <=IWUD :/)8%'#-
+& %1:)/,+&, -./8%8+3 -%(&+3 *)/ 5 0#33-6 !"#
(#/1%&+3 0#&,#/- 0+&&), '#8#3): 0)1:3#,#39
%* <=UJT<=UJ 3%(+&' %&,#/+0,%)& %- '#*#0,%8#6 @*
,"%- %- ,"# 0+-#; @(X %- ,"# )&39 %11.&)(3)$.3%&
,"# 5 0#33- 0+& :/)'.0# $#0+.-# )* + $3)0H#'

$3+-,- )* :+,%#&,- 4%," ,"# 0)11)& 8+/%+&, )* %11.&)(3)$.3%& 03+--2-4%,0"%&( A"9:#/2@(X

+0.,# 391:"+,%0 3#.H#1%+ A0)11)& FGGD6
<=IJ %- +& #?,/+0#33.3+/ K%&02$%&'%&( 1#,+33)2
:/),#%&+-# ,"+, 0+& 0+,+39K# ,"# 03#+8+(# )* 8+/2
%).- :#:,%'#-; -.0" +- -.$-,+&0# L; #&'),"#3%&;
)?9,)0%&; $/+'9H%&%&; +&' +&(%),#&-%&- @ +&' @@6
@, %- #?:/#--#' )& -,/)1+3 0#33-; )& %11+,./#
! +&' 5 0#33- %& ,"# $)&# 1+//)4; +&' )&
(#/1%&+3 0#&,#/ 0#33- %& -#0)&'+/9 391:")%'
)/(+&-6
!"#% %- #?:/#--#' )& ,"# 1#1$/+&# )* +33 5
391:")09,#- +&' %- ,".- + 1+/H#/ )* ,"# #&,%/#
-9&'/)1#D6
!")&; 3%H# <=M>; %- + 1#1$#/ )* ,"# %./%)"1
3)*!"+5"'(/$ /#0#:,)/ *+1%396 G%H# <=IC; %, %- +
$/)+' 520#33 1+/H#/; $., %,- *.&0,%)& %- &),
9#, .&'#/-,))'6 Q+/3%#/ #8%'#&0# ,"+, <=BM
*.&0,%)&- +- + 3%(+&' *)/ <=W "+- &), 9#,
$##& 0)&*%/1#'6
!"*$ +&' !"*+ +/# &), 520#33 3%&#+(#2-:#0%2
*%06 !"#9 +/# #?:/#--#' )& ),"#/ +&,%(#&2:/#2
-#&,%&( 0#33-; -.0" +- 1)&)09,#- +&' '#&'/%,%0
0#33-6 !"# %&,#/+0,%)& )* <=NJT<=NY 4%," ,"#%/

" 5 0#33 -#/%#-6 <=IC .&%,#- 4%," <=MI; <=NI; +&'

G#.2I> ,) *)/1 + 0)2/#0#:,)/ ,"+, 1)'.3+,#-
,"# -%(&+3- ,/+&-'.0#' $9 ,"# 5<E 0)1:3#?6
!"%- +0,%8%,9 %- #-:#0%+339 %1:)/,+&, %& %11+2
,./# 5 0#33-6
!"&$; + O:+&2520#33 1+/H#/P #?:/#--#' )& +33
3%(+&'- )& ! 0#33- A<=MN +&' <!GF2UD %- 0/.0%+3
*)/ ,"# 0)1:3#,# +0,%8+,%)& )/ '#+0,%8+,%)& )*
! 0#33- A-## :6 >YD6

5 0#33- #?0#:, :/)(#&%,)/ 5 0#33-; %- -,/.0,./+339

-%1%3+/ ,) +& %)& 0"+&&#36 @,- ,/+&-1#1$/+&#
-#(1#&, 0/)--#- ,"# 0#33 1#1$/+&# *)./ ,%1#-
+&' -##1- ,) $# +--)0%+,#' 4%," ,"# 09,)-H#3#2
,)&6
!"&# %- + 3)42+**%&%,9 /#0#:,)/ *)/ ,"# 0)12
:3#1#&, 03#+8+(# :/)'.0,- %<>$ +&' <>'6 @, +3-)
-#/8#- +- ,"# Q:-,#%&R5+// 8%/.- /#0#:,)/6 !)2
(#,"#/ 4%," <=IC; <=NI; +&' G#.2I>; <=MI %-
*.&0,%)&+339 +--)0%+,#' 4%," ,"# 520#33 /#0#:,)/6
!"&&; 3%H# <=> )& ! 0#33-; #?"%$%,- $%1)'+3
#?:/#--%)&6 <=MM %- #?:/#--#' )& ,"# 0#33 1#12
$/+&# )&39 %& 1+,./# 5 0#33-; $., %- :/#-#&,
4%,"%& ,"# 09,):3+-1 )* +33 5 0#33-6 @, *.&0,%)&-
+- +& +'"#-%)& 1)3#0.3# ,"+, %&,#/+0,- 4%,"
./%)*)3)*!"!"$4&3%'(.6 G%(+,%)& )* <=MM 3#+'-

!
,) ,"# ')4&/#(.3+,%)& )* -%(&+3 ,/+&-1%--%)&
$9 5<E 0)1:3#?#-; 1#'%+,%&( +& %&"%$%,)/9
#**#0,6
!"&' %- ,"# 520#332+--)0%+,#' /#0#:,)/ *)/ ,"#
S0 */+(1#&, )* @(Q6 !"# $%&'%&( )* <=M> ,) @(Q
9: )/ ,) %11.&# 0)1:3#?#- 0)&,+%&%&( @(Q %&2
'.0#- *##'$+0H %&"%$%,%)& )* @(Q -9&,"#-%-6 F&
 Molecule Molecular Gene locus
weight(kDa) (chromosome)
Cell expression
;%&(4*0/* !"<+.. =/*2>+/8

Function
!
slg 150–900 14 (!-chains) Mature B cells Antigen binding
2 ("-chain) part of B-cell antigen
22 (#-chain) receptor (BCR)

Ig-$(CD79a) 34 19q132 Pre-B cells sIg-associated molecules

Ig-%(CD79b) 39 17q23 Mature B cells signal transducing
part of BCR
100 3q21-q27 Pre-B cells Neutral endopeptidase
B cells of

56/10%+/*0. 742/)2&.+8
germinal center
NH

CD10 (CALLA) Granulocytes

95 16p11.2 All B cells With CD21-, CD81-

incl. progenitor Leu-13 co-receptor
B cells
COOH

for BCR
CD19

35–37 11q-q13 Pre-B cells Ion channel

NH2 COOH

Mature B cells subunit

CD20

140 1q32 Mature B-cells

Follicular
dendritic
C3d/EBV-receptor
(CR2)
BCR-association,
"
COO

CD21 cells (FDC) signal transduction

135 19q13.1 All B cells B-cell adhesion

(cytoplasm) molecule (B-B and B-T
Mature B cells interaction)
COOH

CD22 (surface) modulation of BCR

45 19p13.3 Mature B cells Low-affinity Fc&

FDC receptor (Fc&RII)
NH2

Act. monocytes cleavage product = B-cell

CD23 eosinophils growth factor

48 20q12- Pre-B cells Interaction with CD40

q13.2 Mature B cells ligand (T cell)
COO

Dendritic Anti-apoptosis signal

CD40 cells (DC)

43–39 9p All cells of Adhesion molecule

B-cell lineage
NH2

CD72 Macrophages

!
B cells, T-APC interaction
act. monocytes (ligands for
60 3q21 CD28/CTLA-4)
COOH

Dendritic
CD80/86 cells (DC)
A. Important B-cell antigens
9?

"
! 5&%%A5&%% *+/&01'/.$+)
!" #$%&'(%&) *+,$%,&- .+ *+/&01'/.$+)
2&/3&&+ 4 5&%%) 1+- !65)
!"#"$%& %'(")*+, %,' %--"))+$. /+&"-0&") 1$+2
/+3" 3(" *,3"$%-3*+, +4 5-"&&) 6*3( %,3*7",21$"2
)",3*,7 -"&&) 89:;)<= )0-( %) > -"&&)= '",'$*3*-
-"&&) 8?;)<= %,' /+,+-.3")@
A"0B+-.3" 40,-3*+,2%))+-*%3"' %,3*7",2C
8AD92C<= % 0E*F0*3+0) %,3*7",= E*,') 3+ *,3"$-"&2
&0&%$ %'(")*+, /+&"-0&"2C 8G;9H2C<@ ;?I E*,')
3+ AD92J= % 7&.-+1$+3"*,= 6(*-( *) /%*,&. "K2
1$"))"' +, ",'+3("&*%& -"&&)= "1*3("&*%& -"&&)=
%,' -+,,"-3*#" 3*))0"@ 5(" ;?LMN;?LM2&*7%,'
*,3"$%-3*+, 3$%,)/*3) % )0$#*#%& )*7,%& 3+ 7"$/2
B(+-1@&+/1% 60.+'.?%&)
*,%& -",3"$ > -"&&) %,' *,'0-") ?;) 3+ /%30$"
%,' 1$+'0-" &%$7" F0%,3*3*") +4 GA2CI@ 5(" %'("2
)*+, +4 > -"&&) 3+ 5 -"&&) *) 40$3("$ )3%E*&*O"' E.
*,3"$%-3*+,) +4 3(" ;?CMP %,3*7",= +$ !%)-0&%$
""&& #'(")*+, $+&"-0&"2C 8Q;9H2C<= 6(*-( *)
%&)+ "K1$"))"' +, ",'+3("&*%& -"&&)= 6*3( 3("
;?LR' %,3*7",= %&)+ -%&&"' !"$. %%3" #,3*7",2
L 8QA92L< +, %-3*#%3"' 5 -"&&)@ 5(" *,3"$%-3*+,
+4 3(" 52-"&& /+&"-0&" ;?IS 6*3( ;?SMN;?SP
+, 9:;) (%) % )3*/0&%3+$. "44"-3= 6("$"%) 3("
*,3"$%-3*+, +4 ;?CTI= +$ ".3+3+K*- &2%./1(+2
-.3") #,3*7",2L 8;5A92L<= 6*3( 3(" )%/" %,3*2
"
7",) (%) %, *,(*E*3+$. "44"-3@
7" 8&,&01% 8.9+1%) !0& :&&-&- ;$0 4<5&%%
!'/.,1/.$+
9,3*7", $"-+7,*3*+, E. 3(" 52-"&& $"-"13+$ 85;U<
1$+#*'") % 4*$)3 %-3*#%3*,7 )*7,%& 4+$ % 5 -"&&= E03
*3 *) ,+3 )044*-*",3 3+ *,'0-" 40&& %-3*#%3*+,@ G, 3("
%E)",-" +4 % )"-+,' )*7,%&= 3(" 5 -"&& E"-+/")
3+&"$%,3 +$ %,"$7*-@ 5(" )"-+,' )*7,%& *) 1$+2
#*'"' E. 3(" *,3"$%-3*+, +4 3(" ;?IS %,3*7",=
6(*-( *) -+,)3*303*+,%&&. "K1$"))"' +, $")3*,7
5 -"&&)= 6*3( 3(" -+2)3*/0&%3+$. /+&"-0&") >V@C
8;?SM< +$ >V@I 8;?SP< +, 9:;)@ W, %-3*#%3*+,
E. E+3( )*7,%&)= 3(" %,3*7", ;5A92L 8;?CTI< *)
01$"70&%3"' *, 5 -"&&) 6*3(*, IL2LS (+0$)@
;5A92L *) % (*7("$2%44*,*3. $"-"13+$ 4+$ ;?SMN
;?SPX *3 -+/1"3") 6*3( ;?IS %,' *,(*E*3) -"&&
-.-&" 1$+7$"))*+,@ 5(*) ,"7%3*#" )*7,%& *) 1$+E2
%E&. "/*33"' E. ;5A92L 3+ ",' 52-"&& %-3*#%3*+,
*, +$'"$ 3+ 1$"#",3 %, "K%77"$%3"' *//0,"
$")1+,)"@ 9 40$3("$ *,(*E*3+$. $"-"13+$ *) B,+6,
%) 1$+7$%//"' '"%3( 7","2C 8:?2C<= 6(*-( -%,
!
*,3"$%-3 6*3( 36+ >V 4%/*&. /"/E"$)Y :?2AC +$
>V2ZG %,' :?2AI +$ >V2?;@
5"$/*,%&&. '*44"$",3*%3"' ?;) -%, 1$+'0-"
&%$7" F0%,3*3*") +4 GA2CI +, ;?LMN;?LM2&*7%,'
*,3"$%-3*+,= *,'0-*,7 3(" $"&"%)" +4 *,3"$4"$2
CD +,2! 8GD[2!< %,' 3(" '*44"$",3*%3*+, +4 ;?L\
-"&&) *,3+ 5ZC -"&&)@ GA2CI *) %&)+ % '*$"-3 %,' 1+2
3",3 )3*/0&0) +4 -.3+3+K*- 5 &./1(+-.3") 8;5A)<
%,' ,%30$%& B*&&"$ -"&& 8[]< 40,-3*+,@ GD[2! )3*2
/0&%3") %,3*/*-$+E*%& %,' 1$+*,4&%//%3+$.
%-3*#*3. +4 /%-$+1(%7") %,' ",(%,-") 3(" %-3*2
#%3*+, +4 ;5A)@
5" *5=8 .+ 4<5&%% !'/.,1/.$+
^,&*B" ;?IS= 3(" ;?IS (+/+&+7+0) *,'0-*E&"
52-"&& -+2)3*/0&%3+$ 8G;W!< *) ,+3 -+,)3*303*#"&.
"K1$"))"' +, $")3*,7 5 -"&&) E03 +,&. %43"$ %-3*2
#%3*+, #*% 5;UN;?J -+/1&"K@ _,7%7"/",3 +4
G;W!= &*B" ;?IS= -%, /"'*%3" 1+3",3 -+2)3*/02
&%3*+, +4 5 -"&&) %,' 1$+/+3" 1$+&*4"$%3*+,@ U"2
-",3 )30'*") *,'*-%3" 3(%3 )3*/0&%3*+, #*% G;W!
-%, *,'0-" E+3( 5ZC %,' 5ZI '*44"$",3*%3*+,@
G;W! *,3"$%-3) 6*3( 3(" G;W! &*7%,' G;W!A=
6(*-( *) %&)+ B,+6, %) >V(= >VU:2C= %,' >V2
ZI@ G;W!A *) "K1$"))"' -+,)3*303*#"&. +, > -"&&)=
?;)= /%-$+1(%7")= %,' ",'+3("&*%& -"&&)= %,' *3
*) 01$"70&%3"' E. 5[D2" +$ *,4&%//%3+$. )3*2
/0&*@
>" 8(?&01+/.9&+ 8/.@(%1/.$+
!01"$%,3*7",) %$" /%*,&. E%-3"$*%& 1$+'0-3)
8"@7@= )3%1(.&+-+--%& ",3"$+3+K*,)< +$ #*$%& 1$+2
3"*,) 3(%3 *,'0-" ,+,)"&"-3*#" 52-"&& %-3*#%3*+,@
5(" $")1+,)" +4 5 -"&&) 3+ )01"$%,3*7",) *) ,+3
-&+,%&X % &%$7" ,0/E"$ +4 '*44"$",3 5 -"&&) %$"
%-3*#%3"'@ `(*&" % (*7(&. )1"-*4*- *,3"$%-3*+,
+4 3(" 1$+-"))"' 1"13*'" "/E"''"' *, 3("
HZ; -+/1&"K 6*3( 3(" " %,' # -(%*, +4 3("
5;U *) /%,'%3+$. '0$*,7 %,3*7", )1"-*4*- 52
-"&& %-3*#%3*+,= )01"$%,3*7",) '+ ,+3 $"F0*$" *,2
3$%-"&&0&%$ 1$+-"))*,7@ 5(". E*,' %) 6(+&" 1$+2
3"*,) 3+ 3(" +03"$ )*'" +4 3(" Q# $"7*+, +4 )"#"$%&
5;U)@ 9$+0,' CMM 3*/") /+$" 5 -"&&) $"%-3 6*3(
)01"$%,3*7",) 3(%, 6*3( ,+$/%& %,3*7",)@
!+/" )01"$%,3*7",) *,'0-" %-3*#%3*+, +4 01
3+ CM a +4 1"$*1("$%& E&++' 5 -"&&)@ W, )01"$%,3*2
7", %-3*#%3*+,= ;?L\ 5 -"&&) $"&"%)" % (*7(
%/+0,3 +4 -.3+B*,")= 6(*-( -%, /"'*%3" 3+K*-
"44"-3) *, 3(" (+)3@
 CD 11a/18
*+/&01'/.$+) 2&/3&&+ 4 5&%%) 1+- !+/.9&+<?0&)&+/.+9 5&%%)

CD54 CD40 CD40L

!
(LFA-1) (ICAM-1)
CD54 CD11a/18
CD2 CD58
(LFA-3) CD58 CD2

APC = dendritic cell

CD3 CD8 or CD4
MHC

APC = B cell
T cell

MHC class I TCR

class II (or

T cell
TCR
(or class II)
class I) CD3
CD4 or CD8
ICOS B7h/ICOSL ICOSL/B7h ICOS

CD28/CTLA-4 CD80/CD86 CD80/CD86

(B7.1/B7.2) CD28/CTLA-4
(B7.1/B7.2)
CD106 CD49d

B(+-1@&+/1% 60.+'.?%&)
CD40L CD40 (VCAM)
A. Molecules involved in T cell – APC interaction

APC APC

Non APC CD80/ CD80/ CD80/

CD86 CD86 CD86
APC
CD28 CD152 CD28 CD152

T T

"
MHC I CD80/
MHC I Upregulation of
antigen CD86
TCR CD152/CTLA-4
CD28 3. Self-limitation/downregulation
CD28

APC
T T
CD80/ CD40
CD86 IL12
Anergy/Tolerance T-cell activation
CD28 CD154
TH1 CTL
T IFN-#
1. Signal 1 only 2. Co-stimulation Upregulation of
via CD28 CD154/CD40L
B. Several signals needed for T-cell activation 4. Effector cell induction

APC B cell

IL-6
CD80/ MHC II AgR B7RP-1/ " ! Superantigen
CD86 ICOSL
TCR
CD28 ICOS Variable region

!
IL-4 of ! chain (V!)
T H1
T IL-13
Upregulation
of ICOS IL-2
T H2
C. ICOS in T-cell activation D. Superantigen stimulation
CE

"
! -'*0($78,87 #$,$*0$ /$&&0

!"#$%"& '(&&)% *!+, -)&&. /"') $0 "%1$23 45 6 17

#8) &9/081-9#). (2 #8) :&113; <8)9 &"-' #8) %)=
"%%"2>)/)2# 17 >)2). -13(2> 71% "2#(>)2 %)-)0=
#1%. 71$23 (2 < "23 ? &9/081-9#).; !+ -)&&. 31
21# "##"-' -)&&. #8"# )@0%).. 21%/"& &)A)&. 17
BCD -&".. E /1&)-$&).F :$# #8)9 '(&& -)&&.
G(#8 71%)(>2 BCD.F ". G)&& ". -)&&. G(#8 3)=
-%)".)3 1% ":.)2# BCD E )@0%)..(12; <8(. (.
"2 )A)2# #8"# (. 7%)H$)2#&9 .))2 (2 A(%"& (27)-=
#(12. "23 -"2-)%; !+ -)&&. -"2 :) (3)2#(7()3 (2
0)%(08)%"& :&113 ". &"%>) &9/081-9#). G(#8
"I$%108(&(- *%)3, >%"2$&). *&"%>) >%"2$&"% &9/=
081-9#).F JKJ.,;
=>*?3)$*+3& @48*78(&$0
!(&&)% -)&& "//$21>&1:$&(2=&(') #)-)0#1%. *+EY.,
"23 "//$21>&1:$&(2=$(') %%"2.-%(0#. *EJ<.F
"&.1 '21G2 ". $)$'1-9#) "//$21>&1:$&(2=
&(') #)-)0#1%.F JEY.,; ^8(&) +EY. "%) )@0%)..)3
12&9 12 !+ -)&&. "23 12 " .$:>%1$0 17 < -)&&.F
EJ<.LJEY. "%) "&.1 )@0%)..)3 12 /121-9#).F 3)2=
3%(#(- -)&&.F "23 ? -)&&.; <8).) %)-)0#1%. -"2
/)3("#) "-#(A"#(12 1% (28(:(#(12F 3)0)23(2>
/"(2&9 12 #8) .#%$-#$%) 17 #8)(% (2#%"-9#10&".=
/(- #"(&.; E2 /1.# -".).F " &12> -9#10&"./(- #"(&
(23(-"#). #8) 0%).)2-) 17 "2 !!!"#$%&'&()$%
"*%$+,#&-%,'. !#.,/,)$%* #$),0 *E<EB,; E<EB #%(>=
>)%. " .0)-(7(- 081.08"#".)F G8(-8F (2 #$%2F
:&1-'. #8) (2#%"-)&&$&"% #%"2.3$-#(12 17 .(>2"&.

!" #$%$&'()$*+ ', -. /$&&0
D1//12 !+=-)&&L<=-)&& 0%1>)2(#1%. )@0%)..(2>
DMNF DMOF "23 .1/)#(/). DMP "%) 71$23 (2 #8)
:12) /"%%1GF (2 #8) 7)#"& &(A)%F "23 (2 #8) #89=
/$.; EJ=4PF G8(-8 (. 0%13$-)3 ":$23"2#&9 :9
:12) /"%%1G .#%1/"& -)&&.F (. -%$-("& 71% !+=
-)&& 3(77)%)2#("#(12Q EJ=O "23 EJ=4R 0%1/1#)
#8) 7$%#8)% /"#$%"#(12 17 !+ -)&&.;
<8) &1G="77(2(#9 %)-)0#1% 71% #8) S- 01%#(12
17 E>K *DM4T, "23 #8) DMPT "38).(12 /1&)-$&)
"%) #90(-"& !+ -)&& /"%')%.;
7%1/ "-#(A"#(2> %)-)0#1%.; Y)-)0#1%. G(#8 "
.81%# -9#10&"./(- #"(& &"-' E<EB "23 "..1-("#)
G(#8 #%"2.3$-(2> 01&90)0#(3).F .$-8 ". #8)
"3"0#)% /1&)-$&). MV\4O 1% S-Y#F G8(-8 -12=
#"(2 !!!"#$%&'&()$% "*%$+,#&-/1+&2 $'),31),#4
#$),0 *E<VB,F (2 1%3)% #1 #%"2.3$-) "-#(A"#(2>
.(>2"&.; B1%) #8"2 " 31I)2 3(77)%)2# %)-)0#1%.
8"A) :))2 3)7(2)3 71% :1#8 #8) +EY "23 JEY 7"=
/(&().; V #8(%3 -&".. 17 !+ -)&& %)-)0#1%. :)&12>.
#1 #8) D=#90) &)-#(2=&(') %)-)0#1% 7"/(&9 *.$-8
". #8) "&%)"39 /)2#(12)3 "-#(A"#(2> !+KOM %)=
-)0#1%,; V&#81$>8 /1.# !+ %)-)0#1%. )@(.# (2

" 1" 2345$+ 6$7'5*8+8'* 9: -. /$&&0

B1.# "-#(A"#(2> "23 (28(:(#1%9 !+ -)&& %)-)0#1%.
"%) -13)3 71% :9 >)2). 12 -8%1/1.1/) 4U; V-=
#(A"#(2> %)-)0#1%.F .$-8 ". !+0WTF !+0X5F "23
!+0WW *2"#$%"& -9#1#1@(-(#9 %)-)0#1%.F !DY.,F
:1#8 "-#(A"#(2> "23 (28(:(#1%9 (.171%/.F (# "0=
0)"%. #8"# (28(:(#1%9 .(>2"&. :9 E<EB=:)"%(2>
%)-)0#1%. &"%>)&9 0%)A"(& 1A)% #8) "-#(A"#(2> .(>=
2"&.; _1/) (28(:(#1%9 /1&)-$&). G(#8 #8)(% -1%=
%).0123(2> &(>"23. "%) .81G2 (2 &;

"&&1G !+ -)&&. #1 Z31-'[ 12#1 #"%>)# -)&&.; #" /:+'&:+87 ;$7<3*80)0 ', -. /$&&0
<8)9 :)&12> #1 #8) (//$21>&1:$&(2 *E>, .$0)%=
7"/(&9 "23 8"A) .81%# (2#%"-9#10&"./(- #"(&.; !12.)-%)#1%9 &9.(. (. (2A1&A)3 G8)2 #8) #"%>)#
-)&&. 8"A) 1($()$+,+ %&'&()$%+F .$-8 ". #8) DMUP
<8)%)71%)F #8)9 2))3 #1 "..1-("#) G(#8 #%"2.3$=
"2#(>)2 *"&.1 -"&&)3 S". 1% V\`=4, *'(),F G8(-8
-(2> 01&90)0#(3).F .$-8 ". #8) ! -8"(2F S-"YE#F
#%(>>)%. " #90) 17 Z-)&& .$(-(3)F[ %)7)%%)3 #1 ".
"23 MV\4OF (2 1%3)% #1 #%(>>)% !+ -)&& "-#(A(#9;
(%$4%1!!&2 '&55 2&1). 1% 1($()$+,+ *.)) 0; NW,;
<8)(% &(>"23. "%) .#(&& $2'21G2; V 71$%#8 #%(>=
>)%(2> %)-)0#1% (. !+KOMF " D=#90) &)-#(2 <8) /1.# -1//12 /)-8"2(./ 17 &9.(. :9 !+
-)&&. (. #8) %)&)".) 17 &9#(- >%"2$&). *'(*,; <8)
81/13(/)%F G8(-8 "..1-("#). G(#8 #8) #%"2.=
>%"2$&). -12#"(2 (&%0$%,#F " 0%1#)(2 #8"# -%)"#).
3$-(2> /1&)-$&) MV\45; <8) !+KOM %)-)0#1%
01%). (2 #8) /)/:%"2) 17 #8) 81.# -)&&F "23
(2#)%"-#. G(#8 BCD -&".. E=%)&"#)3 0%1#)(2.
>%"2I9/).F " >%1$0 17 3(77)%)2# 0%1#)(2".).;
-"&&)3 BEDV "23 BED?F G8(-8 "%) )@0%)..)3
E2 #8) 0%).)2-) 17 0)%71%(2F >%"2I9/) ? %)"-8).
G)"'&9 (2 21%/"& -)&&. :$# "%) $0%)>$&"#)3 (2
#8) -)&& 2$-&)$.F G8)%) (# "-#(A"#). -".0".).
.#%)..)3 -)&&. "23 (2 #$/1% -)&&.; <8).) 0%1#)(2.
*(/01%#"2# "010#1.(.=0%1/1#(2> 0%1#)(2.,F (2=
"%) .(/(&"% #1 -&"..(-"& BCD E /1&)-$&). :$# 31
3$-(2> -)&& 3)"#8; !+ -)&&. -"2 3).#%19 "2#(=
21# :(23 0)0#(3). "23 31 21# "..1-("#) G(#8 $O=
:139=-1"#)3 -)&&.; ?(23(2> 17 #8) "2#(:139 #1
/(-%1>&1:$&(2;

!
#8) S- %)-)0#1% 12 " !+ -)&& *DM4T, "-#(A"#).
B"29 %)-)0#1%. "%) (2A1&A)3 (2 #8) %)-1>2(=
#8) -9#1&9#(- 0%1>%"/ 17 +2#(:139=,)0)23)2#
#(12 17 -&"..(-"& BCD /1&)-$&).; E2 -12#%".# #1
-)&&=/)3("#)3 -9#1#1@(-(#9 *VMDD, :9 (23$-(2>
"2#(>)2=.0)-(7(- < -)&&.F #8).) %)-)0#1%. $.$"&&9
#8) %)&)".) 17 0%1#)1&9#(- )2I9/). *'(.,;
%)-1>2(I) " G81&) .)# 17 3(77)%)2# CJV -&".. E
AB "&&)&). :$# 21# #8) 0)0#(3)LBCD -1/0&)@;
<8)9 -"2 :) >%1$0)3 (2 #G1 &"%>) 7"/(&().]
 T progenitor cell CD34+
CD33-
-3+>43& .8&&$4 /$&&0
!
CD2+
TCR CD7+ Further
rearrangement CD5+ T-cell development
CD1+
Thymus CytCD3+
IL-7
CD34
CD33
T/NK-progenitor cell
CD7
NK progenitor cell Mature NK cell
CD2+/- CD34- CD34-
CD5+/- CD33- CD7+
Bone marrow
IL-5 CD7+ CD2+/-
CytCD3 CD2+/- CD5-
CD5- CD1-

=>*?3)$*+3& @48*78(&$0
CD1- CD16+/-
CD16- CD56+
Fetal liver T/NK CD56-

A. Development of NK cells

Target CD95 APO-1 NK cell

cell Fas
Unknown NKp30,44,46 ligand
carbo-
hydrate?

"
NKG2D DNA-
fragmentation
MICA
Activation
MICB
NKR-P1
Apoptosis
Inhibition
1. Nonsecretory lysis
MHC I
KIR3DL1 Target Formation of pores Degranulation
cell Granzyme
Perforin

B. Target recognition by NK cells

DNA-
fragmentation

Cw2,4,5,6 KIR2DL1
Apoptosis +necrosis
2. Secretory lysis
Cw1,3,7,8 KIR2DL2
Target Perforin NK cell
cell Granzyme
Bw4
KIR3DL1

A3, A11
KIR3DL2 DNA Antibody
fragmentation against

HLA-E

C. Inhibitory receptors of
C. NK cells
CD94
+
NKG2A
Apoptosis + necrosis

D. of NK cells
target
antigen
Fc-receptor

3. ADCC (antibody-dependent cellular cytotoxicity)

D. Cytolytic mechanisms
!
AC

"
! 1)2)*+,%. '26 :%26=3,3* 7%>>.
!" #$% &$'()*+,% -+.,%/
!"#$%&'()*+,- .'$'()*+,- #$/ /+$/"0*0( (+&&,
123,4 5#6+ 75#8'()*0( (#7#90&0*0+, 1:"'. *5+
!"++; <'"/ !"#$%&' = *' +#*4> ?5+) #&& /+"06+
:"'. 9&''/ 7"'8+$0*'" (+&&,@ *5+ ()*';0$+ 8"#$A
%&'()*+ ('&'$)A,*0.%&#*0$8 :#(*'" 1!A3BC4 7"'A
.'*+, *5+ /0::+"+$*0#*0'$ 0$*' 8"#$%&'()*+,-
<50&+ 8"#$%&'()*+A.#("'75#8+ ('&'$)A,*0.%A
&#*0$8 :#(*'" 1!DA3BC4- EFAG- #$/ *%.'" $+("',0,
:#(*'"A! 1?HCA!4 7"'.'*+ /0::+"+$*0#*0'$ 0$*'
.'$'()*+, #$/ 23,> ?5+ $'".#& :#*+ ': (0"(%&#*A
0$8 .'$'()*+, 1*5+0" 5#&:A&0:+ 0$ *5+ 9&''/ 0,
'$&) # :+< 5'%",4 0, *' /0::+"+$*0#*+ 0$*' *0,,%+
8?26'/%2,'> &=32*3<>%.
75#8'()*+,> ?5+ .#("'75#8+, "+.#0$ 0$ *5+
*0,,%+ :'" *5+ "+,* ': *5+0" &0:+*0.+ 1%7 *' )+#",4>
D'$'()*+, #"+ &#"8+" *5#$ &).75'()*+,> ?5+)
5#6+ # $%(&+%, *5#* 0, 5'",+,5'+A,5#7+/ '" 90A
I#""+&) ,5#7+/- #$/ *5+) 5#6+ # 9"'#/ "0. ':
()*'7&#,. <0*5 8"#$%&+, ('$*#0$0$8 +$I).+,
17+"'J0/#,+ #$/ 5)/"'&#,+,4> 23, #"+ &#"8+-
.'90&+ (+&&, <0*5 &'$8 ()*'7&#,.0( 7"'(+,,+,
1,'.+ !KL ".4> 23, #"+ ,+&/'. :'%$/ 0$ *5+
9&''/M *5+0" 7"+(%",'", .08"#*+ 0$*' *5+ ,;0$
*' :'". *5+ F#$8+"5#$, (+&&, ': *5+ +70/+".0,
#$/ /+".#& 23,- '" 0$*' *5+ &).75 $'/+,-
"
<5+"+ *5+) 806+ '"080$ *' !$*+"/080*#*0$8 "+$A
/"0*0( #+&&, 1E234 0$ *5+ ?A(+&& #"+#, #$/ *' $+".A
0$#& #+$*+" "+$/"0*0( #+&&, 1!3234> N /0::+"+$*
&0$+#8+ ': 23,- (#&&+/ &).75'0/ 23 '" *)7+AO
23- /0::+"+$*0#*+, :"'. 7"'8+$0*'" (+&&, 0$ *5+
7"+,+$(+ ': EFAP #$/ *5+ ()*';0$+ C&*PF> ?5+)
&'(#*+ 0$ *5+ 7#"#('"*0(#& "+80'$ ': *5+ &).75
$'/+,> E* 5#, 9++$ ,%88+,*+/ *5#* *5+) ('$,*0A
*%*+ *5+ *5).0( 23 7'7%&#*0'$>
0" 1%*$'23./. )4 526)*+,).3.
Q7*#;+ ': ,.#&& :&%0/ 7#"*0(&+, 170$'()*',0,-
:"'. *5+ !"++; <'"/ !&'%&' = *' /"0$;4 9+80$,
<0*5 *5+ :'".#*0'$ ': .+.9"#$+ 0$/+$*#*0'$,-
<50(5 0, /"06+$ 9) # 7"'*+0$ ('.7&+J (#&&+/
()#*"+&'> 3&#*5"0$A('#*+/ 6+,0(&+,- '" R('#*+/
70*,-S :%,+ <0*5 &),','.+,- <5+"+ *5+ #$*08+$,
#"+ /08+,*+/> E$ .#("'70$'()*',0,- *5+ (+&& (#$
#9,'"9 &#"8+ /"'7, %7 *' L>T ". 0$ ,0I+> U#*+"
0, +J7+&&+/ *5"'%85 (5#$$+&,- (#&&+/ #V%#7'"A
0$,> W'&).+"0I#*0'$ ': *5+ ()*',;+&+*'$ 7"'*+0$
#(*0$ 0, $++/+/ :'" *5+ :'".#*0'$ ': &#"8+" 75#A
!
8'()*0( 6+,0(&+,> F#$8+"5#$, (+&&, ': *5+ ,;0$
%*0&0I+ X0"9+(; 8"#$%&+, 1,.#&& 6+,0(&+, <0*5 #
*)70(#& $#""'< $+(;4 :'" 75#8'()*',0,> B'.+
9#(*+"0# 1+>8>- ,%$&-'%))# !'%./-!"&)#4 #"+ 0$*+"A
$#&0I+/ 9) ('0&0$8 75#8'()*',0,- <5+"+9) # ()A
@A *'7&#,.0( 7"'*"%,0'$- (#&&+/ 7,+%/'7'/0%.-
,70"#&, #"'%$/ *5+ 9#(*+"0%. *' :'". # R('0&0$8
75#8','.+>S ?5+ .+.9"#$+, ': *5+ 7,+%/'A
7'/0%. *5+$ :%,+- "+&+#,0$8 *5+ 7#*5'8+$ <0*5A
0$ *5+ ()*'7&#,.>
7" 8*91%63',%6 &$'()*+,).3."
B+6+"#& "+(+7*'", (#$ 90$/ *5+ C( 7'"*0'$ ':
0..%$'8&'9%&0$, 1,++ 7> GP4> Y+(+7*'", :'"
E8!- E8N- #$/ E8Z #"+ (#&&+/ C(#Y- C(!Y- #$/
C($Y "+,7+(*06+&)> ?5+,+ "+(+7*'", ,08$#&
*5"'%85 0..%$"+(+7*'" *)"',0$+A9#,+/ #(*06#A
*0'$ .'*0:, 1E?ND,4- <50(5 #"+ 0$*"#()*'7&#,.0(
/'.#0$, ('$,0,*0$8 ': *<' *)"',0$+ 1[4 "+,0/%+,
,+7#"#*+/ 9) \AKO #.0$' #(0/,> ]$ &08#*0'$- *5+
*)"',0$+, 0$ *5+,+ E?ND /'.#0$, 9+('.+ 75',A
75'")&#*+/- &+#/0$8 *' *5+ "+("%0*.+$* ': *5+
*)"',0$+ ;0$#,+ B);- <50(5 *5+$ *"088+", /0::+"A
+$* 0$*"#(+&&%&#" ,08$#& (#,(#/+,- &+#/0$8 *'
*"#$,("07*0'$#& #(*06#*0'$- ()*',;+&+*#& "+#""#$A
8+.+$*- #$/ "+&+#,+ ': 0$:&#..#*'") .+/0#A
*'",> C(#YEEAN 5#, 0*,+&: #$ E?ND .'*0: 0$ 0*,
0$*"#(+&&%&#" 7'"*0'$- <50&+ C(#YE #$/ C(#YEEE
&#(; E?ND, 0$ *5+0" ()*'7&#,.0( *#0&,> ?5+)
0$*+"#(* "+,7+(*06+&) <0*5 #A #$/ %A*"#$,/%(0$8
7"'*+0$,- <50(5 ('$*#0$ *5+ E?ND, $++/+/ :'"
,08$#& *"#$,/%(*0'$>
:" 1'22).% ;%*%<,)=
D#("'75#8+, #$/ 23, (#$ "+('8$0I+ *5+ ,%8#",
.#$$',+ #$/ :%(',+- <50(5 #"+ 7"+,+$* '$
/0::+"+$* 7#*5'8+$,- *5"'%85 *5+ .#$$',+ "+A
(+7*'" 1DY4- # .'&+(%&+ <0*5 # &'$8 +J*"#(+&&%A
&#" 7'"*0'$ ('$,0,*0$8 ': .%&*07&+ 1#* &+#,* ^4
&+(*0$A&0;+ /'.#0$,> DY &08#*0'$ &+#/, *' *5+
"+&+#,+ ': ()*';0$+,- ,%(5 #, EFAK&- EFA_- !DA3BC-
?HCA!- #$/ EFAKO>
5" 7)/<>%/%2, ;%*%<,)=91%63',%6
&$'()*+,).3.
B+"%. ('.7&+.+$* 7"'*+0$, ('#* 1'7,'$0I+4
#&*+"+/ "+/ 9&''/ (+&&, '" 9#(*+"0#> ?5+ ('.7&+A
.+$* "+(+7*'", 3YK- 3YP- #$/ 3YG #"+ 7"+,+$*
'$ .'$'()*+, #$/ .#("'75#8+,> 3YK 90$/, *'
*5+ ('.7&+.+$* :"#(*0'$, 3P9- 3G9- #$/ 3P90>
3YP #$/ 3YG 1,++ 7> GP4 90$/ ,7+(0:0(#&&) *'
3P90> 3'.7&+.+$*A('#*+/ 7#"*0(&+,- ,%(5 #,
,+$+,(+$* "+/ 9&''/ (+&&,- ,0$; /0"+(*&) 0$*'
*5+ (+&&- #&.',* <0*5'%* 7,+%/'7'/0# :'"A
.#*0'$> E$ *50, 7"'(+,,- *5+ 7"'*+0$, 60$(%&0$-
7#J0&&0$- #$/ CA#(*0$ #"+ 0$6'&6+/> ?5+"+ 0, $'
"+&+#,+ ': 7"'0$:&#..#*'") ()*';0$+,>
 Stem cell
Flt3L IL-3
#$% &$'()*+,% -+.,%/
!
IL-3
SCF Thymic DC
Lymphoid DC
M-SCF
in lymph nodes
IL-3 Promyelocyte
Promonocyte IDC
Granulocytes SF
GM-C
F
G-CS
M-CSF Langerhans cell
IL-3 Dendritic cell in skin/mucosa
Monocyte precursor
GMCSF GCDC
IL-4

8?26'/%2,'> &=32*3<>%.
Dermis/
Interstitial DC

Mesangial Tissue LN/spleen Alveolar Serosa

Kupffer cells cell Microglia macrophage monocyte macrophage macrophage
A. The phagocyte system
0.5 µm

Clathrin
Coated pit Actin
H2O

polymerization
"
1. Pinocytosis 2. Phagocytosis 3. Coiling phagocytosis
B. Mechanism of endocytosis

IgG opsonized particle

Mannose
or fucose C3bi
Fc#RIIA Fc#RI Fc#RIII
i CR4
C3b
C4b C3b CR3
I y I y
T P T P
I
T
y P A y A y Actin CR1
M P M P
A y P Myosin
M
k

k
Sy

Sy
k
Sy

Binding

!
IL-12
– Cytoskeleton – Internalization
IL-1!
rearragement – Actin, vinculin, paxillin
IL-6
– Release of – No inflammatory
TNF-"
inflammatory mediators released
mediators
E. Complement receptor-
C. Fc-mediated phagocytosis D. Mannose receptor mediated phagocytosis
@B

"
! +)%)&,'-. /%0 6-%01('(& 7-88.

!" #$%&'()% )* +)%)&,'-. /%0 +/&1)23/4-."

!"#"$%&'( )#* +)$,"-.)/'( ),' 0+-",&)#& )$1
$'((",% $'22( 3", &.' /'#',)&0"# "3 .0/.2% (-'$01
2'#&2% 6"5#*7 A>V1B; KWP; )#* KWU .)4' 0*'#&01
$)2 XY 9Z) # $.)0#( &.)& ),' ,'$"/#0E'* 6% )#&01
)>:? )#&06"*0'(7 8.' &.,'' " $.)0#( ),' 2),/',
+"2'$52'( "3 BLQ 9Z) :)>::&@;B[Q 9Z) :)>::@@;
30$ )*)-&04' 0++5#' ,'(-"#('( 65& )2(" $,5$0)2
)#* BYQ 9Z) :)>::"@7
+'*0)&",( "3 &.' 0##)&' 0++5#' ,'(-"#('7
V /'#'&0$)22% ,'2)&'* )6('#$' "3 &.' # $.)0#
8.'% $)# )2(" 6' )$&04)&'* 0# ,'(-"#(' &"
2')*( &" ) 2'59"$%&' )*.'(0"# *'3'$&; D.0$. 0(
$%&"90#'( :'7/7; 0#&',3',"#1!< =>?1!@ ,'2')('*
,'32'$&'* 6% )# 'G&,'+'2% .0/. (5($'-&06020&%
6% 8 $'22(7 !"#$%&#$'( "3 +"#"$%&'( )#* +)$,"1
&" 0#3'$&0"#(7
-.)/'( 2')*( &" &.' ('$,'&0"# "3 *033','#& $%&"1
)>:= )#* )>A? ),' 'G-,'(('* "# +"#"$%&'(
90#'(; (5$. )( =A1B; 8?>1"; )#* =A1C; D.0$. ),'
0# &.' -',0-.',)2 62""* :KZBU@ )#* "# &0((5'
,'(-"#(062' 3", (%(&'+0$ :/'#',)20E'*@ '33'$&(7
+)$,"-.)/'( :KZCL@7 KZBU 0( ) ,'$'-&", 3",
F"&. 90220#/ "3 -.)/"$%&"('* 6)$&',0) )#* ,'1
&.' $"+-2'G "3 20-"-"2%()$$.),0*' :A\]@ )#*
2')(' "3 $%&"90#'( ),' +'*0)&'* 6% #0&,0$ "G0*'
A\]160#*0#/ -,"&'0#7 F)$&',0)2 A\] 0( ) -"D',352
#$%0/9-%'/8 :1(%&(28-.

:?H@; ) $'2252), +'&)6"20&' -,"*5$& D0&. ) 6,")*

+0&"/'#; D.0$. 2')*( &" )# 0#$,')('* ,'2')(' "3
,)#/' "3 '33'$&(7 =A1B; 8?>1"; )#* =A1C $)5(' &.'
0#32)++)&",% +'*0)&",( )#* &" 0#$,')('* +01
204', &" ,'2')(' I)$5&'1-.)(' -,"&'0#(;J (5$. )(
$,"60$0*)2 )$&040&%7 KZCL 0( ) 2%("("+)2^'#*"("1
K1,')$&04' -,"&'0# )#* +)##)#160#*0#/ 2'$&0#;
+)2 /2%$"-,"&'0#7
D.0$. "-("#0E' -)&."/'#( )#* 3)$020&)&' &.'0,
!"#"$%&'( 'G-,'(( ,'$'-&",( 3", &.' >$ -",1
'20+0#)&0"#7 =A1B; 8?>1"; )#* =A1C )2(" )$& "#
&0"# "3 =/M 0++5#"/2"6520#(7 8.',' ),' &.,''
&.' .%-"&.)2)+5( ,'/0"# "3 &.' 6,)0#; 0#*5$0#/
&%-'( "3 ,'$'-&",( $.),)$&',0E'* 6% .0/. :>$!W=
3'4', )#* +"6020E)&0"# "3 #'5&,"-.02( 3,"+ &.'
_ )>A=@; +'*05+ :>$!W== _ )><B@; )#* 2"D )31
6"#' +),,"D &" &.' 62""* :2'59"$%&"(0(@7 =A1B
30#0&% :>$!W=== _ )>:A@7 KZCU 0( -,'*"+0#)#&2%
)#* 8?>1" 0#$,')(' 4)($52), -',+')6020&%; 3)$021
'G-,'(('* 0# +"#"$%&'(; KZPR 0# /,)#52"$%&'(;
0&)&0#/ +0/,)&0"# "3 $'22( 0#&" &0((5'7 )*+,'-
)#* KZBC 0# #)&5,)2 9022', :?`@ $'22(7 M,)#52"1
#&.$/ 0( +'*0)&'* 6% =A1L; D.0$. (%#',/0E'(
$%&'( )2(" 'G-,'(( )# 0("3",+ "3 &.' KZBC +"1

"
D0&. &.' 0#$,')('* 4)($52), -',+')6020&% 0#
2'$52'; D.0$. 0( )#$.",'* 0# &.' +'+6,)#' 6%
,'$,50&0#/ /,)#52"$%&'( )#* $)5(0#/ #$//0+ $(-
/2%$"(%2)&'* -."(-.)&0*%20#"(0&"2 :M\=@7 =/MB
12&,,&#$'(7 M,)#52"$%&'( )#* +)$,"-.)/'(
)#* =/MP 60#* 4',% (&,"#/2% &" >$ ,'$'-&",(;
$""-',)&' 0# &.' 3*&4'"5#'/$/ "3 -)&."/'#(
D.',')( =/MR )#* =/MU $,')&' D')9 6"#*(7
)#* ,'+"4)2 "3 *)+)/'* &0((5' :/"&%+(4+6
!5,0#' )#&06"*0'( $)# )2(" 60#* &" .5+)# >$
10("#$'(@ 6% +')#( "3 -,"&'"2%&0$ *0/'(&0"#;
,'$'-&",(< =/MR) )#* =/MP 60#* 4',% D'22; 65&
3"22"D'* 6% &0((5' ,'-)0,; D.0$. 0( 3)$020&)&'*
=/MB *"'( #"&7
6% #'D 4'(('2 3",+)&0"# :)#/0"/'#'(0(@7 8?>1
8.' )>=C; )>?CD )#* )>?A )#&0/'#( ),' $"1
" )#* =>?1! (%#',/0E' 0# 0#*5$0#/ (%#&.'(0(
(&0+52)&",% +"2'$52'( 3", )#&0/'# -,'('#&)&0"#
"3 &.' ,')$&04' #0&,"/'# +'&)6"20&' ?H; D.0$.
:('' -7 PC@7 8.'% ),' 'G-,'(('* "# F $'22(; +"#"1
0( ,'(-"#(062' 3", ("+' "3 &.' +11+"#'6 10("-
$%&'(; )#* *'#*,0&0$ $'22( :ZK(@7
#$'(/ "3 +"#"$%&'( )#* +)$,"-.)/'(; '7/7;
8.' )>?< )#&0/'# 0( 5('352 3", &.' $.),)$&',1
90220#/ "3 0#&,)$'2252), 6)$&',0) )#* &5+", $'22(7
0E)&0"# "3 &.' +)&5,)&0"# (&)/' "3 ZK( )( 0& 0(
H&.', ,')$&04' "G%/'# 0#&',+'*0)&'( :?H ,)*01
-"(0&04' "#2% "# +)&5,' ZK(7 =& 0( )2(" -,'('#&
$)2(; ?HN1; ?HNO@; )( D'22 )( -,"&')('(; -),&0$0-)&'
"# ("+' /',+0#)2 $'#&', F $'22( )#* "# )$&01
0# &.'(' -,"$'(('(7 !"#"$%&'( ),' 0+-",&)#& 0#
4)&'* 8 $'22(7 =& (''+( &" -2)% ) ,"2' 0# $'22 )*1
&(#$4+( 36+/+(#&#$'( &" 8 $'22( :('' -7 PC@7 F%
.'(0"#7
,'2')(0#/ &.' $%&"90#'( =A1BQ )#* =A1BR; &.'% )$&
8.' )>BCA )#&0/'#D ", ,&(('/+ 6+"+3#'6; 0(
)( $,5$0)2 ,'/52)&",( "3 81$'22 ,'(-"#('( 0# &.'
) K1&%-' 2'$&0# :2'$&0#( 60#* &" $),6".%*,)&'(@
,'702&#$'( "3 8SB 4(! 8SR ,'(-"#('(7
&.)& 0( 'G-,'(('* "# +)$,"-.)/'( )#* ZK(7 =&
60#*( D0&. .0/. )330#0&% &" +)##"('1(5/), ,'(01
5" +)%)&,'-. /%0 6-%01('(& 7-88 !%'(4-%.
*5'(; D.0$. ),' -,'('#& "# +)#% -)&."/'#(

!
!"#"$%&'( .)4' &.,'' 0+-",&)#& )*.'(0"#
,'$'-&",(T 2'59"$%&' 35#$&0"#1)(("$0)&'* )#&01
/'#1B :89!-:@ )#* $"+-2'+'#& ,'$'-&",( P
)#* U :);< )#* );=@7 8.'(' )#&0/'#( ),' +'+1
6',( "3 &.' "#$%&'"# 3)+02%; ) 2),/' 3)+02% "3
;< +"2'$52'( $"#(0(&0#/ "3 &D" -"2%-'-&0*'
(565#0&( :" )#* # $.)0#(@ &.)& ),' #"#$"4)1
:6)$&',0); 40,5('(@7 V (0+02), (&,5$&5,' $)22'*
)>BCE 0( 3"5#* "# ZK( )#* (',4'( )( )# )#&0/'#
5-&)9' ,'$'-&",7
8.' )>:& )#&0/'# 0( ) !SK $2)(( =1209' +"1
2'$52'; D.0$. 0( 5('* 3", &.' -,'('#&)&0"# "3 201
-0* )#&0/'#(; &%-0$)22% 'G-,'(('* "# 0++)&5,'
ZK( )#* A)#/',.)#( $'22(7
 1. Activation 2. Chemotaxis, tissue inflammation
+)%)&,'- #$%&'()% /%0 !%'(4-%.

3. Phagocytosis, scavenger
!
Bacteria, LPS TNF-$ IL-8 function, tissue repair
IL-1
TNF-$
IL-1 NO Elastase
IL-6
Collagenase
IFN-# – fibrogenic stim-factor
Acute phase – angiogenic factors
proteins

IL10 – NO
GM-CSF – H2O2
IL12 – O2
TH2 – Toxic factors – Lysozyme
T H1 TNF-$ – TNF proteases – Hydrolase
4. Effector function

#$%0/9-%'/8 :1(%&(28-.
6. Immunomodulation 5. Antigen presentation
A. Function of monocytes/macrophages
Molecule Molecular- Gene locus Cell expression Function
weight (kDa) (chromosome)
CD11a CD11a: 180 16p11-13.1 Monocytes, !", Cell–cell and cell–matrix
CD18: 95 21q22.3 lymphocytes (T-B), adhesion,
LFA-1 granulocytes ligand for ICAM-1, ICAM-2
CD18

CD11b CD11b: 170 16p11-13.1 Myeloid cells, Cell–cell and

CD18: 95 21q22.3 NK cells cell–matrix adhesion,
CR3 ligand for iC3b,
C4b, ICAM-1

"
CD18
CD11c CD11c: 150 16p11-13.1 Macrophages, Cell–cell adhesion,
CD18: 95 21q22.3 myeloid cells ligand for iC3b, C4b,
CR4 ICAM-1, LPS,
fibrinogen
CD18
55 5q31 Monocytes, !", Receptor for LPS
CD14
granulocytes, (B cells) and LPS/LPB complex

50–80 1q23 Monocytes, !", Low-affinity

or CD16 NK cells, Fc-lgG receptor
(FcRIII) granulocytes (GPI)

40 1q23-24 Phagocytes, B cells, Intermediate-

CD32 (FcRII) platelets affinity Fc-lgG receptor

72 1q21 Monocytes, High affinity Fc-lgG

CD64 (FcRI) !" receptor

48 20q12- Pre-B cells, Interaction with

COOH

q13.2 mature B cells CD40 ligand (T cell),

CD40 dendritic cells (DC) anti-apoptosis signal
CD80/86 60 3q21 B cells, act. macrophages, T-APC interaction
COOH

dendritic cells (DC) (ligands for CD28/CTLA-4)

CD83 45 6p23 Mature dendritic cells, Adhesion receptor

some B cells and T cells
Phagocytes, Pattern recognition
180 10p13
Mannose receptors lymphoid endothelium receptor

!
CD1a 43–49 1q22-23 Thymocytes, DC Antigen presentation
(glycolipids)
110 17p13 Monocytes, !", Lysosomal
granulocytes, basophils, and endosomal
CD68 LGL lymphocytes glycoprotein

B: Monocytes and DC antigens

;=

"
! 9/(/+6)&3 2(* #&(*'$)$+ ,&--3
!"#$%&'&( ("))* +!,*- ./0" 12 )"** '3/# 456 7 89
/)) .8#8#1()"/% ("))* &# '3" :)88$ :1' /%" 2%";
*"#' &# /)) 8%</#*5 !,* 3/=" )8#< (>'82)/*.&(
2%8("**"* /#$ 8#)> / 9"? &#'%/(>'82)/*.&( 8%;
</#"))"* :1' / )/%<" #1.:"% 89 .&'8(38#$%&/5
@3"> 3/=" / 3&<3 )"=") 89 .8:&)&'>5 A#)> !,*
(/# 2%&." #/&=" @ ("))*5
!" #$%%&'&() #&(*'$)$+ ,&-- ./01-2)$/(3
!,* :")8#< '8 '3" .>")8&$ )&#"/<"5 @3"> $&99"%;
"#'&/'" 9%8. 3"./'828&"'&( 2%8<"#&'8% ("))* &#
%"*28#*" '8 @BC;!D EF;GD /#$ HI;,JC5 E# '3"
*0&#D !,* /%" 981#$ &# '3" "2&$"%.&* +F/#<"%;
3/#* ("))*D F,*- /#$ &# '3" $"%.&*5 F,* 3/="
;1(*28&()2- .'$(+$0-&3
(3/%/('"%&*'&( &#()1*&8#* +!"#$%&' (#)*+,%--D
2%8:/:)> "#$8*8."*D ?3&(3 2)/> / %8)" &# /#'&;
<"# 12'/0"5 K9'"% (/2'1%&#< /#'&<"#* &# '3" *0&#D
F,* :"<&# ./'1%/'&8# &# %"*28#*" '8 &#9)/../;
'8%> (>'80&#"*D *1(3 /* @BC;!D /#$ .&<%/'" '8
'3" @;(")) %"<&8# 89 )>.23 #8$"*D ?3"%" '3">
/('&=/'" /#'&<"#;*2"(&9&( @ ("))*5 I/'1%" .8#8;
(>'"* (/# $&99"%"#'&/'" &#'8 &#'"%*'&'&/) !,* &#
=/%&81* 8%</#*L / (%1(&/) *'"2 &# '3&* 2%8("**
&* '3" &#'"%/('&8# ?&'3 /$3"*&8# .8)"(1)"*
/#$ (3".80&#"* 89 "#$8'3")&/) ("))* $1%&#<
"
'%/#*"#$8'3")&/) .&<%/'&8#5 I8#8(>'";$"%&="$
!,* /#$ &#'"%*'&'&/) !,* .&<%/'" 2%"9"%"#'&/))>
'8 '3" <"%.&#/) ("#'"%* 89 )>.23 #8$"*D ?3"%"
'3"> (/# /('&=/'" :8'3 @ /#$ M ("))*5 I/'1%" !,*
/%" %/%")> 981#$ &# 2"%&23"%/) :)88$D :1' / *./))
2"%("#'/<" +45N;456 7- 89 :)88$ .8#8#1()"/%
("))* 3/* .8%238)8<&(/) /#$ &..1#8)8<&(/)
9"/'1%"* 89 &../'1%" !,*D &5"5D *./))"% (>'82)/*;
.&( 2%8'%1*&8#*D )8? )"=")* 89 IO, .8)"(1)"*D
/#$ )8? )"=")* 89 (8;*'&.1)/'8%> .8)"(1)"* /#$
'3" !,;/**8(&/'"$ /#'&<"# ,!PQ5 @3"*" ("))*D
(/))"$ !"#$%&$'D "R2%"** .>")8&$ /#'&<"#*D
*1(3 /* ,!NQD ,!NN(D /#$ ,!N(D /* ?")) /*
M!,K;Q5 A#(" &*8)/'"$ &# =&'%8D '3"> $&99"%"#'&;
/'" &#'8 '>2&(/) !,* &# %"*28#*" '8 EF;GD HI;,JCD
/#$ @BC;!5 @3"> *"(%"'" )/%<" /.81#'* 89 EF;NS
+'>2";N !, 8% !,;N-5
J8." %/%" .8#8#1()"/% ("))* 89 '3" :)88$ %";
*28#$ '8 EF;Q /#$ C)'QFD <&=&#< 8%&<&# '8 / ("))
2821)/'&8# '3/' )/(0* '3" .>")8&$ ,!NQ /#$
,!QQ /#'&<"#*D ?3&)" "R2%"**&#< *8." @;("));
/**8(&/'"$ /#'&<"#*D *1(3 /* ,!SD ,!6D /#$
,!TD /#$ '3" #"?)> $"9&#"$ /#'&<"#* M!,K;S
!
/#$ M!,K;GD /* ?")) /* @8));)&0" %"("2'8% U
+@FVU-5 @3"*" ("))* .&<%/'" '8 '3" 2/%/(8%'&(/)
%"<&8# 89 )>.23 #8$"* &# ()8*" /**8(&/'&8#
?&'3 3&<3 "#$8'3")&/) ="#1)"*5 H&="# '3"&% 28;
*&'&=&'> 98% @;("));/**8(&/'"$ /#'&<"#* /#$ '3"&%
<<
.8%238)8<>D '3"*" ("))* ?"%" $"*(%&:"$ &# '3"
2/*' /* W2)/*./(>'8&$ @ ("))*DX )/'"% /)*8 /*
W2)/*./(>'8&$ .8#8(>'"*5X @3"> /%" #8?
(/))"$ !"#$%&$(Y &# %"*28#*" '8 ,!G4 )&</'&8#
/#$ EF;QD '3"> /(Z1&%" '>2&(/) $"#$%&'&( .8%;
238)8<> /#$ *"(%"'" 3&<3 )"=")* 89 ECB;! /#$
EF;N4 +'>2";S !, 8% !,;S) 8% *#'"%9"%8# !%8$1;
(&#< +"))*D ,-&-5
4" 5$%& ,6+-& /% 2 #&(*'$)$+ ,&--
K#'&<"#* /:*8%:"$ '3%81<3 '3" *0&# /%" 2%8;
("**"$ :> F/#<"%3/#* ("))*D ?3&(3 '3"# .&<%/'"
&#'8 '3" "99"%"#' )>.23 '%/(' /* .%",%/ &%,,-D
'%/#*28%'&#< '3" /#'&<"# '8 '3" %"<&8#/) )>.23
#8$"*5 O"%"D '3"> 2%&." /#$ /('&=/'" ,!G!
@ ("))*5 K('&=/'"$ @ ("))* /(Z1&%" 3&<3 )"=")* 89
'3" ,!G4 )&</#$ /#'&<"# +,!N6G-D ?3&(3 &#
'1%# :&#$* '8 ,!G4 8# !,*5 C1%'3"% (8;*'&.1)/;
'&8# &* 2%8=&$"$ :> ,!SPD ?3&(3 &#'"%/('* ?&'3
,!P4[P\5 K('&=/'"$ @ ("))* 3"/$ 98% '3" /#'&<"#
"#'%> *&'"5 @3"> *"(%"'" (>'80&#"*D *1(3 /* EF;S
/#$ ECB;"D ?3&(3 2%8.8'" @;(")) 2%8)&9"%/'&8#
/#$ 91%'3"% (")) %"(%1&'."#'D 9&#/))> )"/$&#< '8
'3" /((1.1)/'&8# 89 @ ("))*D ./(%823/<"*D /#$
8'3"% &#9)/../'8%> ("))*5 @3&* %"/('&8# +$";
)/>"$;'>2" 3>2"%*"#*&'&=&'>- (/# :" $"'"('"$
/:81' GP 381%* /9'"% &#8(1)/'&8# 89 '3" /#'&<"#5
E' &* ./#&9"*'"$ :> '3" 98%./'&8# 89 %"$$&*3
2/21)"* +*"" 225 \\ /#$ UN-5
," 7&+'1$)8&() /% #&(*'$)$+ ,&--
.'&+1'3/'3 2(* #&(*'$)$+ ,&-- 9$:'2)$/(
@3" "2&'3")&/ 89 '8#*&)* /#$ <1' *"(%"'" '3"
(3".80&#" IE];Q!D ?3&(3 &* '3" )&</#$ 98%
'3" (3".80&#" %"("2'8% ,,V\ 2%"*"#' 8# &.;
./'1%" !,* +/#$ /)*8 8# @ ("))* '3/' .&<%/'"
&#'8 <1' "2&'3")&/-5 IE];Q! &* &#$1("$ $1%&#<
&#9)/../'8%> 2%8("**"* /#$ ."$&/'"* (3".8;
/''%/('&8# 98% &../'1%" !,* /#$ F/#<"%3/#*
("))*5 A# ./'1%/'&8#D !,* )8*" ,,V\ "R2%"**&8#D
*8 '3"> "*(/2" 9%8. '3" )8(/) <%/$&"#' 89
IE];Q! /#$ /(Z1&%" '3" (3".80&#" %"("2'8%
,,VT5 @3&* ./0"* '3". %"*28#*&=" '8 '3" (3";
.80&#"* IE];Q# /#$ JF, +."(8#$/%> />.238&$
'&**1" +3".80&#"-D ?3&(3 /%" %")"/*"$ /#$
:81#$ :> )>.23/'&( ="**")*D "#$8'3")&/) ("))*D
/#$ *'%8./) ("))* 89 '3" )>.23 #8$"*5 @ ("))*
/%" /)*8 $%&="# '8 '3" )>.23 #8$"* :> '3&* (3";
.80&#" <%/$&"#'5 E# '3" @;(")) /%"/ 89 )>.23
#8$"*D !,* (/# &#'"%/(' ?&'3 /#'&<"#;*2"(&9&(
@ ("))*5 F>.23 #8$";%"*&$"#' !,* '3".*")="*
2%8$1(" JF, /#$ IE];Q#D )"/$&#< '8 91%'3"%
@;(")) %"(%1&'."#' +&(- /#$ !, /''%/('&8#D
?3&(3 %"*1)'* &# /# /.2)&9&(/'&8# 89 '3" &.;
.1#" %"*28#*"5
 CD34+cell
#&(*'$)$+ ,&-- ./01-2)$/(3
!
Flt3L, IL-3
Thymic
DC
TNF-! M-CSF GM-CSF
GM-CSF IL-4
TNF-!
IL-3
CD11c+
CD11c+ CD1c+ CD123+
CD13+ BDCA3+ CD2/5/7 (+)
CD1a+ CD33+ CD11c+ BDCA2+
CD14+ CD13+ BDCA2+
CD1c+ Pre-DC-1 BDCA4+
Monocyte Pre-DC-2 TLR9+
Langerhans cell LPS CD40 ligation
Endothelium transmigration CD40 ligation viral infection

;1(*28&()2- .'$(+$0-&3
Ag
uptake HEV “Lymphoid”
DC2
IDC Interstitial DC GCDC Myeloid DC 1

– LPS CD83+
– Bacterial
products
A. Different DC populations

Langerhans- Veiled Interdigitating DC

Antigen
cell cell

HLA-DR CD40
CD40L

T
"
CD80/
Eosinophils CD86 CD28

Macrophages IL-2
T cells NK cells IFN-"

B. Life cycle of a dendritic cell Activated T cell

Epithelium (Tonsil, gut) SLC

CCR7
MIP-3! MIP-3!
CCR6 MIP-3#
Mature DC

Immature
DC
CCR7

Lymphatic vessel

1. Migration to and from inflamed tissue

SLC

C. Recruitment of dentritic cell precursors/DC migration

2. Lymph node homing !
<=

"
! -0%0*6)$4 .%& #$%&'()(* +$,,4
!" #$%&'()(* +$,, -.)/'.)(0%1
+2.%3$4 (% 52$%0)67$ .%& 8/%*)(0%
!"# $"#%&'($# &) *#%*+,',- -#../ 012/3 -"4%5#/
4--&+*,%5 '& '"#,+ 64'7+4',&% /'45#8 9664'7+#
12/ #:$+#// ",5" .#;#./ &) '"# 6(#.&,* 4%',5#%/
21<= 4%* 21==> &) '"# -"#6&?,%# +#-#$'&+/
22@<A 22@BA 4%* 22@C> 4%* &) D- +#-#$'&+/8
!"#( "4;# &%.( .&E .#;#./ &) '"# -&F/',67.4'&+(
6&.#-7.#/ 21GHA 21IHA 4%* 21IC 4%* *& %&'
#:$+#// '"# 4%',5#% 21I= 4%* '"# !(/&/&6#F"/F
/&-,4'#* ##6J+4%# $+&'#,% 0%&'()8 K&6# ,6F
64'7+# 12/A ,% $4+',-7.4+ '"# L4%5#+"4%/ -#../
&) '"# /?,%A #:$+#// 4J7%*4%'.( '"# 21<4 4%',F
8/%&.G$%)., 5'(%*(7,$4
5#%8 !"# .#;#./ &) MN2 9 4%* MN2 99 6&.#-7.#/
4+# .&E J#-47/# '"# 6&.#-7.#/ 4+# +#-(-.#*
)+&6 '"# -#.. /7+)4-# ,%'& .(/&/&6#/ 4' 4 ",5"
+4'#8 O+#/#%'#* $#$',*#/ 4+# '"#+#)&+# 4;4,.4J.#
)&+ !F-#.. +#-&5%,',&% &%.( )&+ 4 /"&+' ',6#8 96F
64'7+# 12/ "4;# ",5" $"45&-(',- 4%* 4%',5#%
7$'4?# 4-',;,'( J7'A &E,%5 '& '"#,+ .&E .#;#./ &)
-&F/',67.4'&+( 6&.#-7.#/A '"#( "4;# $&&+ 4%',F
5#%F$+#/#%',%5 -4$4J,.,'(8 9%).4664'&+( /',67F
., 0#858A !PDF!A 9LF<A 9LFCA LOKA J4-'#+,4A 4%*
;,+7/#/3 ,%*7-# 64'7+4',&% &) 12/8 !"# '7+%F
&;#+ &) MN2 99 6&.#-7.#/ *+&$/ '#%)&.* '& 4
"
"7%*+#*)&.*8 2&%/#Q7#%'.(A $#$',*#/ *#+,;#*
)+&6 -4$'7+#* 4%',5#%/ 4+# 4;4,.4J.# )&+ !F-#..
+#-&5%,',&% )&+ /#;#+4. "&7+/8 K,%-# '"# #:F
$+#//,&% &) -&F/',67.4'&+( 6&.#-7.#/ ,/ ",5".(
7$+#57.4'#*A 64'7+# 12/ #)),-,#%'.( /',67.4'#
! -#../8 R$+#57.4',&% &) 4*"#/,&% 6&.#-7.#/A
/7-" 4/ 12FK9SPA 4 2F'($# .#-',% '"4' ,%'#+4-'/
E,'" 92TMF= &% %4,;# ! -#../A )7+'"#+ -&%'+,F
J7'#/ '& !F-#.. /',67.4',&%8 D,%4. 64'7+4',&% ,/
,%*7-#* J( 21GH .,54',&%A E",-" ,%*7-#/ 12/
'& $+&*7-# .4+5# 46&7%'/ &) 9LF<U8
9" 50,.'(:.)(0% 0; <= >$470%4$ ?6
#$%&'()(* +$,,41 @(%$.3$ #/.,()6 A4"
5,.4)(*()6
12/ 4+# ,6$&+'4%' +#57.4'&+/ &) '"# ,667%#
+#/$&%/#8 !"#( -4% *,;#+' '"# ,667%# +#/$&%/#
'&E4+* 4 !N<F'($# &+ 4 !NUF'($# +#/$&%/#8 9%
'"# $+#/#%-# &) ",5" .#;#./ &) 9LF<UA ! -#../
4+# *+,;#% '&E4+* !N<A E,'" /#-+#',&% &)
9DPF"A 9LFUA 4%* 4 $+#*&6,%4%'.( ,%).4664'&+(
!F-#.. +#/$&%/#8 9% -&%'+4/'A 4 .&E -&%-#%'+4',&%
!
&) 9LF<U )4-,.,'4'#/ '"# *,))#+#%',4',&% &) !NU
-#../A E",-" /#-+#'# 9LFG 4%* 9LF<H 4%* $+&6&'#
*,))#+#%',4',&% &) V -#../ ,%'& $.4/64 -#../
/#-+#',%5 95MA 95SUA 4%* 95SG8 9' ,/ /',.. 7%-.#4+
E"#'"#+ '"# 4J,.,'( '& /#-+#'# ",5" .#;#./ &)
HI 9LF<U ,/ 4 W-&%/','7',;#X -"4+4-'#+,/',- &) '($#F<
6(#.&,*F*#+,;#* 12/ 012F<3 ,% -&%'+4/' '& '"#
'($,-4. .(6$"&,*F'($# 12/ &+ 12FUA E",-" *,)F
)#+#%',4'# ,% +#/$&%/# '& D.'= .,54%* 4%* 9LF=
07$$#+ $4+' &) $4%#. *38 9' ,/ 4./& $&//,J.#
'"4' J&'" '($#/ &) 12/ -4% $+&*7-# *,))#+#%'
.#;#./ &) 9LF<UA *#$#%*,%5 &% '"# /',67.7/Y
J4-'#+,4. $+&*7-'/ /7-" 4/ LOK 4%* 7%6#'"(F
.4'#* 2$S &.,5&%7-.#&',*#/A 21GH .,54',&%A
4%* '"# $+#/#%-# &) 4 ",5" 12Z!F-#.. +4',& ,%F
*7-# 12/ '& /#-+#'# ",5" 46&7%'/ &) 9LF<U8
2&%;#+/#.(A ,% '"# $+#/#%-# &) 9LF<HA !SDF#A
$+&/'45.4%*,% OS[UA 4%* 4 .&E 12Z!F-#../ +4',&A
12/ /#-+#'# &%.( .&E .#;#./ &) 9LF<U\'"# ,6F
67%# +#/$&%/# ,/ *+,;#% '&E4+* 4 !NU '($#
0.&E#+ $4+' &) $4%#. *38
!($,-4..(A 12F< #:$+#// '"# 4%',5#% V12TF=A
64%%&/# +#-#$'&+/A 21<A 4/ E#.. 4/ '"# !&..F.,?#
+#-#$'&+/ 0!L@3 U 4%* G8 12FUA &+ W.(6$"&,*
12AX #:$+#// '"# 4%',5#%/ 21<U= 09LF= +#-#$'&+
!F-"4,%3A V12TFUA 4%* V12TFGA 4/ E#.. 4/ !L@]
4%* !L@^8 !($#FU 12/ "4;# 4 .&E $"45&-(',-
-4$4-,'(A 4%* '"#( /#-+#'# '($#F9 ,%'#+)#+&%/
09DPF! 4%* 9DPF#3 4%* 4+# 4./& -4..#* W,%'#+F
)#+&%F$+&*7-,%5 -#../X 09O238 D,%4. 64'7+4',&%
&) 12FU ,/ ,%*7-#* J( ;,+4. 4%',5#%/ ,% '"#
$+#/#%-# &) 9LF=A E",.# LOK 4%* J4-'#+,4. 4%',F
5#%/ 4+# ,6$&+'4%' /',67., )&+ '"# 64'7+4',&%
&) '($#F< 12/8 21GH .,54',&% ,/ ,6$&+'4%' )&+
J&'" -#.. '($#/8
+" 8$$&?.*B >$3/,.)(0% 0; #+CD .%& #+CE
1,))#+#%',4',&% &) ! -#../ ,%'& !NU -#../ ,%*7-#/
'"# /#-+#',&% &) 9LFG8 !",/ -('&?,%# ,/ ,6$&+'4%'
)&+ '"# 5#%#+4',&% &) 12F<A E",.# ,' ,%",J,'/ '"#
*,))#+#%',4',&% &) '($#FU 12/ )+&6 $+#-7+/&+
-#../8 9% '",/ E4(A 4 -#+'4,% J4.4%-# &) !N<Z!NU
+#/$&%/#/ ,/ 64,%'4,%#* *#/$,'# '"# '($# &)
,%,',4. /',67.7/8
#" <0,$'03$%(* 50)$%)(., 0; FGG.)/'$
#$%&'()(* +$,,4
T%',5#% 7$'4?# J( ,664'7+# 12/ ,% '"# /?,%A
67-&/4A 4%* #;#% ,% '76&+/ 64( ,%*7-# 4%',F
5#%F/$#-,),- '&.#+4%-# +4'"#+ '"4% !F-#.. 4-',;4F
',&% ,) )7+'"#+ 64'7+4',&% /',67., 0#858A !PDA LOK3
4+# 6,//,%58 9% '"#/# -&%*,',&%/A -&F/',67.4'&+(
6&.#-7.#/ 4+# %&' 7$+#57.4'#*> 9LF<H ,/ $+&F
*7-#* ,%/'#4* &) 9LF<U8 T%',5#%/ $+#/#%'#* 7%F
*#+ '"#/# -&%*,',&%/ 4+# .,?#.( '& J# '&.#+4'#*8
!",/ 6#-"4%,/6 -&7.* $+&;,*# 4% ,6$&+'4%'
6#-"4%,/6 )&+ 4;&,*,%5 47'&,667%,'( J7'
4./& 4% #/-4$# 6#-"4%,/6 J( E",-" '76&+F
4//&-,4'#* 4%',5#%/ ,%*7-# '&.#+4%-# +4'"#+
'"4% ,667%,'(8
 Immature DC Mature DC
#+ -.)/'.)(0%1 +2.%3$4 (% 52$%0)67$ .%& 8/%*)(0%

Resting DC
Low level of MHC:
Activated DC
High level of MHC:
!
High turnover Extended long life
CD13, CD33, CD14 ++ (+)
CD40, CD80, CD86 (+) +++ Foreign Antigen
antigen + LPS, TNF
CD83 - ++
LAMP - ++
CCR1, CCR5, CCR6 ++ - Recycling
CCR7 - +
Phagocytosis +++ (+)
AG presentation + +++
IL-12 secretion + ++++

A. DC maturation: changes in phenotype and function

8/%&.G$%)., 5'(%*(7,$4
CD34+ CD34+
Myeloid CD11c+
Lymphoid
CD11-
progenitor CD13/33/14+ CD2/7/5(+) progenitor
GMCSF FLT3L TCR-!+
TNF-! IL-3
IL-4
BDCA3+ CD123+
Mannose rec+ BDCA2+ Pre-
Pre- CD1a/b/c+ BDCA4+
DC-1 TLR2+ TLR7+ DC-2
TLR4+ CD40L IL-3 TLR9+
LPS CD40L Viral infection

"
High phagocytic capacity Low phagocytic capacity
DC-1 High IL-12 secretion Low IL-12 secretion DC-2
High costimulation Secretes IFN-!/#(IPC)

High IL-12 Low IL-12

TH TH2
IFN-" High IL-12 Low IL-12 IL-4
IL-10
IFN-"
– Unmethylated
CTL CpG oligo-
nucleotides – IL-10
– CD40 ligation – TGF#
– LPS – PGE2
– IFN-" – Ox40L
$ High DC/T ratio signalling
Both DC-2 and DC-1
B. Polarization of TH responses by DCs: lineage duality vs. plasticity

TH IFN-" – low costimulation

Mucosa – low IL-12 secretion
High – IL-10 secretion
+ IL-12
pre-DC-1 DC-1 TH1
Skin
Low

!
- IL-12 Antigen-
Immature
DC specific
pre-DC-2 DC-2
TH2 IL-4 T-cell
Tumors tolerance

C. Feedback regulation of DC-1/2 D. Tolerogenic potential of immature DCs

HJ

"
! 23! 89:/$' ;<24 89:/$'=

!" #$%&'() *+,-%(.-/(&% &0 /1$ 23!

4&'56$7
!"#$%&'#$( %()*+,% +$ ,-&,"+.,$(#' #$+.#'% ",/
0,#',* (1#( ("#$%&'#$(% (1#( #", $2( 3,$,(+4#''5
+*,$(+4#' #", ",6,4(,*7 !1+% 8#% #(("+9)(,* (2 (1,
#$(+3,$% 2: (1, .#62" 1+%(242.&#(+9+'+(5 42./
&',- ;<=>?7 !1, 42"",%&2$*+$3 %(")4()",%
8,", *+%420,",* +$ 1).#$% +$ (1, @ABC%7 =)/
.#$ <=> #$(+3,$% #", 4#'',* !"#$% &'"()*+,'
$%,-.'%/ ;=DE? 9,4#)%, #$(+92*+,% #3#+$%( 1)/
.#$ ',)F245(,% 8,", ,#%+," (2 *,(,4( +$ (1, 1)/
.#$ %5%(,. #:(," ("#$%&'#$(#(+2$7 !1, #$(+3,$%
1#0, $28 9,,$ *,(,4(,* +$ 0+"()#''5 #'' $)/
>?%@-'$%/-6 A+(%)(56$:
3,$,% ;#?7 !1, ,-&",%%+2$ &"2*)4(% 2: (1,%,
3,$,% 8,", 2"+3+$#''5 4#'',* *&$// 000 $%,-.'%/
;$?7 !1,%, 3,$,% #'%2 *,.2$%("#(, ,-(,$%+0,
&2'5.2"&1+%. 81+41 +% .#*, ,0,$ .2", 42./
&',- 95 3,$, *)&'+4#(+2$ #$*U2" ',$3(1 0#"+#/
(+2$ +$ >T 3,$,%7 S(1," +.&2"(#$( 3,$,% #",
%4#((,",* (1"2)312)( (1, =DE 42.&',-H ,737H
3,$,% :2" !VW/"H !VW/!H (1, ",'#(,* '5.&12(2-/
+$ D!LH #$* ,$G5.,% >XPR@# #$* >XPR@97 !1,
+'')%("#(+2$ *2,% $2( %128 (1, 3,$,% :2" ("#$%/
&2"( &"2(,+$% !EP@ #$* !EPRH 81+41 #", '24#(,*
9,(8,,$ MP #$* MO7 !1, &"2*)4(% 2: (1,+" ,-/
&",%%+2$ #", +.&2"(#$( :2" ("#$%&2"( 2: #$(+/
3,$+4 &,&(+*,% (2 (1, =DE .2',4)',7

4',#(,* 4,''%7 !1, =DE %5%(,. +% 41#"#4(,"+G,*

95 #$ ,-(",.,'5 1+31 ',0,' 2: &2'5.2"&1+%.H
+7,7H +( 42*,% :2" 3,$,(+4 :,#()",% (1#( 244)" +$
.2", (1#$ 2$, &1,$2(5&+4 :2". #$* (1#( #",
&#%%,* 2$ #442"*+$3 (2 <,$*,'I% '#8%7 !1+%
&2'5.2"&1+%. 2: (1, <=> %5%(,. ",%)'(% +$
1+31'5 42.&",1,$%+0, #$(+3,$ &",%,$(#(+2$7
!1, 3,$,% :2" (1, 1).#$ <=> #", ,$42*,*
2$ (1, %12"( #". 2: 41"2.2%2., J7
=DE #$(+3,$% #", *+0+*,* +$(2 (82 3"2)&%H
*&$// 0 #$* *&$// 001 E% 8+(1 2(1," %&,4+:+4+(+,%H
(1, 4'#%%,% *,$2(, (1, 1+%(2"+4#' 2"*," 2: (1,+"

"
*+%420,"5H #$* $2( (1,+" #4()#' 42$:+3)"#(+2$ 2$
(1, 41"2.2%2.,7 >'#%% K #$(+3,$% :2". 42./
&',-,% 2: #$(+3,$% '24#(,* #( (1",, 2(1," #*6#/
4,$( 3,$, '24+ ;=DE/EH =DE/LH =DE/>?7 !1,%,
#$(+3,$% 8,", :+"%( *,:+$,* %,"2'23+4#''57 2345
6 $%,-.'%/H 2$ (1, 2(1," 1#$*H 8,", *+%420,",*
+$ 4,'')'#" %()*+,% 2: .+-,* ',)F245(, 4)'()",%7
=DE/M :2".% 42.&',-,% 42.&"+%+$3 =DE/MN
;M/",'#(,*?H =DE/MOH #$* =DE/MP #$(+3,$%7
Q$'+F, (1, 4'#%% K #$(+3,$%H 812%, 1,#05
41#+$% #", #%%24+#(,* 8+(1 (1, %#., '+31( 41#+$
;! R/.+4"23'29)'+$H 81+41 +% $2( ,$42*,* 2$
41"2.2%2., J?H *+::,",$( 3,$, '24+ 42*, :2"
(1, " 41#+$ ;MNEH MOEH MPE? #$* ! 41#+$
;MNLH MOLH MPL? 2: (1, 4'#%% KK #$(+3,$%7 !1,
$).9," #$* %(")4()", 2: (1,%, '24+ 0#"5 :"2.
2$, +$*+0+*)#' (2 (1, $,-(H *,&,$*+$3 2$
(1, =DE 1#&'2(5&,7 >2.9+$+$3 (1, *+::,",$(
! 41#+$% 2: (1, MN #$(+3,$%H :2" ,-#.&',H 5+,'*%
(1, 0#"+2)% 3"2)&% %128$ +$ ;!?7 S(1," %(")4/
()"#''5 ",'#(,* 3,$,% #", +$ (1, 0+4+$+(5 2: (1,
MPH MOH #$* MN 3,$,% ;"?7 !1,%, #",H +$ .#$5
4#%,%H )$("#$%'#(,* &%,)*23,$,% 8+(12)( #$5

! BC
F$28$ :)$4(+2$7
!1, 42$:+3)"#(+2$ 2: (1, #4()#' 3,$, %(")4/
()", +% *+0+*,* +$(2 # $).9," 2: ,-2$% (1#(
:2". (1, 0#"+2)% *2.#+$%7 !1, 3,$,% (1#(
42*, :2" 42.&',.,$( :#4(2"% >RH >TH #$* L:
#", '24#(,* 9,(8,,$ (1, <=> 4'#%% K #$* KK
1. 21B C4B long 21A C4A
#$%&'() *+,-%(.-/(&% &0 /1$ 23! 4&'56$7

Chromosome 6
!
p
Short
21B C4B short 21A C4A
arm

21B C4B short

21B C4A

21A C4A
q
21B C4B short 21A C4B short 21A C4A

21B C4B short 21B C4B short 21A C4A

>?%@-'$%/-6 A+(%)(56$:
21A C4B long 21A C4B long 21A C4B long 21A C4A

C4/CYP21 gene organization (haplotypes)

2. MHC class II TNF MHC class I

D-region C4B C4A Bf C2 !" B C A

CYP 21 CYP 21P LTB

Direction of transcription

DPB2

3.
DPA2
DPB1
DPA1
DNA
DMA
DMB
DOB
DQB2
DQA2
DQB3
DQB1
DQA1
DRB1
DRB2
DRB3
DRB9
DRA
"
4. B1 B6 B9
DR1, 10, 103 (DR1 group)
B1 B6 B5 B9
DR15, 16, (DR51 group)
B1 B2 B3 B9
DR3, 11, 12, 13, 14, 1403, 1404 (DR52 group)
B1 B7 B8 B4 B9
DR4, 7, 9 (DR53 group)
B1 B9
DR8 (DR8 group)
DRB gene organization (haplotypes)

5. Exon 1 Exon 2 Exon 3 Exons 4, 5, 6

DRB1 gene

1 4 9 13 25 38 57 60 67
Amino acids

A. Genomic organization of the HLA complex

74 94
DRB1 polypeptide
First domain

!
BD

"
! #$! ,A50(. +%#: ,A50(.7

!" #$! %&'()*'(

+,)-(./01) 2(34(5(60/01&67
!"#$ %&' #(")) * +,(-#.(- #,/)0)1) ,2 " 33 45"
$-"67 #$"0/ "/8 " 9: 45" (0;$1 #$"0/ 4/,</ ")
!:=+0#>,;(,?.(0/@ A$- " #$"0/ 0) " 1>"/)+-+=
?>"/- B>,1-0/ #,/)0)10/; ,2 1$>-- 8,+"0/) C"9D
":D "/8 "ED <01$ FG "+0/, "#08) -"#$HD B(.) "
1>"/)+-+?>"/- 2>";+-/1 C:I ''H "/8 "/ 0/1>"=
#-((.("> 2>";+-/1 CEG ''H@ A$- " #$"0/) 2,>+
/,/#,6"(-/1 ?,/8) <01$ 1$- -J1>"#-((.("> !:=
+0#>,;(,?.(0/@
!"#$ #(")) ** %&' +,(-#.(- #,/)0)1) ,2 1<,
#$"0/)D /"+-(7D " EEKEI 45" " #$"0/ "/8 "
F*6?/.(60/' @416)13'(5
./02,>+ 0/1->/"10,/"( /,+-/#("1.>- 2,> 1$-+
<") 0/1>,8.#-8@ A$- /-< 8-)0;/"10,/ 2,> %&'
#(")) * +,(-#.(-) #,/)0)1) ,2 " #,8- 2,> 1$-
;-/- >-;0,/ "/8 "/ 08-/1020#"10,/ /.+?->D )-=
B">"1-8 ?7 "/ ")1->0)4@ '(( #.>>-/1(7 4/,</
"/8 1>"8010,/"((7 8-20/-8 "((-(-) ">- (0)1-8 0/
1$- 1"?(-@
#$! <2= <>= /6? <@ !''('(5 16 0-(
#$! ,A50(. +0/B'(5 &6 33" CD= CE7
A$-)- 1"?(-) #,/1"0/ "/"(,;,.) #("))020#"10,/)
,2 1$- #(")) ** "/10;-/)@ A$- /,+-/#("1.>- 0) )10((
>"1$-> #,+B(0#"1-8 ,<0/; 1, 1$- B,(7+,>B$0#
/"1.>- ,2 1$- " "/8 ! #$"0/)@ A$- ).?>-;0,/

:LK:M 45" ! #$"0/@ N,1$ #$"0/) $"6- 1<, -J1>"=

#-((.("> 8,+"0/) <-0;$0/; FGK9GG 45" -"#$
C8-)0;/"1-8 "9D ": "/8 !9D !:H <$0#$ ./01-
<01$ " 1>"/)+-+?>"/- 2>";+-/1 #,/1"0/0/;
:GK:I "+0/, "#08) "/8 <01$ "/ 0/1>"#-((.(">
2>";+-/1 #,/)0)10/; ,2 MK9I "+0/, "#08)@ A$-
": "/8 !: 8,+"0/) ">- B>-)->6-8D <$->-")
1$- "9 "/8 !9 8,+"0/) ">- $0;$(7 B,(7+,>B$0#@
A$- ("11-> 8,+"0/) #,/)0)1 ,2 " O?")- B("1-P
+"8- ,2 ?-1"=B(-"1-8 )$--1)D 1, 1$- )08- ,2
<$0#$ "(B$" $-(0#-) ?0/8@ A$0)D "(1,;-1$->D
70-(8) " ?")4-1(04- )1>.#1.>- 2,> "/10;-/ "##,+=
%&'=5TD 2,> -J"+B(-D #,/1"0/) " ;-/- 2,> 1$-
" #$"0/ C5T'9H "/8 2,> )-6->"( ! #$"0/)
C5TN9D 5TN:D 5TNED 5TN3D 5TNID 5TNLD "/8
5TNFHD <$0#$ 8, /,1 "(( ,##.> )0+.(1"/-,.)(7
C)-- " ,/ B@ 3IH@ A$- ).?>-;0,/ %&'=5U #,/1"0/)
1$- #,80/; ;-/-) 5U'9 "/8 5UN9D "/8 1$- ).?=
>-;0,/ %&'=5V #,/1"0/) 1$- #,80/; ;-/-)
5V'9 "/8 5VN9@ A$- 8-)0;/"10,/ 2,> 1$-
;-/- ,> ).?>-;0,/ 0) 2,((,<-8 ?7 "/ ")1->0)4D
1$-/ 1$- 08-/1020#"10,/ /.+?-> ,2 1$- "((-(-D 0+=
+-80"1-(7 2,((,<-8 ?7 1$- /.+?-> ,2 1$- ).?=

"
+,8"10,/ C)-- "(), !H@ 17B-@ %&'=5TN9WG9G9 1$->-2,>- +-"/)X 5TN9
(,#.) C#,8-8 2,> ! #$"0/ 9HD "((-(- G9D ).?17B-
8" ,04*)0*4( &9 #$! :'/55 ; %&'()*'(5 G9@ A$- 1"?(- ,/ B@ I: (0)1) 1$- 1>"8010,/"( /,=
+-/#("1.>- C-@;@D 5T3H 2,((,<-8 ?7 1$- #-((.(">
A$- )B"10"( )1>.#1.>- ,2 %&' "/10;-/) #"/ ?- 8-=
17B- 8-)0;/"10,/ "/8 ,1$-> #,8-) 2,> ,(0;,/.=
+,/)1>"1-8 ?7 +-"/) ,2 J=>"7 )1>.#1.>"( "/"(7=
#(-,108- 17B0/;@
)0)D ") 0) )#$-+"10#"((7 )$,</ 2,> " #(")) * +,=
(-#.(-@ !"#$ ,2 1$- "9 "/8 ": 8,+"0/) #,/)0)1)
,2 2,.> "/10B">"((-( ?-1"=B(-"1-8 )$--1)D 1$-
Q=1->+0/"( -/8) ,2 <$0#$ ?0/8 1, "(B$" $-(0#-)@
A$0) 0/8.#-) 1$- 8-6-(,B+-/1 ,2 "/ "/10;-/=
#,+?0/0/; )1>.#1.>- 1$"1 #,>>-)B,/8) 1, " B-B=
108-=#,+?0/0/; ;>,,6- C)-- 20;.>-H@ A$- A=#-((
>-#-B1,> /,< >-#,;/0R-) 01) +"1#$0/; %&'
"/10;-/ CS%Q >-#-B1,>H ") <-(( ") 1$- B-B108-
#,/1"0/-8 0/ 01) ;>,,6- C!"#$%&'()&*" (%$+&',H@
A$- ?,/8 ?-1<--/ 1$- "/10;-/=?-">0/; #-((
"/8 1$- A #-(( 0) )1"?0(0R-8 ?7 O$-(B-> +,(-=
#.(-)DP ).#$ ") Q5M 0/ 1$- #")- ,2 #71,1,J0#
A #-(()@

:" #$! :'/55 ; !''('(5

A$- %&' "/10;-/) <->- 1>"8010,/"((7 /"+-8 0/

!
1$- ,>8-> ,2 1$-0> 80)#,6->7 ") 'D ND "/8 Q C#("))
*H "/10;-/) "/8 5 "/10;-/) "/8 "))0;/-8 /.+=
?->) <01$0/ 1$- 0/80608."( ;>,.B)@ ') " >-).(1D
1$- 8-)0;/"10,/) ?-#"+- 1,, 6">0-8 "/8 #,/2.)=
0/;@ '21-> 1$- -J"#1 )1>.#1.>- ,2 1$- ;-/-) <")
CG 08-/1020-8 ?7 +,(-#.("> ?0,(,;0#"( +-1$,8)D "
 Class II !1 NH2
"1
#$! %&'()*'( ,04*)0*4( /6? :'/55 ; !''('(5

T-cell receptor
!
Antigenic peptide
CHO !1 !2
CHO

!2 "2

CHO !1 N

!2 !3
NH2
COOH COOH
NH2
CHO C Antigen
COOH CD8
"2m C
!3 "2 m N

F*6?/.(60/' @416)13'(5
CD8 HVIII
Exosol
View from above
on antigen-binding
part
COOH Class I Cytosol
A. HLA molecules (schematic) B. Structure of an HLA class I molecules

HLA-A alleles HLA-B alleles HLA-C alleles

New Old New Old New Old
nomen- nomen- nomen- nomen- nomen- nomen-
clature clature clature clature clature clature
A*0101
A*0201
A*0202
A*0203
A*0204
A*0205
A*0206
A*0207
A1
A2, A2.1
A2, A2.2F
A2, A2.3
A2
A2, A2.2Y
A2, A2.4a
A2, A2.4b
B*0701
B*0702
B*0801
B*1301
B*1302
B*1401
B*1402
B*1501
B7, B7.1
B7, B7.2
B8
B13, B13.1
B13, B13.2
B14
Bw65 (14)
Bw62 (15)
Cw*0101
Cw*0201
Cw*02021
Cw*02022
Cw*0301
Cw*0501
Cw*0601
Cw*0701
Cw1
Cw2, Cw2.1
Cw2, Cw2.2
Cw2, Cw2.2
Cw3
Cw5
Cw6
Cw7
"
A*0208 A2, A2.4c B*1801 B18 Cw*0702 Cw7, JY328
A*0209 A2, A2-ZB B*2701 B27, 27f Cw*1101 Cw11
A*0210 A2, A2-LEE B*2702 B27, 27e, 27K, B27.2 Cw*1201 Cx52
A*0301 A3, A3.1 B*2703 B27, 27d, 27J Cw*1202 Cb-2
A*0302 A3, A3.2 B*2704 B27, 27b, 27C, B27.3 Cw*1301 CwBL18
A*1101 A11, A11E B*2705 B27, 27a, 27W, B27.1 Cw*1401 Cb-1
A*1102 A11, A11K B*2706 B27, 27D, B27.4
A*2401 A24 (9) B*3501 B35
A*2501 A25 (10) B*3502 B35
A*2601 A26 (10) B*3701 B37
A*2901 A29 (w19) B*3801 B38 (16), B16.1
A*3001 A30 (w19), A30.3 B*3901 B39 (16), B16.2
A*3101 A31 (w19) B*4001 Bw60 (40)
A*3201 A32 (w19) B*4002 B40, B40*
A*3301 Aw333 (w19), Aw33.1 B*4101 Bw41
A*6801 Aw68 (28), Aw68.1 B*4201 Bw42
A*6802 Aw68 (28), Aw68.2 B*4401 B44 (12), B44.1
A*6901 Aw69 (28) B*4402 B44 (12), B44.2
B*4601 Bw46
B*4701 Bw47
B*4901 B49 (21)

!
B*5101 B51 (5)
B*5201 Bw52 (5)
B*5301 Bw53
B*5701 Bw57 (17)
B*5801 Bw58 (17)
B*7801 B'SNA'
C. HLA class I alleles
CH

"
! !"# $%&'()&'*+ ,&-** .. #&&'&'* /.0

New
nomenclature
Old
nomenclature
New Old
nomenclature nomenclature

DRB1-alleles DRB1-alleles

DRB1*0101 DR1, Dw1 DRB1*1304 DRw6, DRw13

DRB1*0102 DR1, Dw20 DRB1*1305 DRw6, DRw13
DRB1*0103 DR' BR', Dw' BON' DRB1*1401 DRw6, DRw14, Dw9, Drw6b
DRB1*1501 DR2, DRw15, Dw2 DRB1*1402 DRw6, DRw14, Dw16
DRB1*1502 DR2, DRw15, Dw12 DRB1*1403 DRw6, DRw14
DRB1*1601 DR2, DRw16, Dw21 DRB1*1404 DRw6, DRw6b.2
1)23-4'25-& 6782(89&'*

DRB1*1602 DR2, DRw16, Dw22 DRB1*1405 DRw6, DRw14

DRB1*0301 DR3, DRw17, Dw3 DRB1*0701 DR7, Dw17
DRB1*0302 DR3, DRw18, DRB1*0702 DR7, Dw'DB1'
DRB1*0401 DR4, Dw4 DRB1*0801 DRw8, Dw8.1
DRB1*0402 DR4, Dw10 DRB1*08021 DRw8, Dw8.2
DRB1*0403 DR4, Dw13, 13.1 DRB1*08022 DRw8, Dw8.2
DRB1*0404 DR4, Dw14, 14.1 DRB1*08031 DRw8, Dw8.3
DRB1*0405 DR4, Dw15 DRB1*08032 DRw8, Dw8.3

" DRB1*0406
DRB1*0407
DRB1*0408
DRB1*0409
DR4, Dw'KT2'
DR4, Dw13, 13.2
DR4, Dw14, Dw14.2
DR4
DRB1*0804
DRB1*09011
DRB1*09012
DRB1*1001
DRw8
DR9, Dw23
DR9, Dw23
DRw10
DRB1*0410 DR4
DRB1*0411 DR4
DRB1*1101 DR5, DRw11, Dw5, DRw11.1 Other DRB alleles

DRB1*1102 DR5, DRw11, DRw11.2 DRB3*0101 DRw52a, DW24

DRB1*1103 DR5, DRw11, DRw11.3 DRB3*0201 DRw52b, Dw25
DRB1*1104 DR5, DRw11 DRB3*0202 DRw52b, Dw25
DRB1*1201 DR5, DRw12, Dw'DB6' DRB3*0301 DRw52c, Dw26
DRB1*1202 DR5, DRw12, DRw12b DRB4*0101 DRw53
DRB1*1301 DRw6, DRw13, Dw18, DRw6a DRB5*0101 DR2, DRw15, Dw2
DRB1*1302 DRw6, DRw13, Dw19, DRw6c DRB5*0102 DR2, DRw15, Dw12
DRB1*1303 DRw6, DRw13, Dw'HAG' DRB5*0201 DR2, DRw16, Dw21

! :;
DRB1*1304 DRw6, DRw13 DRB5*0202 DR2, DRw16, Dw22

A. HLA-DR, HLA-DQ, and HLA-DP alleles in the HLA system (class II alleles)
New Old
nomenclature nomenclature
New
!"# $%&'()&'*+ ,&-** .. #&&'&'* /..0

Old
nomenclature nomenclature
!
DQA1 alleles DPA1 alleles

DQA1*0101 DQA 1.1, 1.9 DPA1*0101 LB14/LB24, DPA1

DQA1*0102 DQA 1.2, 1.19, 1.AZH DPA1*0102 pSBa-318
DQA1*0103 DQA 1.3, 1.18, DRw8-Dqw1 DPA1*0103 DPw4a1
DQA1*0201 DQA 2, 3.7 DPA1*0201 DPA2, pDAa13B
DQA1*03011 DQA 3, 3.1, 3.2
DQA1*03012 DQA 3, 3.1, 3.2, DR9-DQw3 DPB1 alleles

1)23-4'25-& 6782(89&'*
DQA1*0302 DQA 3, 3.1, 3.2, DR9-DQw3 DPB1*0101 DPw1, DPB1, DPw1a
DQA1*0401 DQA 4.2, 3.8 DPB1*0201 DPw2, DPB2.1
DQA1*0501 DQA 4.1, 2 DPB1*02011 DPw2, DPB2.1
DQA1*05011 DQA 4.1, 2 DPB1*02012 DPw2, DPB2.1
DQA1*05012 DQA 4.1, 2 DPB1*0202 DPw2, DPB2.2
DQA1*05013 DQA 4.1, 2 DPB1*0301 DPw3, DPB3
DQA1*0601 DQA 4.3 DPB1*0401 DPw4, DPB4.1, DPw4a
DPB1*0402 DPw4, DPB4.2, DPw4b
DQB1 alleles
DQB1*0501
DQB1*0502
DQB1*05031
DQw5 (w1), DQB 1.1, DRw10-DQw1.1
DQw5 (w1), DQB 1.2, 1.21
DQw5 (w1), DQB 1.3, 1.9, 13.1
DQw5 (w1), DQB 1.3, 1.9, 13.2
DPB1*0501
DPB1*0601
DPB1*0801
DPB1*0901
DPw5, DPB5
DPw6, DPB6
DPB8
DPB9
"
DQB1*05032 DPB1*1001 DPB10
DQB1*0504 DQB 1.9 DPB1*1101 DPB11
DQB1*0601 DQw6 (w1), DQB 1.4, 1.12 DPB1*1301 DPB13
DQB1*0602 DQw6 (w1), DQB 1.5, 1.2 DPB1*1401 DPB14
DQB1*0603 DQw6 (w1), DQB 1.6, 1.18 DPB1*1501 DPB15
DQB1*0604 DQw6 (w1), DQB 1.7, 1.19 DPB1*1601 DPB16
DQB1*0605 DQw6 (w1), DQB 1.8, 1.19b DPB1*1701 DPB17
DQB1*0201 DQw2, DQB 2 DPB1*1801 DPB18
DQB1*0301 DQw7 (w3), DQB 3.1 DPB1*1901 DPB19
DQB1*0302 DQw8 (w3), DQB 3.2
DW4 DRB1*0401
DQB1*03031 DQw9 (w3), DQB 3.3 DW10 DRB1*0402
DQB1*03032 DQw9 (w3), DQB 3.3 DW13 DRB1*0403

!
DW14 DRB1*0407
DQB1*1401 DQw4, DQB 4.1, Wa DR4
DW15 DRB1*0404
DQB1*0402 DQw4, DQB 4.2, Wa DW"KT2" DRB1*0408
DRB1*0405
DRB1*0406

B. HLA-DR, DQ, and DP alleles in the HLA system (continued)

:<

"
! $<! =>(0,9 ?#$% =>(0,9@
!" #$% %&'(( ))*+,-,./,.0 !.012,.
3456,((1.2
!"#$%&#'( )&*+$%&(, +&-.'/+&$ 0#1%+$& 2#.%3
-'.%( #1 2+-1##1$)&+(2(, 2'(* 4% +&*%1&).+5%/,
/+$%(*%/ +&*# 6%6*+/% 01)$2%&*(, )&/ 4#'&/ *#
*7% 6%6*+/%34+&/+&$ $1##8% #0 9:; 2#.%-'.%(
4%0#1% )&*+$%&3(6%-+0+- ;<=> ? -%..( 1%-#$&+5%
*7%2@ ?71#'$7 1%-%6*#132%/+)*%/ %&/#-A*#(+(
#1 67)$#-A*#(+( B(%% 6@ =CD, %"#$%&#'( )&*+$%&(
)1% -#&8%A%/ +&*# %&/#(#2). 8%(+-.%(@ ?7%(%
/%8%.#6 01#2 6)1*( #0 *7% +&*%1&).+5%/ -%..
2%241)&% )&/ 7)8% ) &%'*1). 6:, (# )-+/+- 61#3
*%)(%( )1% +&)-*+8%@ E+*7+& 7#'1(, *7% 6: #0 *7%
AB./'9,.0'& 341.61-&,(
%&/#(#2% /%-1%)(%(, )&/ +&*%1&).+5%/ 61#*%+&(
)1% /+$%(*%/ 4A -A(*%+& 61#*%)(%( -)..%/ -)*7%3
6(+&(@ ?7% %&/#(#2%( *7%& 0'(% F+*7 8%(+-.%(
-#&*)+&+&$ 9:; -.)(( GG 2#.%-'.%(@ H%-%&*.A
(A&*7%(+5%/ *1)&(2%241)&% 61#*%+&(, ('-7 )(
9:; 2#.%-'.%(, )1% *1)&(.#-)*%/ 01#2 *7%
-A*#(#. *# *7% %&/#6.)(2+- 1%*+-'.'2 B!HD,
F7%1% *7%A )1% 0#./%/ )&/ )((%24.%/ -#11%-*.A@
?7%A 0+1(* #--'1 )( /+2%1( #0 ! )&/ " -7)+&(@
I *7+1/ -7)+&, *7% $)22) #1 J+&8)1+)&*K -7)+&
B!"3-7)+&D, 4+&/( &#&-#8).%&*.A *# )& 9:; GG
!3" 7%*%1#/+2%1 4.#-L+&$ +*( 4+&/+&$ (+*%@
"
?7+( 61%8%&*( *7% 4+&/+&$ #0 %&/#$%&#'(.A
(A&*7%(+5%/ 6%6*+/%(, F7+-7 )1% )4'&/)&* +&
*7% !H B(%% ).(# 6@ MND@ ?7% 6)1* #0 *7% +&8)1+)&*
-7)+& *7)* 4.#-L( *7% $1##8% #0 *7% !3" 7%*%1#3
/+2%1 +( -)..%/ #$)((3GG )((#-+)*%/ "&8)1+)&*
-7)+& %%6*+/% B&'!(D@ ?7% 61#*%+& #)$*+,"* 1%3
*)+&( *7% -#26.%" F+*7+& *7% !H '&*+. )((%24.A
+( -#11%-*, *7%& /+((#-+)*%( )&/ )..#F( *7% -#23
6.%" #0 9:; GGOG+ *# .%)8% *7% !H 8+) (2).. -#)*3
#2%13-#)*%/ 8%(+-.%(@ ?7%(% 0'(% F+*7 *7% P#.$+
)66)1)*'( #& /+((#-+)*+#& #0 *7% -#)*#2%13
-#)*%/ 61#*%+&@ ?7% +&8)1+)&* -7)+& *)1$%*(
*7% 9:; -#26.%"%( *# *1)&(6#1* 8%(+-.%( #0
*7% J*1)&(3P#.$+ &%*F#1L,K F7+-7 *1)00+- *# %&3
/#(#2). 8%(+-.%(@ ?7% +&8)1+)&* -7)+& +( -.%)8%/,
.%)8+&$ #&.A *7% (2).. ;QGR 01)$2%&* 4#'&/ *#
*7% 4+&/+&$ (+*% #0 *7% 9:; GG 7%*%1#/+2%1@ ?7%
-#26)1*2%&* F7%1% 0'(+#& #0 *7% *1)&(6#1* 8%3
(+-.%( F+*7 *7% %&/#(#2%( #--'1( +( -)..%/ -:;
-.)(( !! ##26)1*2%&* B-!!&D@ I& 9:; -.)(( GG3
.+L% 2#.%-'.%, -)..%/ :QI3<9, +&/'-%( 1%.%)(%
#0 *7% ;QGR 6%6*+/% 01#2 *7% 4+&/+&$ $1##8%
#0 *7% 9:; )&/ (*)4+.+5%( *7% %26*A 9:; GG
! CD
7%*%1#/+2%1 '&*+. )& )661#61+)*% %"#$%&#'(
6%6*+/% +( 4#'&/@ S+&)..A, :QI3<9 /+((#-+)*%(
)&/ *7% 6%6*+/%O9:; GG -#26.%" +( *1)&(6#1*%/
*# *7% -%.. 2%241)&%@ R%6*+/%( *7)* F%1% '&3
)4.% *# 4+&/ *# 9:; 2#.%-'.%( )1% /%$1)/%/
+& .A(#(#2%(@
7" !.6854 !91.5 !61/( 1. #$% )) 3,-01/,("
?7% 6%6*+/%34+&/+&$ $1##8% #0 9:; -.)(( GG 2#3
.%-'.%( +( #6%& )* 4#*7 %&/(, (# *7% (+5% #0 6%63
*+/%( *7)* -)& 4+&/ 1)&$%( *A6+-)..A 01#2 TU *#
U= )2+&# )-+/ 1%(+/'%(@ V#*7 -7)+&( #0 *7% 9:;
GG 2#.%-'.% +&*%1)-* F+*7 *7% (+/% -7)+&( #0 *7%
6%6*+/% )&/ /%*%12+&% 4+&/+&$ )00+&+*A@ !)-7
-.)(( GG )..%.% 7)( /+00%1%&* (+/% -7)+& -#&*)-*(,
)..#F+&$ #&.A 6%6*+/%( F+*7 -%1*)+& )2+&#
)-+/( *# 4+&/ +&*# 6)1*+-'.)1 L%A 6#(+*+#&( B)&3
-7#1 6#(+*+#&(D@ ?7% )&-7#1 6#(+*+#& -.#(%(* *#
*7% W:U *%12+&'( B6#(+*+#& TD )--%6*( #&.A )1#3
2)*+- #1 .)1$% ).+67)*+- )2+&# )-+/(X*7+( +( %(3
(%&*+). 0#1 7+$73)00+&+*A 6%6*+/% 4+&/+&$@ Y*7%1
+26#1*)&*, ).*7#'$7 .%(( -1+*+-). )&-7#1(, )1%
*7% )2+&# )-+/( )* 6%6*+/% 6#(+*+#& =, N, )&/
Z@ Y& *7% #*7%1 7)&/, (+/% -7)+&( #0 -%1*)+& )2+3
&# )-+/( -)& +&*%10%1% F+*7 6%6*+/% 4+&/+&$ B+&3
7+4+*#1A )2+&# )-+/(D@ I&-7#1 6#(+*+#&( )1% *7%
2#(* +26#1*)&* -#&*)-* (+*%( #0 *7% 6%6*+/%
F+*7 *7% 9:; GG 2#.%-'.%, (# +* +( &#* ('161+(+&$
*7)* *7% ()2% L%A 6#(+*+#&( )1% -1+*+-). 0#1 4+&/3
+&$ +&7+4+*+#&@ I2+&# )-+/( *7)* 0)8#1 #1 +&7+4+*
6%6*+/% 4+&/+&$ *# :QI3<HVT[C=CT )1% (7#F&
+& &@ ?7% ;QGR 6%6*+/% #0 *7% +&8)1+)&* -7)+& -)&
4+&/ 61#2+(-'#'(.A *# /+00%1%&* 9:; GG )..%.%(\
+* 7)( 2%*7+#&+&% )* 6#(+*+#& T )&/ (+/% -7)+&(
*7)* )1% )--%6*%/ 4A ).. <H )..%.%( +& 6#(+*+#&( U3
Z@ ;#26'*%1 61#$1)2( -)& &#F 61%/+-* 4+&/+&$
2#*+0( 0#1 ) 6)1*+-'.)1 :QI3<H )..%.% 01#2 *7%
61#*%+& (%]'%&-%@
+" :*%,&& !601;'015. ;1' #$% ))
?7% 6%6*+/%O9:; -.)(( GG -#26.%" -)& )-*+8)*%
;<=> ? -%..( )&/ +&/'-% *7% 61#.+0%1)*+#& )&/ (%3
-1%*+#& #0 8)1+#'( -A*#L+&%(@ ?'2#1 &%-1#(+(
0)-*#13! B?WS3!D 1%.%)(%/ 4A *7% )&*+$%& 61%3
(%&*+&$ -%.. 6.)A( )& +26#1*)&* 1#.% +& *7+( 61#3
-%((@ G* .%)/( *# *7% 0#12)*+#& #0 #"A$%& 1)/+-).(
*7)* )1% )4.% *# L+.. +&*1)-%..'.)1 2+-1##1$)&3
+(2(@ S'1*7%12#1%, )-*+8)*%/ ;<=> ? -%..( -)&
(*+2'.)*% )&*+4#/A 0#12)*+#& +& V -%..(@ V#*7
2%-7)&+(2( )1% /+1%-*%/ )* *7% %.+2+&)*+#&
#0 %"*1)-%..'.)1 6)*7#$%&(@
 Extracellular protein
#$% %&'(( ))*/,-,./,.0 !.012,. 34,(,.0'015.
!
Coat proteins

Endocytosis

Early
endosome Golgi

MHC class II Transport

compartment vesicles
Calnexin
Terminal Ii
lysosome

AB./'9,.0'& 341.61-&,(
Endogenous
proteins
mRNA
ER HLA-DM

A. MHC class II-dependant antigen processing

Anchor AA Inhibitory AA

P1 Phe, Ile, Leu, Met, Val, Trp, Tyr

P1

N
P4 P6 P9

HVIII
P4

P6
Asp, Met, Gln, Ser Gly, Lys, Pro, Arg, Trp, Tyr

Ser, Thr, Val Gln, Phe, Gly, His, Lys, Leu, Met, Tyr
"
P9 Ser Asp, Gln, Leu, Asn, Pro

C. Allele-specific motifs in DRB1*0401-binding

B. Anchor AA in MHC II peptides peptides

IL-2
CD4
CD4 B
IL-4
IFN-! IL-6

TNF-"

NO
H2O2
O2

D. T-cell activation via MHC II

Antibody
production
!
CC
! 23! 45(.'6 7829 45(.'6:
!" #$%&'(()*+ ,*- #$'('*.,.)%*
%/ 0*-%+'*%1( !*.)+'*(
!"# $%&'' ()*+,',-.,/ *,*.0/,' /,+01, 2+34
*+3.,0-' .5&. &+, *+,',-. 0- .5, $6.3*%&'47
850' &%%39' .5, 044:-, '6'.,4 .3 +,$3;-0<,
$,%%' .5&. 5&1, =,,- 0-2,$.,/ =6 10+:',' 3+ =6
0-.+&$,%%:%&+ =&$.,+0&7 85,3+,.0$&%%6> .50' &%'3 &%)
%39' +,$3;-0.03- 32 4:.&.,/ *+3.,0-' 32 $&-$,+
$,%%'7
(- 3+/,+ .3 *+,',+1, $,%% 10&=0%0.6> /&4&;,/>
/,-&.:+,/> :-&'',4=%,/> 3+ 40'23%/,/ *+3.,0-'
4:'. =, ,%040-&.,/7 ?3+4&% *+3.,0-' &%'3 -,,/
.3 =, $3-'.&-.%6 /,;+&/,/ &-/ +,*%&$,/ @90.5
;1*-,6'*.,< #$)*&)=<'(
5&%2)%01,' +&-;0-; 2+34 & 2,9 40-:.,' .3 ',1)
,+&% /&6' 3+ 9,,A'B7 C+3.,0-' &+, .&;;,/ 23+
/,'.+:$.03- =6 .5, *+3.,0- :=0D:0.0-7 !:%.0)
:=0D:0.0-&.,/ *+3.,0-' &+, +,$3;-0<,/ =6 .5,
*+3.,&'34,> & %&+;, *+3.,&', $34*%,E 90.5 &
43%,$:%&+ 9,0;5. 32 FGGG AH&7 (. 0' =&++,%)
'5&*,/ &-/ 4&/, 32 & $3+, :-0. 32 FGI @JKG
AH&B &' 9,%% &' 32 .93 &//0.03-&% 3:.,+ +0-;'
32 LMI @,&$5 NGG AH& 0- '0<,B7 85, 23:+ +0-;'
32 .5, FGI *+3.,&'34, $3-'0'. 32 .93 0--,+ !
:-0.' &-/ .93 " :-0.'> &%% 32 .5,4 $3-'0'.0-;
32 ',1,- /022,+,-. ':=:-0.'> 950$5 ':++3:-/ &
"
$,-.+&% $5&4=,+ 95,+, *+3.,3%6'0' 3$$:+'7
85, 4&O3+0.6 32 *,*.0/,' *+3$,'',/ =6 .5,
*+3.,&'34, &+, D:0$A%6 /,;+&/,/ 0-.3 '0-;%,
&40-3 &$0/' =6 $6.3'3%0$ 3+ -:$%,&+ ,-<64,'7
P-%6 & 2,9 *,*.0/,' @43'.%6 90.5 & '0<, 32
QRLG &40-3 &$0/'B &+, .+&-'*3+.,/ 0-.3 .5,
,-/3*%&'40$ +,.0$:%:4 @STB =6 & 5,.,+3)
/04,+U*+3.,0- $34*%,E $&%%,/ !+&-'*3+.,+ &''3)
$0&.,/ 90.5 "-.0;,- #+3$,''0-; @$%&B7 (- .5, ST>
*,*.0/,' =0-/ .3 .5, *,*.0/,)=0-/0-; ;+331, 32
!"# $%&'' ( *+3.,0-' 02 .5, '0/, $5&0-' 32 .5,0+
&40-3 &$0/' 20. *+3*,+%6 90.5 .5, &40-3 &$0/'
32 .5, =0-/0-; ;+331, 32 .5, !"# ( " $5&0-7
(-0.0&%%6> .5, " $5&0- 0' =3:-/ =6 V$5&*,+3-W
*+3.,0-'> ':$5 &' $&%-,E0-> $&%+,.0$:%0-> S+*KN>
950$5 +,;:%&., *,*.0/, =0-/0-;7 8&*&+0- =+0/;,'
.5, " $5&0- .3 8XC7 893 3+ .5+,, *3$A,.' 0- ,&$5
!"# 43%,$:%, &$$,*. 3-%6 *&+.0$:%&+ &40-3
&$0/' @,7;7> &%0*5&.0$ &40-3 &$0/'> =&'0$ &40-3
&$0/'B7 85,', &+, $&%%,/ &-$53+ +,'0/:,'7 85,6
/022,+ 23+ /022,+,-. !"# ( &%%,%,'> '0-$, ,&$5
&%%,%, 5&' & /022,+,-. ',D:,-$, 32 .5, " $5&0-7
(- 43'. $&','> .5, &40-3 &$0/' 0- *3'0.03- F
!
&-/ M &+, $+:$0&% 23+ =0-/0-;7 X-$53+ +,'0/:,'
32 *,*.0/,' .5&. =0-/ 90.5 50;5 &220-0.6 .3 .5+,,
2+,D:,-. "YX &%%,%,' &+, '539- 0- '7 C,*.0/,'
90.5 & /022,+,-. &40-3 &$0/ 0- .5,', *3'0.03-'
4&6 =0-/> =:. 90.5 & %39,+ &220-0.67
>?
85, +,'.+0$.03-' /0$.&.,/ =6 .5, &-$53+ +,'0)
/:,' &+, +,'*3-'0=%, 23+ .5, 2&$. .5&. 3:. 32 &
953%, *+3.,0- 3-%6 & '4&%% -:4=,+ 32 *,*.0/,'
=0-/ 90.5 50;5 &220-0.6 .3 & *&+.0$:%&+ "YX)&%)
%,%, @(B7 "39,1,+> '0-$, ,&$5 0-/010/:&% 4&6
5&1, :* .3 '0E /022,+,-. "YX &%%,%,' @4&.,+-&%
&-/ *&.,+-&% &%%,%,' 32 "YX)X> )Z> &-/ )#B> &
=+3&/ '*,$.+:4 32 *,*.0/,' $&- '.0%% =, *+,)
',-.,/7 #34*:.,+ *+3;+&4' &1&0%&=%, .5+3:;5
.5, (-.,+-,. $&- *+,/0$. =0-/0-; ,*0.3*,' 32 &
;01,- *+3.,0- 23+ .5, 43'. $3443- "YX 5&*)
%3.6*,'7
Y64*530/ .0'':, &-/ $,%%' ,E*3',/ .3 ([?)#
5&1, & '%0;5.%6 /022,+,-. *+3.,&'34, $34*%,E &'
'34, 32 .5, ! ':=:-0.' &+, ':='.0.:.,/ =6 ':=)
:-0.' 90.5 /022,+,-. ':='.+&., *+,2,+,-$,'> ':$5
&' Y!CF> Y!CN> &-/ !S#YL @044:-3*+3.,&)
'34,> )B7 85, *+3.,3%6.0$ &$.010.6 32 .5, 044:)
-3*+3.,&'34, &**,&+' .3 =, ,-5&-$,/ $34)
*&+,/ 90.5 .5, $3-'.0.:.01, *+3.,&'34,>
950$5 0' 0- &$$3+/&-$, 90.5 .5, 50;5,+ &-.0)
;,-)*+3$,''0-; +,D:0+,4,-.' 32 &-.0;,-)*+,)
',-.0-; $,%%' &-/ 32 10+:')0-2,$.,/ $,%%' ,E*3',/
.3 ([?)#7 C+3.,0-' *+3$,'',/ =6 .5, 044:-3)
*+3.,&'34, $&- ;,-,+&., & 953%, /022,+,-.
',. 32 *,*.0/,'7
8)$,%% +,$3;-0.03- $&- =, *+,1,-.,/ =6 V04)
4:-, ,'$&*,W 4,$5&-0'4' @*B\ /,2,$.'],7;7>
4:.&.03-'> 0- .5, ',D:,-$, 32 8XC *+3)
.,0-']$&- *+,1,-. .5, .+&-'*3+. 32 *,*.0/,'
0-.3 .5, ST '3 .5&. ,4*.6 !"# ( 43%,$:%,'
&+, ;,-,+&.,/ .5&. &+, :-'.&=%, &-/ /0''3$0&.,
D:0$A%6 2+34 .5, $,%% 4,4=+&-,7 ^0+&% *+3.,0-'>
':$5 &' .5, ",+*,' ^0+:' *+3.,0-' _IF &-/ _ILL>
$&- 0-/:$, &$.01, ,E*3+. 32 !"# 43%,$:%,'
2+34 .5, ST> *+,1,-.0-; %3&/0-; 32 10+&% *,*)
.0/,' 0- .5, !"# 43%,$:%,'7 (-/,,/> %39 %,1,%'
32 !"# ( &+, 2+,D:,-.%6 23:-/ 0- 10+&% 0-2,$.03-'7
I0-$, 4&-6 ,-/3;,-3:' V',%2W *,*.0/,' &+,
*+,',-.,/ .3 8 $,%%' =6 !"# ( 43%,$:%,'> .93
4&O3+ 4,$5&-0'4' ,E0'. .3 *+,1,-. &:.3+,&$)
.010.67 (- .5, .564:'> *+,',-.&.03- 32 ',%2)&-.0)
;,-' =6 .5640$ ,*0.5,%0& 3+ /,-/+0.0$ $,%%' $&-
%,&/ .3 $%3-&% /,%,.03- 32 &-.0;,-)'*,$020$ 8 $,%%'
@$,-.+&% .3%,+&-$, =6 .5640$ /,%,.03-> + &-/ *7
LFB7 (- .5, *,+0*5,+6> +,$3;-0.03- 32 ',%2)&-.0)
;,-' =6 &-.0;,-)'*,$020$ 8 $,%%' .5&. 4&6 5&1,
':+101,/ .5640$ ',%,$.03- %,&/' .3 &=3+.01, &$)
.01&.03- 3+ &*3*.3'0' =,$&:', 32 & %&$A 32 $3)'.0)
4:%&.3+6 43%,$:%,' @*,+0*5,+&% .3%,+&-$,> ,B7
 829 9<,(( @A-'='*-'*. !*.)+'* #$'('*.,.)%*
!
Subunits Exocytosis
Ubiquitinated ! " " ! via Golgi
protein
Ubiquitin
TAP
Erp57

19S 19S
20S
"2m
26S proteasome Tapasin

;1*-,6'*.,< #$)*&)=<'(
Enzymatic
digestion

Single AA Unfolded MHC I chain Calreticulin

A. Processing and presentation of endogenous antigens

HLA-A*0201 P2=Leucine MAPPQVLAFGLLLAAATATFAAAQEECVLENY

P9=Valine, KLAVNCFVNNNRQCQCTSVGAQNTVICSKL
Tyrosine AAKCLVMKAEMNGSKLGRRAKPEGALQNND
NH3+

COO

P2 P9 GLYDPDCDESGLFKAKQCNGTSTCWCVNTA

"
GVRRTDKDTEITCSERVRTYWIIIELKHKAREK
HLA-A3: P2=Leucine
P9=Lysine PYDSKSLRTALQKEITTRYGLDPKFITSILYENN
VITIDLVQNSQQKTQNDVDIADVAYYVEKDV
Pockets
KGESLFSHKKMDLTVNGEQLDLDPGQTLIYY
in ! chain
HLA-B7: P2=Leucine VDEKAPEFSMQGLKAGVIAVIVVVVIAVVAGI
P9=Proline
of MHC I VVLVISRKKRMAKIEKAEIKEMGEMHRELNA
C. HLA-A2-binding epitopes of a 314 AA
B. Binding motifs protein
VPYGSFKHV
Non-APC cells Lack of presentation

••TGSTA US2
VPYGSFKHV KHVDTRLQ US11
DTRLQ••• Virus infected cells
– tumor cells

APC, IFN-#-treated cells

D. Immunoproteasome E. Immune escape mechanisms

Thymic medulla Non-APC

dendritic cell cell Apoptosis/
Self antigen Self-antigen anergy

CD4+/CD8+
Thymocyte
Apoptosis

F. Central tolerance to self antigens

Clonal deletion
Lack of
co-stimulation
G. Peripheral tolerance to self-antigens
!
>B

"
! 27( #$%&'(%()* 418*(%

!" #$%&'(%()* !+*,-.*,$)

!"# $%&'()#'#*+,-./ ,%+010+. &2 3#-4' 03 -#5
640-#7 2&- +"# ).303 &2 %#))3 &- 8,%+#-0, 8. ,*+05
8&70#39 : *4'8#- &2 (-&+#,3#3 -#2#--#7 +& ,3
!"#$%&#&'( !"#$"'&'() ,-# -#3(&*308)# 2&-
+"03 3#-4' ,%+010+.9 ;03+&-0%,)).< +"#3# (-&+#0*3
,-# 7#30=*,+#7 >0+" +"# )#++#- $?/ 2&))&>#7
8. , *4'8#-9 !"# ',@&-0+. &2 %&'()#'#*+ (-&5
+#0*3 ,-# *+#",&')< 09#9< 0*,%+01# (-&#*A.'#3
+",+ 8#%&'# ,%+01,+#7 ,2+#- (-&+#&).3039 !"#
%)#,1,=# (-&74%+3 ,-# ),8#)#7 >0+" ,* ,7705
+0&*,) )&>#-5%,3# )#++#-9
!"# ?B (-&+#0*< >"0%" 03 (-#3#*+ 0* (),3', ,+
96):.%()*.' ;3,)+,&'(8
/" 01*,+ 2(3%,).' 4(56()+(
!>& (-&+#&).+0% ?L %&*1#-+,3#3 ,-# +"# +#-'0*,)
(-&74%+3 &2 +"# %),330%,) ,*7 ,)+#-*,+01# %&'5
()#'#*+ ,%+01,+0&* (,+">,.39 P* #,%" (,+">,.<
?B8 3#-1#3 ,3 +"# 80*70*= 30+# 2&- +"# ?L 3#-4'
(-&+#0*< >"0%" 03 3()0+ 0*+& ?L, ,*7 ?L8 2-,=5
'#*+3 8. (-&+#&).3039 ?L8 03 %,(,8)# &2 80*70*=
%&'()#'#*+ (-&+#0*3 ?Q ,*7 ?R9 ?L8QR 03 , ".5
7-&("&80% +-0'&)#%4),- %&'()#H +",+ 8#%&'#3
>#)) ,*%"&-#7 0* +"# )0(07 7&48)# ),.#- &2 +"#
%#)) '#'8-,*#9 ?&'()#'#*+ (-&+#0*3 ?S ,*7
?T %,* 80*7 +& ?L8QR< .0#)70*= , ?L8QRST &-
?L85?T %&'()#H9 ?T 2&-'3 (&).'#-0% %&'5

%&*%#*+-,+0&*3 &2 C =D)< (),.3 , %#*+-,) -&)#9
!"#-# ,-# +>& %&'()#'#*+ ,%+01,+0&* (,+"5
>,.3 E%),330%,) ,*7 ,)+#-*,+01#F9 G&+" )#,7 +&
+"# 2&-',+0&* &2 , (-&+#&).+0% %&'()#H -#2#--#7
+& ,3 -. !"'/&0(1)&9
!"# !%1))2!1% !"#$%&#&'( $1(341+ 03 ,*+05
8&7.57#(#*7#*+9 ?)43+#-#7 0''4*&=)&84)0*3
34%" ,3 +"&3# 0* 0''4*# %&'()#H#3 ",1# ,
"0=" ,220*0+. 2&- +"# ?C6 (&-+0&* &2 ',**,*5
80*70*= ?C (-&+#0*9 ?C6 80*70*= 0*74%#3 , %&*5
2&-',+0&*,) %",*=# 0* ?C9 !"03 )#,73 +& +"# ,%5
+01,+0&* &2 ?C- ,*7 ?C3< >"0%" %,+,).A#3 +"#
()#H#3 %&*+,0*0*= 4( +& CI '&*&'#-0% ?T '&5
)#%4)#39 !"# &1#-,)) %&'()#H 03 K*&>* ,3 +"#
#&#601'& 1((1!7 !"#$%&8 E9:-F< >"0%" %-#,+#3
(&-#3 0* +"# %#)) '#'8-,*#9 U*7&=#*&43 %#))3
",1# , 34-2,%# (-&+#0*5'#70,+#7 (-&+#%+01# '#5
%",*03' +",+ (-&+#%+3 +"#' 2-&' V:?50*74%#7
).3039 ?NLT< 2&- #H,'()#< 03 8&4*7 +& +"# %#))
'#'8-,*# 8. =).%&3.)("&3(",+07.)0*&30+&)
EWOPF ,*%"&-0*=9 M0*%# WOP58&4*7 '&)#%4)#3
-#',0* $3&)48)#/ 0* +"# )0(070% %#)) '#'8-,*#<
+"#. ",1# , "0=" )#1#) &2 $),+#-,) '&80)0+.9/
?NLT '&)#%4)#3 0*"080+ +"# 0*3#-+0&* ,*7 (&).5

"
(-&+#&).303 &2 3#-4' (-&+#0* ?I< .0#)70*= , '#-0A,+0&* &2 ?NT9 N.324*%+0&* &2 WOP5,*5
?I, ,*7 , ?I8 2-,='#*+9 ?I8< +"# ),-=#3+ 2-,=5 %"&-#7 (-&+#0*3 %,* )#,7 +& 0*%-#,3#7 343%#(+5
'#*+< 80*73 +& %&'()#'#*+ (-&+#0* ?J< >"0%" 080)0+. &2 #-.+"-&%.+#3 +& ).303 8. ,4+&)&=&43
03 +"#* 8-&K#* 7&>* 8. ?C3 0*+& ?J, ,*7 ?J8 %&'()#'#*+ 0* 703#,3#3 34%" ,3 (,-&H.3',)
2-,='#*+39 !"# ?J, 2-,='#*+ -#',0*3 8&4*7 +& *&%+4-*,) "#'&=)&80*4-0, EOX;F9
?I8< +"43 (-&74%0*= +"# ?B %&*1#-+,3# ?I8J,9
?I8J, %,+,).A#3 +"# (-&+#&).303 &2 ?B 0*+& ?B,
,*7 +"# "0="). -#,%+01# ?B8 2-,='#*+9 !"# ?L
%&*1#-+,3# ?I8J,B8 03 3.*+"#30A#7 ,3 +"# 20*,)
(-&74%+ &2 %),330%,) %&'()#'#*+ (,+">,. ,%+05
1,+0&*9
M',)) 64,*+0+0#3 &2 ?B ,-# %&*+0*4&43). ".5
7-&).A#7 +& ?B, ,*7 ?B8 0* (),3',9 !"# 1%(&0'15
(2/& !"#$%&#&'( $1(341+ %,* 8# ,%+01,+#7
>"#* ?B8 80*73 +& +"# 34-2,%# &2 , '0%-&&-=,*5
03'9 N4# +& 0*+#-,%+0&* >0+" ?B8< (),3', 2,%+&-3
G ,*7 N %,+,).A# +"# %)#,1,=# &2 2,%+&- G 0*+& G,
,*7 G8 2-,%+0&*39 !&=#+"#- >0+" ?B8< 2,%+&- G8
2&-'3 +"# ?B8G8 %&'()#H< ,*&+"#- ?B %&*1#-5
+,3#9 G0*70*= >0+" (-&(#-70* E2,%+&- OF 3+,805
)0A#3 +"# ?B8G8 %&'()#H9 !"# 3+,80)0A#7 %&'5
()#H %,+,).A#3 +"# %&*+0*4#7 ,*7 %&'()#+#
(-&+#&).303 &2 ?B E,'()020%,+0&*F9 ?B8G8 80*73

! <=
&+"#- ?B8 2-,='#*+3< 4)+0',+#). (-&74%0*=
?B8G8B8< +"# ?L %&*1#-+,3# &2 +"# ,)+#-*,+01#
%&'()#'#*+ (,+">,.9
 Antigen
!+*,-.*,$) .): >??(+*$38

C3
!
Immune C1r
C1s Spontaneous hydrolysis Contact with
complex
microorganisms
C1q
C1s C1s
C4 C4b C2a C2
C3a
C3b

C4a C2b
Factor D Factor B

96):.%()*.' ;3,)+,&'(8
Amplification Ba
C4b2a = loop
C3 convertase of the C3b Bb
classical pathway Properdin
C3bBb =
P C3 convertase
of the alternative
C3 C3b pathway
C3a
C3bBbP

C4b2a3b =
C5 convertase
of the classical pathway

1. Classical pathway

A. Complement activation
C3b
C4b

Cell
C2a
C3bBb3b =
C5 convertase of the
alternative pathway

2. Alternative
pathway
Cell
C3b
C3bBb
"
C5 C5a C6 C7 C8

C5
convertase

C5b C5b67 C5b678

C9 C9 (Up to 14 molecules) Inhibition of the stable

C9 bond by CD59
(MAC-inhibitor)

Unstable
C9 bond

B. Lytic terminal sequence

Stable
C9 bond
Poly-C9
membrane attack complex (MAC)
CD59

!
<@

"
" =>' 0%56-'5'*& ?2/&'5

!" #$%&'(&)%* %+ !,&%-%.%,/ 0'--/ 12

3'.,-4&)%* %+ 0%56-'5'*& !(&)7)&2
!"# $#%&' ()*+,-*$ , *&'.#% )/ %#0&1,+)%2
3%)+#-*$ +",+ 3%#4#*+ ()'31#'#*+ /%)' ,++,(56
-*0 *)%',1 (#11$7 8*# )/ +"#$# 3%)+#-*$ -$ , 3%)6
+#,$# 9:;< -*"-.-+)% +",+ -*,(+-4,+#$ :;% ,*= :;$7
:)*0#*-+,1 :; -*"-.-+)% =#/-(-#*(2 1#,=$ +)
("%)*-( ,*= $3)*+,*#)&$ ()'31#'#*+ ,(+-4,6
+-)*> ?"-(" ',*-/#$+$ ,$ $#4#%# ,*= %#(&%%#*+
#3-$)=#$ )/ #=#', 9,*0-)*#&%)+-( #=#',<7
!"#%# ,%# ,1$) , *&'.#% )/ ()'31#'#*+6
()*+%)11-*0 3%)+#-*$> $&(" ,$ !"#$%&$##"'"($)*+,
-$#).( 9@AB< ,*= #./0'"/"+) ("#"0).( )%0" 1
:,*@45'*&4- #$)*()6-'/
!"#%# ,%# /)&% +23#$ )/ ()'31#'#*+ %#(#36
+)%$N
!
$%! )% :@JK> ?"-(" -$ ',-*12 #F3%#$$#= .2
#%2+"%)(2+#$> *#&+%)3"-1$> ')*)(2+#$ ,*=
',(%)3",0#$G -+ .-*=$ +) :J.> :E.> ,*=
-:J.> ,*= 3%)')+#$ 3",0)(2+)$-$7 !"# :C;
%#(#3+)%$ )* +"# #%2+"%)(2+#$ 31,2 ,* -'3)%6
+,*+ %)1# -* +"# #1-'-*,+-)* )/ -''&*)()'6
31#F#$ /%)' +"# (-%(&1,+-)* 9"<7 !"# -''&*#
()'31#F#$ ,%# +%,*$3)%+#= +) +"# 1-4#% ,*=
+"# $31##*> ?"#%# ',(%)3",0#$ .#,%-*0
.)+" :C; ,*= B( %#(#3+)%$ (,* %#')4#
+"#' /%)' +"# $&%/,(# )/ +"# #%2+"%)(2+#$7
!
$%"> ?"-(" -$ #F3%#$$#= ,$ :@D;> 3%-',%-12

9:C;<7 @AB -*"-.-+$ +"# .-*=-*0 )/ :D +) :E.
9!< ,*= 3%)')+#$ +"# =-$$)(-,+-)* )/ #F-$+-*0
:E.D, ()'31#F#$ 9"<7 :)'31#'#*+ %#(#3+)%
:C; ",$ #//#(+$ $-'-1,% +) +")$# )/ @ABG -+
,1$) 3%)')+#$ +"# (1#,4,0# )/ :E. .2 #*H2'#
/,(+)% I 9BIG #<7 B,(+)% I (,+,12H#$ +"# (1#,4,0#
)/ :J. ,+ '&1+-31# $-+#$7 !"-$ /-%$+ 2-#1=$ +"# -*6
+#%'#=-,+# -:J.> +"#* &1+-',+#12 +"# /%,0'#*+$
:J( ,*= :J=07 !"# :J=0 /%,0'#*+ %#',-*$ (#11
'#'.%,*#6.)&*=7 BI ,1$) *##=$ +"# "#13 )/ :C;
+) /&1/-11 +"-$ /&*(+-)*7
)* O 12'3")(2+#$> .&+ ,1$) )* $)'# ! (#11$
,*= #3-+"#1-,1 (#11$7 I+ .-*=$ +) :J=> -:J.>
,*= :J=07 :CD -* O (#11$ -$ 3,%+ )/ +"# O6
(#11 ()6%#(#3+)% ()'31#F7 I+ ,1$) $#%4#$ ,$ %#6
(#3+)% /)% P3$+#-*QO,%% 4-%&$#$7
!
$%# )% :@;RS:@;;.7 !"-$> 1-5# $%& 9:@;RS
:@;;(<> -$ , '#'.#% )/ +"# -*+#0%-* /,'-127
O)+" )/ +"#$# ()'31#'#*+ %#(#3+)%$ ,%#
#F3%#$$#= )* (#11$ )/ +"# '2#1)-= 1-*#,0#>
-*(1&=-*0 ')*)(2+#$> ',(%)3",0#$> =#*6
=%-+-( (#11$> 0%,*&1)(2+#$> ,*= .)+" .-*= +)
-:J.7

#
8" 8)%-%.)(4- 9++'(&/ %+ 0%56-'5'*&
I''&*# ()'31#F#$ .#,%-*0 (1#,4,0# 3%)6
:4(&%$/; <*+-4554&%$2 9++'(&/ =&(+$ )/ ()'31#'#*+ ,%# #//-(-#*+12 %#')4#=
:1#,4,0# )/ :J ,*= :K 2-#1=$ +?) $',11 /%,06 /%)' +"# (-%(&1,+-)*> ',-*12 .2 3",0)(2+)$-$
'#*+$ 9:J, ,*= :K,< +",+ -*=&(# +"# =#0%,*&6 -*=&(#= .2 ()'31#'#*+ %#(#3+)%6.#,%-*0 (#11$7
1,+-)* )/ .,$)3"-1$ ,*= ',$+ (#11$7 !"#$# (1#,6 :)'31#'#*+ %#(#3+)%$ ,*= ()'31#'#*+ 3%)6
4,0# 3%)=&(+$ ,%# 5*)?* ,$ $+$02%'$).3*+47 +#-*$ )* +"# (#11 '#'.%,*# ,1$) 3%)')+#
:K, -$ 4#%2 3)+#*+ 9,1')$+ ;LL +-'#$ $+%)*0#% (#11Q(#11 -*+#%,(+-)* 9#<7 I*+#%,(+-)* .#+?##*
+",* :J,<7 :E,> )* +"# )+"#% ",*=> ",$ '&(" /)11-(&1,% =#*=%-+-( (#11$ ,*= O (#11$ 4-, ()'31#6
?#,5#% ,*,3"21,+)F-* ,(+-4-+2 9,33%)F-',+#12 '#*+ %#(#3+)%$ ,*= B( %#(#3+)%$ 31,2$ ,* -'6
)*#6+#*+" +",+ )/ :J,<7 A*,3"21,+)F-* ,(+-4-+2 3)%+,*+ %)1# -* +"# 0#*#%,+-)* )/ '#')%2 O
-$ '#=-,+#= .2 %#(#3+)%$ +",+ -*=&(# $'))+"6 (#11$ 9&<7
'&$(1# ()*+%,(+-)*$> -*(%#,$#= 4#$$#1 3#%'#6
,.-1-+2> ,*= +"# =#0%,*&1,+-)* )/ .,$)3"-1$
,*= ',$+ (#11$7 !"-$ ,(+-4-+2 ,1$) -*=&(#$ ("#6
')+,F-$ ,*= ,(+-4,+-)* )/ 0%,*&1)(2+#$> %#$&1+6
-*0 -* +"# %#1#,$# )/ 3%)+#)12+-( #*H2'#$ ,*=
+"# 3%)=&(+-)* )/ /%## %,=-(,1$7

0" 8)%-%.)(4- 9++'(&/ %+ 0%56-'5'*&;

<55,*%-%.)(4- 9++'(&/
!"# +#%'-*,1 $#M&#*(# )/ ()'31#'#*+ 1#,=$ +)
=-%#(+ 12$-$ )/ .,(+#%-, .2 '#,*$ )/ 3)%# /)%',6

" AB
+-)* 9!<7 !"# 3%)(#$$ )/ (),+-*0 '-(%))%0,*-$'$
?-+" ()'31#'#*+ -*+#%'#=-,+#$ 9.04.+*5$)*.+<
1#,=$ +) -*(%#,$#= 3",0)(2+)$-$ )/ +"# '-(%))%6
0,*-$'$7 !"-$ ,(+-4-+2 ,1$) 3%#4#*+$ +"# ,((&6
'&1,+-)* )/ , =,*0#%)&$ #F(#$$ )/ ,*+-.)=26
%-(" -''&*# ()'31#F#$7
 C2 C2a
3'.,-4&)%* 4*@ 9++'(&/
"
C2a
C4b C4b C4b C4b FI C3b FI C3c
DAF
CR1 CR1 C3dg

1. Blockage 2. Dissociation of C2a and C4b, 3. Cleavage of C4b and C3b by CR1/FI
of binding 2. enhanced by DAF or CR 1
A. Regulation of complement effects: protection of autologous cells

1. Contraction of
1. smooth muscles
Anaphylatoxins
:,*@45'*&4- #$)*()6-'/
2. Increased 3. Degranulation 4. Chemotaxis, release
permeability of 3. of basophils 4. of O2-radicals and
blood vessles 4. lysosomal enzymes

C3a + + + -
C4a (+) (+) (+) -
C5a ++++ ++++
B. Biological effects of complement factors: inflammatory effects

C3b/C3d/iC3b
receptor
+ ++++

#
1. Antimicrobial effects 2. Clearing of immune complexes

APC Killer cell FDC

FcR

C3b C3d FcR B

CR1 CR2
MHC C3b B

"
CR1

T cell Target cell B cell B

CR2 C3d
3. Cell adhesion 4. B-cell stimulation Memory B cell
C. Biological effects of complement: immunological effects
AC
! =**$%) =??2*.%@
!" #$%&'()*+!,,'-.$%)/ 0'1)-21$3 #$%%)3*,
$*/ #$%%)3* 4)-'(*.%.'* 4)-)5%'3,
!"# #$%&'()%*+,)&- +*.)#*( /-/(#0 %1 )**+(# )02
0'*)(- ,#.%3*)4#/ 0%&#.'&+, /(,'.(',#/5 .+&&#6
!+("%3#*2"//%.)+(#6 #%&#.'&+, !+((#,*/
789:8/;5 <")." +,# ")3"&- .%*/#,$#6 +0%*3
0).,%%,3+*)/0/ ='( *%( #>?,#//#6 =- "%/( ()/2
/'#/@ !"#- +,# ,#.%3*)4#6 =- /?#.)1). !+((#,* $#2
.%3*)()%* $#.#?(%,/ 7%&&;5 <")." +,# #>?,#//#6
0%/(&- %* ?"+3%.-(#/@
9 (-?).+& 89:8 )/ =+.(#,)+& AB95 <")."
/"%</ + ")3" 1,#C'#*.- %1 '*0#("-&+(#6 ?+),/
%1 .-(%/)*# +*6 3'+*%/)*# 6)*'.&#%()6#/ 7D?E;@
A2*/$?)*%$1 #3.*-.51),
!"#/# %&)3%*'.&#%()6#/ +,# ,#.%3*)4#6 =- !%&&2
&)F# ,#.#?(%, G 7!HIG;@ !"#,# +,# +( &#+/( (#*
0#0=#,/ %1 ("# !%&& 1+0)&- %1 ,#.#?(%,/@ J( )/
*%< #$)6#*( ("+( !HIK )/ ("# ,#.#?(%, 1%,
&)?%?%&-/+.."+,)6# 7H8L;5 ("# 0+M%, .%0?%'*6
%1 .#&& <+&&/ %1 E,+02*#3+()$# =+.(#,)+@ H8L2
=)*6)*3 ?,%(#)* 7HN8; ?&+-/ + ,%&# +/ +* %?/%*)*
7)@#@5 (+33)*3 ("# 0%&#.'&# 1%, =#((#, .&#+,+*.#;5
+*6 DAOK )/ +* %?/%*). ,#.#?(%, 1%, .%0?&#>#/
%1 H8L +*6 HN8@ J1 ("# 6%/# %1 H8L #>.##6/ ?"-2
/)%&%3).+& &#$#&/5 H8L .+* +&/% =# (+F#* '? =-
#*6%.-(%/)/ $)+ /.+$#*3#, ,#.#?(%,/@ J* .%*(,+/(
"
(% E,+02*#3+()$# =+.(#,)+5 E,+02?%/)()$# =+.2
(#,)+ (-?).+&&- #>?%/# ?#?()6%3&-.+*/ +( ("# .#&&
/',1+.#5 <")." +,# ,#.%3*)4#6 =- !HIP@ Q("#,
&)3+*6/ 1%, !HIP +,# &)?%?,%(#)*/5 &)?%?#?()6#/5
?#?()6%3&-.+*/5 +*6 &)?%+,+=)*%0+**+*@ !"#
&+((#, )/ + 3&-.%&)?)6 ("+( )/ ?,#/#*( )* 0-.%=+.2
(#,)+ +*6 .+* =# ?,#/#*(#6 $)+ DAO 0%&#.'&#/ (%
! .#&&/@ !"# -#+/( .#&& <+&& .%*/()('#*(/ 4-0%/+*
+*6 0+**+* +&/% =)*6 (% 0+**%/# ,#.#?(%,/
("+( 0#6)+(# ?"+3%.-(%/)/@ !")/ ?,%.#// )/ 1+2
.)&)(+(#6 =- 0+**%/#2=)*6)*3 ?,%(#)* %, &#.()*5
<")." <%,F +/ %?/%*)*/@
6" #$%%)3* 4)-'(*.%.'* 4)-)5%'3,
8+((#,* ,#.%3*)()%* ,#.#?(%,/ .+* =# 6)$)6#6
)*(% (",## 3,%'?/R /#.,#(#65 #*6%.-().5 +*6
/)3*+&)*3 ,#.#?(%,/@
L#.,#(#6 ?+((#,* ,#.%3*)()%* 0%&#.'&#/ +,#
%?/%*)*/ ("+( =)*6 (% 0).,%=)+& .#&& <+&&/ (%
(+3 ("#0 1%, 6#3,+6+()%* =- ("# .%0?&#0#*(
/-/(#0 %, =- ?"+3%.-(#/ 7'(;@ !"# =#/(2F*%<*
,#.#?(%, %1 (")/ .&+// )/ 0+**%/#2=)*6)*3 &#.()*5
!
<")." )/ /#.,#(#6 =- ("# &)$#, +/ +* S+.'(#2
?"+/#T ?,%(#)*@ J( ,#.%3*)4#/ .+,=%"-6,+(#/
%* =+.(#,)+5 -#+/(5 +*6 /%0# ?+,+/)(#/ +*6
$),'/#/@ :+**%/#2=)*6)*3 &#.()* .%*(+)*/ (<%
0+**+*2=)*6)*3 &#.()*2+//%.)+(#6 ?,%(#+/#/
BC 7:9L8 O +*6 P; ("+( +,# ,#&+(#6 (% DO, +*6
DO/ %1 ("# .&+//). .%0?&#0#*( ?+("<+-@ !"#),
+.()$+()%* .&#+$#/ DU5 ("# ("),6 .%0?%*#*( %1
.%0?&#0#*(5 <")." )*)()+(#/ ("# .+/.+6# %1
.%0?&#0#*( +.()$+()%* 7/## ?@ VW;@
X*6%.-(). ?+((#,* ,#.%3*)()%* ,#.#?(%,/ +,#
#>?,#//#6 %* ("# /',1+.# %1 ?"+3%.-(#/ +*6
0#6)+(# ("# '?(+F# +*6 (,+*/?%,( (% &-/%/%0#/
7');@ 91(#, &-/%/%0+& 6#3,+6+()%* +*6 +*()3#*
?,%.#//)*35 ("# 0).,%=)+& ?#?()6#/ .+* =# ?,#2
/#*(#6 (% ! .#&&/ $)+ :YD .&+// JJ 0%&#.'&#/
7+6+?()$# )00'*)(-;@ !"# 0+**%/# ,#.#?(%,
+*6 /.+$#*3#, ,#.#?(%,/ =#&%*3 (% ("# .&+//
%1 #*6%.-(). ?+((#,* ,#.%3*)()%* ,#.#?(%,/@
!"# 0+**%/# ,#.#?(%, ,#.%3*)4#/ 1,#C'#*( 0%2
()1/ %1 0+**%/# (-?).+&&- #>?,#//#6 )* 0)2
.,%=#/Z ("# /.+$#*3#, ,#.#?(%, =)*6/ (% =+.(#,)+
<+&&/5 ("#,#=- .&#+,)*3 ("#0 1,%0 .),.'&+()%*@
!"# &+/( 3,%'?5 ("# /)3*+&)*3 ?+((#,* ,#.%32
*)()%* ,#.#?(%,/5 #*.%0?+//#/ ("# 0#0=#,/
%1 ("# !%&&2&)F# 1+0)&- 7'*;@ !"# =#/(2/('6)#6
?+("<+- )/ ("# %*# 0#6)+(#6 =- !HIK +1(#, ,#2
.%3*)()%* %1 H8L@ :A2P )/ + 0%&#.'&# ("+( =)*6/
(% ("# #>(,+.#&&'&+, 6%0+)* %1 !HIK +*6 )/ ,#2
C'),#6 1%, !HIK /)3*+&)*3@ !HIK "+/ + .-(%?&+/2
0). 6%0+)* /)0)&+, (% ("+( %1 ("# JH2O ,#.#?(%,@
J*6##65 .%00%* /)3*+&)*3 /(#?/ )*.&'6# =)*62
)*3 %1 ("# +6+?(#, 0%&#.'&# :-AWW5 +.()$+()%*
%1 ("# JH2O ,#.#?(%,2+//%.)+(#6 F)*+/# 7JI9[;
+*6 %1 ("# +6+?(#, 0%&#.'&# !B\ ,#.#?(%,2+//%2
.)+(#6 1+.(%, ] 7!I9\];5 ("# )*$%&$#0#*( %1 0)2
(%3#*2+.()$+(#6 ?,%(#)* F)*+/#/ 7:98[;5 +*6
("# 1)*+& ,#&#+/# %1 ("# (,+*/.,)?()%* 1+.(%,
B\!N 1,%0 )(/ )*")=)(%,- ?,%(#)* J!N (% )*6'.#
(,+*/.,)?()%* %1 )00'*# ,#/?%*/# 3#*#/@
7" 8)*/3.%.- 7)11, $, $ 9.*: ;)%<))* =**$%)
$*/ !/$5%.>) =??2*.%@
A#*6,)(). .#&&/ 7AD/; #>?,#// =%(" /)3*+&)*3
8II/5 /'." +/ !HI/5 +*6 #*6%.-(). 8II/5 /'."
+/ /.+$#*3#, ,#.#?(%,/@ !HI/ /#*/# H8L +/
?+,( %1 ("# .#&& <+&& %1 E,+02*#3+()$# =+.(#,)+
+*6 0#6)+(# /)3*+&)*3 ("+( ,#/'&(/ )* ("# /#.,#2
()%* %1 ?,%)*1&+00+(%,- .-(%F)*#/ +*6 ."#0%2
F)*#/@ !"# )**+(# )00'*# ,#/?%*/# )/ +.()$+(#6
<)(")* "%',/@ !",%'3" /.+$#*3#, ,#.#?(%,/5
=+.(#,)+ +,# ?"+3%.-(%/#6 +*6 6#/(,%-#6@ J* +62
6)()%*5 !HI/ )*6'.# AD 0+(',+()%* +*6 '?,#3'2
&+()%* %1 .%2/()0'&+(%,- 0%&#.'&#/5 /'." +/
DAW^_DAW]5 <")." ?,%0%(# ("# ?,#/#*(+()%*
%1 0).,%=)+& ?#?()6#/@ 91(#, U2V 6+-/5 /()0'&+2
()%* =- AD/ ,#/'&(/ )* /'11).)#*( *'0=#,/ %1
.&%*+&&- #>?+*6#6 +*()3#*2/?#.)1). !2#11#.(%,
+*6 !2"#&?#, .#&&/5 ("# .%0?%*#*(/ %1 +6+?()$#
)00'*)(-@
 Bacterial DNA
#$%&'()*+$,,'-.$%)/ 0'1)-21$3 #$%%)3*, $*/ #$%%)3* 4)-'(*.%.'* 4)-)5%'3,

PAMPs PRR
!
– CpG Toll-like-receptor 9
Mycobacteria Scavenger receptors, LBP,
– LPS CD14, Toll-like receptors 4
– Lipoproteins Toll-like-receptor 2
Gram +ve bacteria
– Peptidoglycans CD14, Toll-like-receptor 2
– Lipoarabinomannan CD1, Toll-like-receptor 2
Gram -ve bacteria
Mannose receptor
– Mannan Mannose-binding protein

Yeasts Mannose receptor, !-glucan

– Zymosan receptors, Toll-like receptor 2

A. Pathogen-Associated Molecular Patterns and Pattern Recognition Receptors

A2*/$?)*%$1 #3.*-.51),
Bacteria

Mannose- C3 C3b
“Acute phase”
binding
lectin Complement C3a
MASP1 MASP2 activation
1. Secreted pattern recognition receptors

"
Mannose receptor
MHC II

Scavenger receptor Lysosome Presentation

2. Endocytic pattern recognition receptors

MD-2 P I"B Nucleus

MyD88
TLR4 IRAK
Bacterial MAPK
lipopoly- Adapter TRAF 6 NF"B Activation of
saccharide CD14 proteins inflammatory
and immune
3. Signaling pattern recognition receptors
response genes
B. Pattern recognition receptors

LPS IL-1, IL-12

Toll-like receptor
MHC II TCR Clonal
expansion

Endocytic
PRR CD80/86 CD28

C. Dendritic cells as a link between innate and adaptive immunity

Quiescent
T cell

Help
!
BD
! #$%&'()*$ :.;30*.'/
!" #$%&'()*$ !+,$-.'/ 0/+ 12*3040-0*.'/
!"#$%&'"()* +),-) (%) './'0+,(.&1 2" $,**.13
(%/&03% (%) )14&(%)+.0#5 61 (%) $&*(',$.++,/"
-)10+)* &7 +"#$% 1&4)* ,14 8)")/9* $,('%)*:
, *$)'.,+.;)4 )14&(%)+.0# #,4) 0$ 2" 010<
*0,++" %.3% )14&(%)+.,+ ')++*: ',++)4 !.3%<"1<
4&(%)+.,+ #)10+)* =$%&>: ,++&?* #.3/,(.&1 &7
/)*(.13 +)0@&'"()*5 A.3/,(.&1 .* )1%,1')4 .1
.17+,#)4 (.**0)*5 B* , 7./*( *()$: (%) './'0+,(.13
+)0@&'"()* )13,3) ,4%)*.&1 #&+)'0+)* .1 &/4)/
(& *+&? 4&?15 C%.* *()$ .* ',++)4 D()(%)/.13E ,14
.* #)4.,()4 2" *)+)'(.1*5 !<*)+)'(.1 .* )F$/)**)4
&1 +)0@&'"()*: ?%)/),* )14&(%)+.,+ ')++* )F<
@%/+0?$/*09 A3./(.B9$-
$/)** G<*)+)'(.1 ,* ?)++ ,* 8<*)+)'(.1 =?%.'%
,/) ,+*& 7&014 &1 $+,()+)(*>5 B++ *)+)'(.1* 2.14
*.,+&#0'.1<+.@) 3+"'&$/&().1* &7 (%) *.,+"+<!)<
?.*F ("$): *0'% ,* '<()+)'(.1 )*"'&$/&().1 *.<
3,14<+ =',-./+>: ,1 )**)1(.,+ +.3,14 7&/ 8<*)<
+)'(.1 20( ,+*& 7&/ G<*)+)'(.1 ,14 !<*)+)'(.15 61
,44.(.&1: !<*)+)'(.1 2.14* (& ,44/)**.1*: *0'%
,* 0)/.$%)/,+ 1&4) 234/)**.1 ='453>: , *$)'.7.'
7),(0/) &7 $)/.$%)/,+ +"#$% 1&4)*: ,14 60'&<
*,+ 234/)**.1 7)++ 24%)*.&1 6&+)'0+)<+ =853/
958/+>: ("$.',+ 7&/ 8)")/9* $,('%)*5 C%) ,4%)<
*.&1 2&14* 4.**&'.,() ,14 20.+4 0$ &-)/ ,14
"
&-)/: /)*0+(.13 .1 , *+&? /&++.13 #&(.&15 C)(%)/<
.13 ,14 /&++.13 &7 +)0@&'"()* .* 70/(%)/ *0$<
$&/()4 2" ! .1()3/.1*: *0'% ,* !H"I =,+*& /)7)//)4
(& ,* J!B<H> ,14 !H"K5 L&?)-)/: *)+)'(.1<
#)4.,()4 2&14* ,/) 1&( *077.'.)1( (& $)/#,<
1)1(+" ,//)*( (%) ')++*5 G14&(%)+.,+ ')++* *)'/)()
'%)#&@.1)* (%,( 2.14 (& *$)'.7.' '%)#&@.1) :)<
')$(&/*: ?%.'% %,-) *)-)1 ;/,1*#)#2/,1) 3&<
#,.1* =<=8>> )F$/)**)4 &1 /&++.13 +)0@&'"()*5
B7()/ (%) /,$.4 ,'(.-,(.&1 &7 "M .1()3/.1*: )535:
!!"M =!NB<I: OPII,QOPIR> &/ !A"M =A,'<I:
OPII2QOPIR>: ,* ?)++ ,* !H .1()3/.1*: (%) .1<
()3/.1* 2.14 *)-)/,+ ,4%)*.&1 #&+)'0+)* (%,(
2)+&13 (& (%) .##01&3+&20+.1 *0$)/7,#.+":
*0'% ,* 6OBA<I =OPSH>: 6OBA<M =OPITM>:
JOBA<I =OPITU>: ,14 AB4OBA<I5 C%.* $/&<
-.4)* , (.3%()/ 2&14 &7 (%) +)0@&'"()*: ?%.'%
7.1,++" ,//)*( ,14 #.3/,() (%/&03% (%) )14&(%)<
+.0#5
5" 678$99 :.;30*.'/
C& 7.14 ,1(.3)1*: C +"#$%&'"()* $)/.&4.',++"
!
#.3/,() (& (%) *)'&14,/" +"#$%&.4 &/3,1*5
V%)1 C +"#$%&'"()* /&++ ,+&13 (%) )14&(%)<
+.0# ,7()/ .1.(.,(.&1 &7 *)+)'(.1<#)4.,()4 ,4%)<
*.&1: (%)" )1'&01()/ (%) ()'&14,/" *"#$%&.4
(.**0) 7%)#&@.1) =,.9> &1 LGJ*5 W!O .* $/&<
CD 40')4 2" LGJ* 20( ,+*& 2" *(/&#,+ ')++* .1
(%) C<')++ ;&1) &7 *)'&14,/" +"#$%&.4 &/3,1*5
C ')++* )F$/)** (%) '%)#&@.1) /)')$(&/ OOXK: ,
/)')$(&/ 7&/ W!O ,14 7&/ (%) %$*().1YZ,// -./0*<
.140')4 /)')$(&/ *.3,14 7%)#&@.1) =G!O>:
?%.'% .* ,+*& /)7)//)4 (& ,* 6,'/&$%,3) ?17+,#<
#,(&/" 0/&().1<[" =8@'/A">5 C<')++ #.3/,(.&1 .*
4/.-)1 2" W!O $/&40')4 2" *(/&#,+ ')++* ,14
G!O #,4) 2" 4)14/.(.' ')++* ,14 #,'/&$%,3)*
.1 (%) +"#$% 1&4) C ;&1)5 A)#&/" C ')++*
%,-) , +&? )F$/)**.&1 &7 OOXK '&#$,/)4
?.(% 1,.-) C ')++*: ?%.'% #," '&1(/.20() (&
(%)./ /)40')4 (/,77.'@.13 (%/&03% +"#$% 1&4)*5
\)(: .7 /)*(.#0+,()4 2" ,1(.3)1: (%)" ]0.'@+" /)<
,'( (& W!O ,14 G!O ,3,.15 CLM ')++* ,+*& %,-) ,
?),@ )F$/)**.&1 &7 OOXK: *& (%)" 4& 1&( #.<
3/,() (& (%) C<')++ ;&1) 20( ,/) /,(%)/ 7&014
,( (%) )43) &7 Z<')++ ,/),*: ?%)/) (%)" ',1 $/&<
-.4) %)+$ (& Z ')++*5
8" 578$99 :.;30*.'/
Z ')++* #," )1'&01()/ ,1(.3)1* .1 2+&&4: +"#$%
1&4)*: &/ (%) *$+))15 C%)" ',1 ,+*& /)'&31.;)
,1(.3)1* &1 (%) *0/7,') &7 ,1(.3)1<$/)*)1(.13
')++* &/ B&++.'0+,/ 3)14/.(.' 7)++* =CD9> ?.(%.1
7&++.'+)*5 Z +"#$%&'"()* ,/) ,((/,'()4 .1(&
+"#$% 1&4)* 2" E *"#$%&'"() 7%)#&,((/,'(,1(
=Z!O> $/&40')4 2" NPO* ,14 *(/&#,+ ')++*5 C%)
'&//)*$&14.13 /)')$(&/ 7&/ Z!O &1 Z +"#$%&<
'"()* .* (%) '%)#&@.1) /)')$(&/ O^OXS5
<" <$/+3.*.( 8$99 :.;30*.'/ ./*' =/>90?$+
6.--%$
B( *.()* &7 .17+,##,(.&1: #.'/&2.,+ ,1(.3)1* ,/)
',$(0/)4 2" (%) !,13)/%,1* ')++* =!O> &7 (%)
)$.4)/#.*5 A.'/&2.,+ '&#$&1)1(*: *0'% ,* *.$&<
0&+"(,''%,/.4) =!8W>: .1.(.,() #,(0/,(.&1 &7 !O:
?%.'% (%)1 #.3/,() (& (%) 4)/#,+ +"#$%,(.'
-)**)+*5 !8W .140')* *)'/)(.&1 &7 .17+,##,(&/"
'"(&@.1)*: *0'% ,* C_N<!: ,14 '%)#&@.1)*:
*0'% ,* A68<I!: AO8<I: 6!<R: ,14 XB_CGW: 2"
4)/#,+ 4)14/.(.' ')++* =PO*> ,14 #,'/&$%,3)*5
6##,(0/) PO* (%,( )F$/)** (%) '&//)*$&14.13
'%)#&@.1) /)')$(&/* OOXI: OOXM: OOXS: OOXU:
,14 O^OXI ,/) ,((/,'()45 P0/.13 #,(0/,(.&1:
(%)*) /)')$(&/* ,/) 4&?1/)30+,()4 *& (%,(
PO* ',1 +),-) (%) *.() &7 .17)'(.&15 B( (%)
*,#) (.#): #,(0/.13 PO* 0$/)30+,() (%) '%)<
#&@.1) /)')$(&/* OOXK ,14 O^OXH5 A,(0/)
PO* (%,( )F$/)** OOXK ,/) ,((/,'()4 2" )1<
4&(%)+.,+ ')++* &7 4)/#,+ +"#$%,(.' -)**)+*
(%,( )F$/)** (%) OOXK +.3,14 W!O ,14 ,/)
(%)1 4/.-)1 (& (%) *02',$*0+,/ *.10*)* &7
/)3.&1,+ +"#$% 1&4)*5 L)/): (%)" ,/) 30.4)4
2" , 3/,4.)1( &7 2&(% G!O ,14 W!O (& (%)
C<')++ ,/),*5
 #$%&'()*$ !+,$-.'/ 0/+ :.;30*.'/
!
Endothelium

Tethering Rolling Activation Arrest

Glycoprotein !4"7 !4"1 7TMR ! L" 2 ! M" 2 !4"7 !4"1

PSGL-1 L-selectin integrin integrin integrin integrin integrin* integrin*

@%/+0?$/*09 A3./(.B9$-
Chemokines

P-selectin PNAd MAdCAM-1 VCAM-1 ICAM-2 ICAM-1 MAdCAM-1 VCAM-1

E-selectin
*activated
A. Leukocyte adhesion and extravasation

T cell

"
CCR 7
HEV SLC CXCR5
Lymphoid BLC
follicle
T cell

B cell
CCR 7 FDC,
ELC c stromal cells
DC, MØ
B. T-cell migration C. B-cell migration

RANTES
IL-8 MCP-1

MIP-1!

TNF-!
CCR1
CCR2
CCR5
(CCR6)
Immature DC CXCR1
D. DC migration into inflamed tissue
Mature DC
CCR7
CXCR4
Migration to
lymph nodes !
CE
! 31.4(5(6-215 7889,& :&241,-'8' 1,; #(5&+1,2&

!"#$$#%&'()*+ ') ,)$#(-* %*'(-#*+ &%* .#%/ ')

'(++0# /%1%-#2 30&4 $#+5)*+#+ %$# 6*)7* %+
!"#$%&$'&()(*()" %$+,)(-'&8 74(&4 %$# /("(/#/
(*') ,)0$ '95#+2 :95# ;<;;; $#%&'()*+ %$#
1#/(%'#/ =9 %*'(=)/(#+8 74#$#%+ '95# ;> $#%&?
'()*+ %$# 1#/(%'#/ =9 : &#..+2
!" #$%&' () *$%&+'&,'-.-/-.$ 0&12.-(,'
!"#$ %& '(($)'*+$ ,$*-+'./0 3)1# %*'(-#*+
@%..#$-#*+A8 +0&4 %+ (*+#&' "#*)18 ,))/+8 5)..#*8
%*/ /0+' 1('#8 &%* (*/0&# '4# ,)$1%'()* ),
;-B %*'(=)/(#+ (* (*/("(/0%.+ 7('4 % &)$$#?
+5)*/(*- 5$#/(+5)+('()* @%')5(&+C +## %.+)
52 DEFA2 :4# ;-B %*'(=)/(#+ =(*/ "(% G& $#&#5')$+
<9,;18&,.15 3+-,2-%5&'
!"#$ %%%& '((4/$ -.(#5$32($)'*+$) ,$*-2
+'./0 X*'(=)/9<%*'(-#* &)15.#I#+ @(110*#
&)15.#I#+A &%* ,)$1 /0$(*- %* (110*# $#?
+5)*+#2 ;110*# &)15.#I#+ &%* +#''.# (* "#++#.
7%..+8 '4# =%+#1#*' 1#1=$%*# ), '4# .0*-+
%*/J)$ 6(/*#9+8 %*/ (* '4# Z)(*'+ @+9*)"(%A2
:4#9 &%* (*/0&# (*,.%11%')$9 5$)&#++#+ (*
'4#+# +'$0&'0$#+ =9 =(*/(*- &)15.#1#*' ,%&?
')$+ R[% %*/ R\% @%*%549.%')I(*+A2
X 5%$'(&0.%$ '95# ;;; $#%&'()* (+ '4# X$'40+ $#?
%&'()*W 74#* %* %*'(-#* 4%+ 5#*#'$%'#/ '4#
+6(* ), %* (*/("(/0%. 74) 4%+ 5$#,)$1#/ ;-V
%*'(=)/(#+8 '4# (110*# &)15.#I#+ &%* =(*/
') G& $#&#5')$+ ), 1)+' &#..+ (*/0&(*- /#-$%*0?

.%'()*](*,.%11%')$9 &#..+ %$# $#&$0('#/ %*/

') 1%+' &#..+ @+#*+('(H%'()*A2 ;, '4# (*/("(/0%. (+
&)15.#1#*' (+ %&'("%'#/8 .#%/(*- ') '4# $#.#%+#
$##I5)+#/ ') '4# %..#$-#*8 &$)++?.(*6%-# ), '4#
), R\% %*/ .)&%. (*,.%11%'()*8 5.%'#.#' %&&010?
1#1=$%*#?=)0*/ ;-B )&&0$+2 :4(+ $#+0.'+ (*
.%'()*8 %*/ #"#*'0%..9 ') =.))/ "#++#. )&&.0+()*
'4# (11#/(%'# $#.#%+# ), 1#/(%')$+ @#2-28 4(+'%?
7('4 *#&$)+(+2
1(*#8 6(*(*)-#*A8 74(&4 (*/0&# "%+)/(.%'()*8
!"#$ %6& )$5*"$)2+"#$ 7"#$,8$/8'+'9'+" ,$2
+1))'4?10+&.# &)*'$%&'()*8 10&0+ +#&$#'()*8
*-+'./0 N%5'#*+ %$# 1).#&0.#+ ), "#$9 +1%..
#/#1%8 %*/J)$ +6(* =.(+'#$+2 K)+' %..#$-#*+
1).#&0.%$ 7#(-4' @),'#* ! P 6T%A2 :4#9 %$#
%$# +1%.. 5$)'#(*+ '4%' &%* #%+(.9 /(,,0+#
')) +1%.. ') ,0*&'()* %+ %*'(-#*+8 =0' '4#9
'4$)0-4 '4# +6(* )$ 10&)+%2 :4#9 %$# ,$#?
&%* 5#*#'$%'# '4# #5(/#$1(+ %*/ =(*/ ')
L0#*'.9 5$)'#%+#+ %*/ %$# %&'("# %' "#$9 .)7
&#$'%(* 5$)'#(*+ (* '4# +6(* @&%$$(#$ 5$)'#(*+A2
/)+#+2 ;M?F ,%")$+ /(,,#$#*'(%'()* ), :ND &#..+2
N%5'#*<&%$$(#$ &)15.#I#+ %$# =)0*/ =9 %*'(?

"
:4# #I%&' 1#&4%*(+1 '4%' .#%/+ O &#..+ ') 5$)?
-#*?5$#+#*'(*- &#..+ ), '4# +6(* @M%*-#$4%*+
/0&# ;-B (+ *)' 6*)7*2
&#..+A8 74(&4 '4#* 1(-$%'# ') $#-()*%. .9154
!"#$ %%& */+'1.)"2($)'*+$) -"+.+.3'- ,$*-2
*)/#+ @+## %.+) 52 F\A2 :?&#.. +'(10.%'()* '4#*
+'./0 :4# (110*(H%'()* ), (*/("(/0%.+ ') #$9?
)&&0$+ %' '4# .9154 *)/#2 :4# +)?&%..#/
'4$)&9'# %*'(-#*+ /0$(*- 5$#-*%*&9 (+ % '95(&%.
&$'&()(2+)(-' #!+&$ .%+'+ &%2 PE<PF /%9+2 ;, '4#
#I%15.# ), % '95# ;; $#%&'()* @+## %.+) 52 PPQA2
(*/("(/0%. (+ $##I5)+#/ ') '4# 4%5'#*8 %*'(?
R4(./$#* 74) (*4#$(' '4# S4T #$9'4$)&9'# %*'(?
-#*?+5#&(,(& : &#..+ 1(-$%'# ') '4# +6(*8 74#$#
-#* ,$)1 '4#($ ,%'4#$ &%* (*/0&# (110*(H%'()*
'4#9 %&&010.%'# %*/ 5$).(,#$%'#2 :4#9 %.+)
%-%(*+' '4# S4TU %*'(-#* (* '4#($ S4T? 1)'4#$2
&%0+# #/#1% ,)$1%'()* %*/ .)&%. (*,.%11%'()*
3#*+('(H%'()* 0+0%..9 )&&0$+ %' =($'4 74#* ,#'%.
7('4 '4# 4#.5 ), &9')6(*#+2 R)15)0*/+ &)*?
=.))/ &#..+ &)1# (*') &)*'%&' 7('4 '4# 1%'#$*%.
'%(*(*- *(&6#. )$ &4$)1# %*/ &4#1(&%.+ +0&4
(110*# +9+'#12 ;* %*9 +0=+#L0#*' 5$#-*%*?
%+ '4)+# ,)0*/ (* $0==#$ %$# '95(&%. '$(--#$+
&(#+8 1%'#$*%. %*'(?S4T %*'(=)/(#+ ), '4# ;-V
), '95# ;> 495#$+#*+('("('9 $#%&'()*+ @+## %.+)
'95# &%* 5%++ (*') '4# 5.%&#*'% %*/ &%0+# +#?
52 DEDA2
"#$# 4#1).9+(+ ), ,#'%. S4TU #$9'4$)&9'#+2
.)!$% $/+0#1$&W T$0-+ @#2-28 5#*(&(..(*A &%*
5%++("#.9 =(*/ ') #$9'4$)&9'#+2 X*'(=)/(#+ /(?
$#&'#/ %-%(*+' 5#*(&(..(* '4#* .#%/ ') .9+(+ ),
'4# #$9'4$)&9'#+ @+## %.+) 52 PDFA2 :4# ,)$1%?
'()* ), %*'(=)/(#+ /($#&'#/ %-%(*+' '4# =%+#?
1#*' 1#1=$%*# @OKA ), '4# -.)1#$0.0+ &%*
/#"#.)5 /0$(*- '4# &)0$+# ), 6(/*#9 (*,.%11%?
'()* @+## %.+) 52 DDQA2 M0*- /%1%-# %&&)15%?

!
*(#/ =9 50.1)*%$9 4#1)$$4%-# %*/ $#*%.
(*,.%11%'()* @-.)1#$0.)*#54$('(+A 1%9 )&&0$
/0# ') &$)++?$#%&'()* ), '4#+# %*'(=)/(#+ 7('4
'4# =%+#1#*' 1#1=$%*# ), '4# .0*- @V))/?
5%+'0$#Y+ +9*/$)1#A2
==
 *$%&+'&,'-.-/-.$ 0&12.-(,'

Mucus secretion
!
Antigen

Reexposure to antigen
Second
antigen
Insect venom Food Pollen Dust mite

constriction
contact

Bronchial
Increased
Urticaria
permeability
Antigen Fc!R of blood
vessels
IgE

Basophil/mast cell Degranulation,

Type I: Immediate hypersensitivity mediator release

<9,;18&,.15 3+-,2-%5&'
Penicillin Mother
RhD-
Antigen

Fetus
RhD+ Complement
Anti-BM
R' S CH3 antibodies
CH3 1st pregnancy
C N Immune
O COO complex

Immune
Post
partum
anti-
RhD

Pulmonary
bleeding
complex
deposit C3a
C5a
"
Enzyme
release,
2nd pregnancy cell
Lysis Nephritis damage

Type II : Cytotoxic antibody reactions Type III: Immune complex reaction

Hapten Hapten – Langer- Hapten/antigen

carrier hans reexposure
complex cell Lymph nodes

Epidermis

Dermis

Lymphatic

A. Types of hypersensitivity reactions

Induction of
antigen-specific
T cells
Type IV: Delayed type hypersensitivity (DTH ) !
=>

"
! :2(;*0*5)'20 #==&$/ </';2$)7=7 2$% ,*0/12$'/

!" #$%&'()*$ *+ ,-./00 ,*0/12$'/ 34

!$()5/$-61/7/$()$5 8/$%1)()' ./007
!"# $%&&%'()* #+,#-(.#)/0& .%1#& 1#.%)2
3/-0/#3 /"# ()145/(%) %$ /%&#-0)5# 67 5#)/-0&
.#5"0)(3.38 9,&#)(5 /(334# 3#5/(%)3 '#-# -#2
.%:#1 $-%. 0 3/-0() ; 014&/ .%43#< 0)1 ,-#2
,0-0/(%)3 5%)/0()()* 1#)1-(/(5 5#&&3 '#-#
.01#8 !"# 5#&&3 '#-# ()5460/#1 '(/" /"# !"#
$%&' ! 5#&&3 %$ 0 3/-0() = .%43#8 ;3 #+,#5/#1<
/"(3 ()145#1 /"# 05/(:0/(%) 0)1 -#05/(%) %$
/"# 3/-0() = 5#&&38 !"(3 '03 )%/ /"# 503# '"#)
()&'*+, 3/-0() ; 5#&& ,-#,0-0/(%)3 '#-# ()542
60/#1 '(/" *!!"$%&' 3/-0() = /"7.43 5#&&38
>&$%2=/$(20 :1)$')60/7
0)1 -0/38 N) /"#3# 3/41(#3< %)# %- .%-# $%-#(*)
*#)#3 '#-# ()/-%145#1 ()/% /"# *#-.&()# %$ /"#
0)(.0&3 67 .(5-%()O#5/()* PH; /"0/ 5%1#3 $%-
/"#3# *#)#3 () /"# ,-%2)45&#( %$ $#-/(&(I#1
#**38 !"# #**3 '#-# /"#) (.,&0)/#1 () 3"0.2
,-#*)0)/ .(5#8 !"# %$$3,-()* /"0/ 1#:#&%,#1
$-%. /"#3# #.6-7% '#-# E/-0)3*#)(58F N) %/"#-
'%-13< /"# $%-#(*) *#)# '03 ,#-.0)#)/&7 ()/#2
*-0/#1 ()/% /"#(- *#-.&()# *#)#3 0)1 /-0)32
.(//#1 /% ,-%*#)78 !"(3 #+,#-(.#)/0& 373/#.
"03 %)# 1#5(3(:# 01:0)/0*# %:#- /"# ,-#:(%43
#+,#-(.#)/0& .%1#&38 !"# *#)# ,-%145/ '(/"
/"# /%&#-0)5#2()145()* $#0/4-# %$ ()/#-#3/ (3
,-#3#)/ () /"# 1#:#&%,()* %-*0)(3. -(*"/

>#)5#< 0 3,#5($(5 )%)-#05/(%) ?$)-'&",.'@ %52 $-%. 6(-/"8 N/ 1%#3 )%/ )##1 /% 6# 0-/($(5(0&&7 (.2
54--#18 !%&#-0)5# 0,,0-#)/&7 1#:#&%,#1 14# ,&0)/#1 0/ 0 &0/#- /(.#8
/% /"# ,-#)0/0& 5%)/05/ '(/" /"# $%-#(*) 1#)1-(2
/(5 5#&&38 !"43< /"# ,-#)0/0& ,"03# 0)1 (..#1(2
0/# ,%3/)0/0& ,#-(%1 0-# %$ 5-(/(50& (.,%-/0)5#
() /"# ()145/(%) %$ /%&#-0)5#< (8#8< $%- /"# ,-#2
:#)/(%) %$ &0/#- 04/%(..4)(/7 ?3## 0&3% ,,8 AB
0)1 CD@8

9" :/1)6;/120 </';2$)7=7 +*1 #$%&'()*$

*+ ,*0/12$'/

"
!"# ,-#)0/0& 0)1 (..#1(0/# ,%3/)0/0& 3#&#5/(%)
.#5"0)(3.3 3/0-/ /% $4)5/(%) '"#) 0 ,%/#)/(0&
04/%0)/(*#) ,033#3 ()/% /"# /"7.43 6#$%-#
6(-/"8 ;4/%-#05/(:# ! 5#&&3 '(/" )% 0)/(*#)3 ,-#2
3#)/ () /"# /"7.43 #350,# $-%. )#*0/(:# 3#&#52
/(%)8 !"#7 50)< "%'#:#-< 6# E6-(1&#1F 67 ,#-(,"2
#-0& /%&#-0)5# .#5"0)(3.3< #8*8< -#*4&0/%- 5#&&3
?3## 0&3% ,8 GB@8 H% (..4)# -#05/(%) (3 ,%33(6&#
6#$%-# /"(3 .#5"0)(3. "03 $0(&#18
;,0-/ $-%. /"# 05/(:# .#5"0)(3.3 %$ 34,2
,-#33(%)< (/ (3 0&3% (.,%-/0)/ /"0/ ,%/#)/(0&&7
04/%-#05/(:# ! 5#&&3 0-# 4)06&# /% -#5%*)(I#
/"#(- 0)/(*#)3 ($ /"#7 0-# E"(11#)F ?() /"# #+/-02
:0354&0- %- ()/-0:0354&0- 3,05#@ %- '#-# )%/
34(/06&7 ,-#3#)/#1 67 ,-%$#33(%)0& 0)/(*#)2
,-#3#)/()* 5#&&3 ?(*)%-0)5# .%1#&< 3## 0&3%
,8 GJ@8 !"# $05/ /"0/ .%3/ %-*0) 5#&&3 1% )%/
6#0- 055#33%-7 !25#&&205/(:0/()* .%&#54&#3 (3
0&3% (.,%-/0)/8 !"#-#$%-#< )% (..4)# -#3,%)3#
50) 1#:#&%,< #:#) '"#) /"# 5#&& (3 6%4)1 :(0
/"# !KL8
M) /"# %/"#- "0)1< 5%)/05/ '(/" 3#&$20)/(2
*#)3 50) &#01 /% /"# 1#,&#/(%) %$ -#05/(:# 5#&&3<

!
/% !KL .%14&0/(%) 0)1< 4&/(.0/#&7< /% 0)#-*78

." ,12$75/$)' <)'/

N.,%-/0)/ "7,%/"#3#3 5%)5#-)()* /"# -#03%)3
$%- /"# *,/%.$*), ",/ 0&'1'&2"$*), )( $)-'&",.'
?@ '#-# 1#-(:#1 $-%. 3/41(#3 () /-0)3*#)(5 .(5#
Adult mouse, strain A
#$%&'()*$ 2$% :1/7/1A2()*$ *+ ,*0/12$'/

Embryonic mouse, strain B

!
Embryonic
Spleen thymus with
immature
thymocytes
Dendritic
cell + antigen

>&$%2=/$(20 :1)$')60/7
Mature T cells Tolerance
of strain B to A

T cell activation against A

A. Induction of T-cell tolerance by antigen-presenting dendritic cells

Mature T cell

Auto-peptide/MHC Foreign antigens/recognizable

not accessible autoantigens

"
T -cell receptor
Co-receptor
Elimination,
deletion, TCR/
Ignorance loss by co-receptor Regulatory
innocence consumption Anergy modulation cells
B. Peripheral mechanisms of tolerance induction

Fertilized Microinjection Own gene

egg of foreign gene product
Foreign gene
product
Implantation of egg
in syngenic mouse

C. Transgenic mice
Transgenic
offspring
Tolerance

!
?B
! A5(>*6*@)'56 #,,&$- B-'>5$)/,/ 5$% 7*6-45$'-

!" #$%&'()*$ *+ !&(*),,&$- .-/0*$/-

12 3)45662 #$%&'-% 789-66 !'():5()*$
!"#$%&'(#)*& + (&,,- ('..$# /& '(#)*'#&0 /1
#'%2&# (&,,- ). #3& '/-&.(& $4 ' ($5-#)6",'#$%1
-)2.', 7-&& ',-$ 89 :;<9 +5(&,, '(#)*'#)$. '.0
0&-#%"(#)$. $4 #3& #'%2&# (&,,- ('. $.,1 $(("%
'4#&% #3& '.#)2&. 3'- /&&. 8%&-&.#&0 #$ #3&
+ (&,,- /1 =8%$4&--)$.',> '.#)2&.58%&-&.#).2
(&,,- 7!?@-<A &929A ). ).4&(#)$.9
+3& 8%&*)$"-,1 0&-(%)/&0 &B8&%)6&.# 8%$5
0"(&0 0$"/,&5#%'.-2&.)( 6)(& C)#3 + (&,,-
#3'# ',, /$%& #3& -'6& +5(&,, %&(&8#$% 0)%&(#&0
'2').-# ' ,1683$(1#)( (3$%)$6&.).2)#)- *)%"-
<&$%5,-$(56 A4)$')06-/
&.0$2&.$"- -#%"(#"%&-9 O&('"-& $4 6)-#'G&.
)0&.#)#1A #3& /$01 #3&. '##'(G- 4$%&)2. '- C&,,
'- &.0$2&.$"- 6$,&(",&- C3&. ).4&(#&0 C)#3
#3& '.#)2&.9
C" #$%&'()*$ *+ 5$ !&(*),,&$- .-5'()*$
5+(-4 3)456 #$+-'()*$ %&- (* !1-445$(
B?9 965// ## !$()@-$/
I. 6'.1 '"#$)66".& 0)-&'-&-A HD! (,'-- II
'.#)2&.- '%& 4$".0 $. #'%2&# (&,,- #3'# 0$ .$#
&B3)/)# #3& ($%%&-8$.0).2 (&,, -1-#&6- ).
3&',#31 ).0)*)0"',-9 IQL5!5%&,'#&0 ).0"(#)$.
($",0 /& ' 8$--)/,& 6&(3'.)-6 ). -"(3 ='/&%5

7D@EF< 8%$#&).9 +3& 2&.& 4$% #3& *)%', 8%$#&).
C'- '00)#)$.',,1 ,).G&0 #$ #3& ).-",). 8%$6$#&%
'.0 ).#%$0"(&0 ).#$ '.)6',- $4 #3& -'6& -#%').9
H&.(&A ',, )-,&# (&,,- &B8%&--&0 #3)- 8%$#&). *)'
#3&)% EH@ 6$,&(",&-9 I. #3&$%1A #3& )-,&# (&,,-
-3$",0 3'*& /&&. G),,&0 J")(G,1 -).(& #3&1 ',,
/$%& ' 6$,&(",& %&($2.)K&0 /1 (1#$#$B)( + (&,,-9
I. 8%'(#)(&A 3$C&*&%A 8%&.'#', #$,&%'.(& 0)0 .$#
0&*&,$8 /&('"-& #3& #%'.-2&.)( 2&.& 8%$0"(#
'88'%&.#,1 3'0 .$# &.#&%&0 #3& #316"-9 L$
+5(&,, %&'(#)$. $(("%%&0A '.0 #3& '.)6',- 0)0
.$# 0&*&,$8 0)'/&#&- 6&,,)#"-9 M)%&(# ).4&(#)$.
%'.#> (,'-- II '.#)2&. &B8%&--)$.9 ! *)%"- ).4&(#-
' (&%#'). (&,, 2%$"8A '.0 )#- -"%4'(& 6$,&(",&-
'%& )0&.#)4)&0 '- 4$%&)2. /1 -8&()4)( + ,1683$5
(1#&-9 M"%).2 #3& 0&4&.-& 8%$(&--A #3& + ,165
83$(1#&- -&(%&#& IQL5!A C3)(3 ,&'0- #$ #3& ).5
0"(#)$. $4 (,'-- II '.#)2&.- ). 8%&*)$"-,1
".).*$,*&0 (&,,-9 +3)- ='/&%%'.#> &B8%&--)$.
$4 (,'-- II '.#)2&.- 6)23# 8%$68# '"#$%&'(#)*&
+ (&,,-A ). '--$()'#)$. C)#3 (,'-- II '.#)2&.-
#3'# '%& .$# .$%6',,1 &B8%&--&0A #$ )0&.#)41
'"#$'.#)2&.- $. #3& (&,, -"%4'(& '- 4$%&)2.
'.0A ",#)6'#&,1A #$ 0&-#%$1 &.0$2&.$"- (&,,-9

"
$4 #3& '.)6',- C)#3 #3& D@E *)%"-A $. #3& $#3&%
3'.0A ,&0 #$ +5(&,, '(#)*'#)$. '.0 0&-#%"(#)$. $4
)-,&# (&,,-9 N.,1 #3&. 0)0 #3& (1#$#$B)( + (&,,- %&5
(&)*& ' 7($5-#)6",'#$%1< -)2.', *)' '.#)2&.58%&5
-&.#).2 (&,,- '.0 '(#)*'#&0 +53&,8&% (&,,-9

;" #$%&'()*$ *+ !$()1*%2 <*4,5()*$

=)(> 789-66 ?-60 5+(-4 !&(*5$()1*%28
,-%)5(-% !$()@-$ A4-/-$(5()*$
!"#$%&'(#)*& O (&,,- ('..$# /& '(#)*'#&0 #$ 4$%6
'.#)/$0)&- C)#3$"# #3& 3&,8 $4 + (&,,-9 P)#3 #3&
3&,8 $4 #3&)% (&,,5/'-&0 )66".$2,$/",).A 3$C5
&*&%A #3&1 '%& '/,& #$ %&($2.)K&A /).0A 8%$(&--A
'.0 8%&-&.# 6$,&(",&- ($.#').).2 &.0$2&.$"-
'.#)2&. 7!"#$!%#&'(%< '.0 4$%&)2. '.#)2&. ($65
8$.&.#-9 N.(& -"(3 '. '.#)2&. 3'- /&&. 8%$5
(&--&0A #3& O (&,,- 8%&-&.# #3& 4$%&)2. ($68$5
.&.# $4 #3& '.#)2&. #$ + (&,,- *)' #3&)% EH@
6$,&(",&9 +3& + (&,,- #3&. #%'.-6)# -)2.',- 4$%
O5(&,, 3&,89 I. #3)- ('-&A #3& O (&,,- '%& #3$-& #3'#
%&($2.)K& '. '"#$'.#)2&. '.0A #3"-A -&(%&#& #3&
($%%&-8$.0).2 '"#$'.#)/$0)&-9

! DE
9" #$%&'()*$ *+ !&(*),,&$)(2 :)5
B*6-'&654 B),)'42
!(($%0).2 #$ #3& )$*(+"*!, )&)&+,- .-/$#.(0&0A
' (&%#'). '.#)2&.A -"(3 '- ' *)%', $% /'(#&%)',
'.#)2&.A 3'- ' 2%&'# 0&2%&& $4 -)6),'%)#1 C)#3
 B-'>5$)/,/ *+ !&(*),,&$)(2 F#G
!
TC

Resting
T cells
Islet cell

LCM Antigenic peptide Cyto-

virus toxicity

<&$%5,-$(56 A4)$')06-/
TH APC
Signal Signal Activated T cells
A. Induction of an autoimmune response by virally induced T-cell activation

Antigen Surface Autologous cell

Foreign part immuno-
Autoantigenic globulin
part Virus

Processing
Auto
antigen
T cell

C. Induction of an autoimmune reaction

Viral
antigen
"
C. by molecular mimicry
B cell Autoantibodies
Target cell T cell that
HLA class II and virus recognizes
antigen Viral viral Ag
presentation antigen
Help

T-cell IFN-!
receptor

HLA class II
antigen

Auto-
antigen T cell that

!
T cell
recognizes
Cell damage auto-Ag
B. Induction of autoantibodies by T-cell D. Induction of an autoimmune response
help after autoantibody-mediated after viral infection by aberrant
antigen presentation MHC class II antigens
DH

"
" D6(.*5*0)'65 #,,&$1 71'.6$)3,3 6$% E*51/6$'1

!" #$%&'()*$ *+ !&(*),,&$)(- (./*&0.

(.1 2*33 *+ 410&56(*/- 71'.6$)3,3
!"#$%&"#'( #")*('+,#- ."/&'0$1.1 1+$(( "2$1+
'3+"# "'#(- 4"'/+$5'+$,0 ,3 '*+,#"'/+$5" 67/"((
/(,0"1 $0 +&" +&-.*1 &'1 ,//*##"4 81"" %9 ::;9
<,+& =>?@ '04 =>A@ 6 /"((1 /'0 &'5" ' #")*('7
+,#- 3*0/+$,09 B*+,$..*0$+- /'0 4"5"(,% '3+"#
+&" (,11 ,3 1*/& #")*('+,# /"((19
C0 '44$+$,0 +, +&"1" /"((*('# ."/&'0$1.1D
+&"#" '#" '(1, &*.,#'( ."/&'0$1.1 3,# %#"1"#7
5$0) +,("#'0/"9 B0+$7$4$,+-%$/ '0+$E,4$"1 4$#"/7
+"4 ')'$01+ 4"+"#.$0'0+1 ,3 +&" &-%"#5'#$'E("
#")$,0 ,3 ,+&"# '0+$E,4$"1 3,#. '0 !"#$%$&$'#(%
F&$%6,1$(65 D/)$')<513
&$)& 1*1/"%+$E$($+- +, /"#+'$0 4$1"'1"1D +&" 567
/(/#+0 81"" %%9 AAST:; $1 '0 $.%,#+'0+ 4"+"#.$7
0'0+ ,3 +&" )"0"+$/ /,.%,0"0+9 ="#+'$0 QRB
'0+$)"01 '#" ,3+"0 '11,/$'+"4 H$+& 1%"/$3$/ 4"7
+"#.$0'0+1 ,3 1,." '*+,$..*0" 4$1"'1"1 8+&"
,(4 0,."0/('+*#" $1 *1"4 $0 +&" +'E(" 3,# 1$.7
%($/$+-;9 U%,04-('#+&#$+$1D 3,# "2'.%("D $1 1, /(,7
1"(- '11,/$'+"4 H$+& +&" QRB7<VW '0+$)"0 +&'+
4$')0,1$1 ,3 +&" 4$1"'1" $1 )#"'+(- &"(%"4 E- +&"
4"+"/+$,0 ,3 +&$1 $.%,#+'0+ 4"+"#.$0'0+9 U,."
,3 +&" .,1+ $.%,#+'0+ '11,/$'+$,01 '#" ($1+"4
E"(,H9
!
82!// 9 !//'*$!#$'"P 1"#,0")'+$5" 1%,04-('#7
+&#$+$1 '04 QRB7<VWX

)$* "+#,'-. 8'//,#4$0) +, F9 G"#0"; +&'+ /,0+#$7 !

E*+"1 +, +,("#'0/"9 >$1+*#E'0/"1 $0 +&" 0"+H,#I
/'*1"4 E- +&" (,11 ,3 '0+$7$4$,+-%$/ '0+$E,4$"1
,# +&" %#"4,.$0'0/" ,3 %'+&,)"0$/ '*+,'0+$E,7
4$"1 ("'4 +, +&" (,11 ,3 +,("#'0/"9 J2+"#0'( 1*%7
%("."0+'+$,0D "9)9D E- '4.$0$1+"#$0) 0,#.'(
$..*0,)(,E*($01D /'0 #"1+,#" +&" E'('0/" ,3
+&" 0"+H,#I9
8" 9/06$:;<1')+)' 6$% =*$:9/06$:;<1')+)'
!&(*),,&$1 >)316313
82!// 99 !//'*$!#$'"P #&"*.'+,$4 '#+&#$+$1
8/&#,0$/ %,(-'#+&#$+$1; '04 QRB1 >YA '04
>Y:X +-%" C 4$'E"+"1 ."(($+*1 '04 QRB1
>YZ '04 >YAX 0'#/,("%1- '04 QRB7>YV9
F'#/,("%1- '04 QRB7>YV '#" 1, 3#"K*"0+(-
'11,/$'+"4 +&'+ +&" -+2!#$:+ -$/. /'00,+ E" /'(7
/*('+"4 .'+&".'+$/'((-P #"('+$5" #$1I ! 80*.7
E"# ,3 %'+$"0+1 H$+& QRB '0+$)"0"0*.E"# ,3
/,0+#,(1 H$+&,*+ QRB '0+$)"0;#80*.E"# ,3
%'+$"0+1 H$+&,*+ QRB '0+$)"0"0*.E"# ,3
/,0+#,(1 H$+& QRB '0+$)"0;9

#
B*+,$..*0" 4$1"'1"1 .'- E" 4$#"/+"4 ')'$01+
5"#- 1%"/$3$/ ,#)'0 4"+"#.$0'0+1 ,# ')'$01+ 5'#7
$,*1 +$11*" 1+#*/+*#"1 81-1+".$/ '*+,$..*0"
4$1"'1";9

?" ;1@&13(1/1% !$()01$3

6&" /,0/"%+ ,3 1"K*"1+"#"4 '0+$)"01 H'1 4"7
#$5"4 3#,. +&" ,E1"#5'+$,0 +&'+ '3+"# "-" $0L*7
#$"1D 3,# "2'.%("D +&" &"'(+&- "-" 1*44"0(- 4"7
5"(,%1 1-.%+,.1 ,3 /(0)!#1+#$* ')1#1!20$!9
6&*1D /"#+'$0 #")$,01 ,3 +&" E,4- '#" 0,+ '//"17
1$E(" +, +&" $..*0" 1-1+". ,# '#" M1"K*"17
+"#"49N 6&$1 0,+ ,0(- '33"/+1 %#,+"$01 $0 +&"
("01 ,3 +&" "-"D E*+ '(1, +&" /'#+$(')" '04 +"1+$7
/*('# +$11*"9 O0/" +&$1 $1,('+$,0 $1 E#,I"0D "9)9D
4*" +, $0L*#- ,# 1"5"#" $03('..'+$,0D +&" $.7
.*0" 1-1+". &'1 '//"11 +, +&" +$11*" $+ +&"0
$4"0+$3$"1 '1 M3,#"$)09N

>" 4156()*$3.)< A1(B11$ >)316313 6$% (.1

C2! ;-3(1,
6H, /,04$+$,01 .*1+ "2$1+ $0 ,#4"# 3,# '*+,$.7

"
.*0" 4$1"'1"1 +, 4"5"(,%P ' )"0"+$/ /,.%,7
0"0+ '04 "05$#,0."0+'( 3'/+,#1 8-+!2$3!#$'" 4!*%
#'-/;9 J05$#,0."0+'( 3'/+,#1 /'0 ("'4 +, +&"
.'0$3"1+'+$,0 ,3 '0 '*+,$..*0" 4$1"'1"
H&"0 +&"#" $1 ' )"0"+$/ E'1$1 8%#"4$1%,1$+$,0;
GH 3,# +&" 4$1"'1"9 <"/'*1" /"#+'$0 QRB /,01+"(('7
+$,01 '#" '11,/$'+"4 H$+& +&" +#'01.$11$,0 ,3 '
 Antigen Antibody
(anti-idiotypes)
Organ-specific
diseases
71'.6$)3,3 *+ !&(*),,&$)(- I##J

Non-organ-
specific diseases
"
Brain
MS Brain
SLE
Cartilage
Polychondritis Nose
APC TH Wegener’s
B
Thyroid gland granulomatosis
T-helper/ Hashimoto’s
thyroiditis,
inducer primary myxedema, Lung
cell thyrotoxicosis Scleroderma,
(Graves’ disease) MCTD,
Macrophage Wegeners’
Stomach granulomatosis
Pernicious
TR TZ anemia

F&$%6,1$(65 D/)$')<513
Muscle/skin
Presentation Autoaggressive Liver Dermato-
Regulatory PBC, myositis
of effector autoimmune
autoantigens cell functions hepatitis
Pancreas Kidney
A. Induction of autoimmunity by loss Juvenile diabetes SLE,
A. of regulatory mechanisms Wegeners’
Intestine granulomatosis
Crohn’s disease,
d ulcerative colitis
Lens er e Joints
es t Rheumatoid
qu Bone marrow
Se Autoimmune hemolytic arthritis
Hidden
antigens anemia, ITP

#
Skin
An Skin Scleroderma,
tig
Cartilage en Pemphigus SLE
s Testes
B. Organ-specific and non-organ-
C. Sequestered antigens B. specific autoimmune diseases
Frequency (%)
Disease Allele*
Patients Controls Relative risk
Behçet’s disease B5 41 10 6,3
Ankylosing spondylitis B27 90 9 87,4
Reiter’s syndrome B27 79 9 37,0
Acute anterior uveitis B27 52 9 10,4
Subacute thyroiditis B35 70 15 13,7
Psoriasis vulgaris Cw6 87 33 13,3
Dermatitis herpetiformis DR3 85 26 15,4
Celiac sprue DR3 79 26 10,8
Graves’ disease DR3 56 26 3,7
Diabetes mellitus type I DR3 and/or DR4 91 57 7,9
Myasthenia gravis DR3 50 26 2,5
Systemic lupus erythematosus DR3 70 26 5,8
Idiopathic membr. nephropathy DR3 75 26 12,0
Narcolepsy DR2 100 25 N.D.
Multiple sclerosis DR2 59 25 4,1
Rheumatoid arthritis
Hashimoto’s thyroiditis
Pernicious anemia
Juvenile chronic arthritis
DR4
DR5
DR5
DRw8
D. Associations between diseases and the HLA system (*old nomenclature)
50
19
25
23
19
6
6
8
4,2
3,2
5,4
3,6 "
GK

#
! !2/2,/*$*

!"##$ %&$' ()*$'+*'#, -." ') "*$&/" '0" *)/%+#

-"1"#)2%"*' )3 +* )/4+*.$% +*- ') %+.*'+.*
'0" 5+#+*(" 5"'6""* '0" 4"*"/+'.)* +*- #)$$
)3 ("##$ 7!"#$"%&'%(%89 :0.$ +('.1.', .$ /"4&#+'"-
5, )*"+*'##$, -$.. ,$'&!; + ',2" )3 <("## $&.(.-";=
'0" %)/20)#)4.(+# ()//"#+'.1" )3 60.(0 .$ +2)2>
')$.$9 ?2)2')$.$ 2#+,$ +* .%2)/'+*' /)#" 3)/ '0"
()//"(' 3&*('.)* )3 '0" .%%&*" $,$'"%9
!" #$%%&'&()&* +&,-&&( .&)'/*$* 0(1
!2/2,/*$*
!"## *"(/)$.$ )((&/$ +$ '0" /"$&#' )3 $"1"/" .*@&>
/."$ -&"; 3)/ "A+%2#"; ') 5&/*$; )A,4"* -"3.>
(."*(, 7"949; 0"+/' +''+(B8; +*- '/+&%+9 C* *"(/)>
>6(10?&(,07 ='$()$27&*
3/+4%"*'+'.)* 2/)("$$ ,."#-$ + #+--"/>#.B"
2+''"/* '0+' 0+$ 5""* .-"*'.3."- +$ + ',2.(+#
3"+'&/" )3 +2)2')$.$ 7!89
?2)2')$.$ .$ +(()%2+*."- 5, '0" +('.1+'.)*
)3 + *&%5"/ )3 4"*"$9 M*" )3 '0" %)$' .%2)/>
'+*' .$ (1&$*.$32(145! -"16$*&(1+ $1/7#$ 7C!V89
:0" (>#7-; )89; +*- 13*:: 4"*"$ +/" +#$) &2/">
4&#+'"- .* '0" .*.'.+# 20+$" )3 +* +2)2')'.( 2/)>
("$$9 :0" 0-.4; 4"*"; )* '0" )'0"/ 0+*-; ()-"$
3)/ + 2/)'".* '0+' 2/"1"*'$ +2)2')$.$9 W.40 '.'"/$
)3 '0" 2/)'".* (+* 5" 3)&*- .* '0" 3)##.(&#+/ ()/>
'"A )3 ("##$ '0+' 0+1" $&(("$$3&##, /"+//+*4"-
'0"./ .%%&*)4#)5&#.* 4"*"$; 60.#" '0" 2/)'".*
(+**)' 5" -"'"('"- .* '0" 4"/%.*+# ("*'"/;

60"/" '0" /+'" )3 +2)2')$.$ .$ 1"/, 0.409 L/)>

$.$; '0" ("## %"%5/+*" #)$"$ .'$ .*'"4/.',9 ?$ +
-&('$ )3 '0" 0'< +*- 0', 4"*"$ +/" 5(#>X 2/)'".*
/"$&#'; '0" ("## $'+/'$ ') $6"##; +*- '0" ("## ()*>
+*'+4)*.$'$; +*- +('.1+'.)* )3 '0"$" 2/)-&('$ .$
'"*'$; ')4"'0"/ 6.'0 + *&%5"/ )3 ')A.( $&5>
+$$)(.+'"- 6.'0 +2)2')$.$9 :0" 0'< 4"*" 3)/%$
$'+*("$; +/" /"#"+$"- .*') '0" $&//)&*-.*4 '.$>
()%2#"A"$ 6.'0 5(#>X 2/)'".*; '0"/"5, .*+('.>
$&"; '0&$ .*-&(.*4 +* .*3#+%%+')/, /"+('.)*9
1+'.*4 .'9 5(#>Y 2/)'".*; 60.(0 )((&/$ .* '6)
?2)2')$.$; )* '0" )'0"/ 0+*-; .$ + 1"/, $&5'#"
3)/%$Z +* +*'.>+2)2')'.( #)*4>$2#.(" 1+/.+*'
2/)("$$9 :0" 3./$' $.4*$ )3 +2)2')$.$ +/" (0/)%+>
75(#>Y[8 +*- + 2/)>+2)2')'.(; $0)/'>$2#.(" 1+/>
'.* ()*-"*$+'.)* +*- $0/.*B+4" )3 '0" ("##9 :0"
.+*' 75(#>YD8; .$ /"#+'"- ') 5(#>X9 I)6*/"4&#+'.)*
("## %"%5/+*" '0"* -"1"#)2$ $%+## 5&#4"$ .* +
)3 0'< +*- )'0"/ +2)2')$.$>2/)%)'.*4 4"*"$
2/)("$$ B*)6* +$ /$("%(% 70.$00(1+89 :0" ("##
%+, 2#+, + /)#" .* '0" -"1"#)2%"*' )3 *")>
'0"* 5"4.*$ ') "A2"# .'$ ()*'"*'$ .*') 1"$.(#"$;
2#+$%$9

"
$)%" )3 60.(0 ()*'+.* 2+/'$ )3 '0" 3/+4%"*'"-
+*- ()*-"*$"- 72,B*)'.(8 ("## *&(#"&$9 :0" 1">
8" 80*20*& !),$90,$/( +: ;$,/)</(1'$0
$.(#"$ +/" .*4"$'"- +*- -"4/+-"- 5, %+(/)>
20+4"$9 D.*(" '0" (,')2#+$%.( "*E,%"$ +*- ?2)2')$.$>.*-&(.*4 +4"*'$; $&(0 +$ ("/+%.-";
')A.( %"'+5)#.'"$ +/" +#6+,$ $&//)&*-"- 5, )A.-+*'$; 0'<; (+#(.&%; +*- +('.1+'"- (+$2+$"$
%"%5/+*"$; *) .*3#+%%+')/, /"+('.)* )((&/$9 (+* /"#"+$" '0" 2/)'".* (,')(0/)%" - 3/)% %.>
')(0)*-/.+9 !+$2+$"$ +/" ",$'".*" #$2+/'+'"
3" 4&5670,$/( /% !2/2,/*$* 2/)'"+$"$ '0+' (#"+1" ("##&#+/ 2/)'".*$; /"$&#'.*4
.* ("## -"+'09 ?3'"/ 5".*4 /"#"+$"- .*') '0"
?2)2')$.$ .$ + 4"*"'.(+##, /"4&#+'"- 2/)("$$ '0+'
(,')$)#; (,')(0/)%" - 5.*-$ ') .'$ +-+2'"/ %)#">
/"F&./"$ "*"/4, +*- 2/)'".* $,*'0"$.$9 ?2)2')>
(&#" ?2+3>N; 60.(0 +('.1+'"$ 2/)>(+$2+$" J9 :0.$
'.( ("## 3/+4%"*'+'.)* (+* 5" .*-&("- 5, + *&%>
()%2#"A .$ (+##"- +2)2')$)%"9 !+$2+$" J .*
5"/ )3 $.4*+#$; .*(#&-.*4 20,$.)#)4.(+# $'.%&#.;
'&/* +('.1+'"$ -)6*$'/"+% (+$2+$"$ G +*- \; /">
$&(0 +$ +*'.4"* /"("2')/ 5.*-.*49 :0.$ '+B"$
$&#'.*4 .* IP? 3/+4%"*'+'.)* +*- +2)2')$.$9
2#+("; 3)/ "A+%2#"; 60"* '0" $'.%&#&$ )((&/$
!+$2+$"$ (+* 5" .*0.5.'"- 5, C?L$ 7.*0.5.')/$
6.'0)&' '0" +(("$$)/, $.4*+#$ 7$"" 29 GH89
)3 +2)2')$.$ 2/)'".*$89
D&/3+(" %)#"(&#"$; $&(0 +$ !IJK 7?LM>N
)/ O+$ +*'.4"*8; +/" .%2)/'+*' %"-.+')/$ )3
#" =<05/):,/*$* /% !2/2,/,$) 8&77*
+2)2')$.$9 !IJK .$ + %"%5"/ )3 '0" '&%)/
*"(/)$.$ 3+(')/ 7:PO8Q*"/1" 4/)6'0 3+(')/ I&/.*4 +2)2')$.$; 20)$20+'.-,#$"/.*" 7LD8 .$
7PRO8 3+%.#, )3 /"("2')/ 2/)'".*$9 S0"* +('.> "A2)$"- +' '0" ("## $&/3+("9 D(+1"*4"/ /"("2')/$
1+'"- 5, ?LM>NQO+$ #.4+*-$; !IJK '/.44"/$ +* ? +*- "*-)')A.* /"("2')/ !IN] (+* 5.*- ') LD9
+2)2')'.( $.4*+# .* + *&%5"/ )3 ("##$9 ?2)2')$.$ :0" 1.'/)*"('.* /"("2')/ ())2"/+'"$ 6.'0 '0"
'0/)%5)$2)*-.* 7:DL8 /"("2')/ !IGH ') 5.*-

!
(+* 5" '/.44"/"- 5, '0" #)$$ )3 ("##T("## ()*'+('
7'1"(2(%8 )/ '0" 6.'0-/+6+# )3 4/)6'0 3+(')/$ 5, :DL9 :/.44"/.*4 )3 '0"$" /"("2')/$ .*-&("$ +('.*
4#&()()/'.().-$; 0,2"/'0"/%.+; +*- 4/+*E,%" /"+//+*4"%"*'; #"+-.*4 ') .*'"/*+#.E+'.)* )3
7$"" 29 GU89 ? ()%%)* .*'/+("##&#+/ %"-.+')/ +2)2')'.( ("##$9 :0" /"#"+$" )3 2/).*3#+%%+')/,
%+, 5" )A.-+'.1" $'/"$$; 60.(0 (+&$"$ *&(#"+$" (,')B.*"$ )/ (0"%)B.*"$ .$ -)6*/"4&#+'"-9
@A +('.1+'.)*9 :0.$ #"+-$ ') '0" (#"+1+4" )3 IP?
.*') 3/+4%"*'$9 C* IP? "#"('/)20)/"$.$; '0.$
– Ischemia Necrosis
Inflammation
!2/2,/*$*
!
– Hyperthermia
– Hypothermia
– Physical
or chemical
damage
– Trauma Swelling
of the cell, Lysis –
Apoptosis damage to organelles destroyed
signal organelles chromatin destroyed

>6(10?&(,07 ='$()$27&*
Chromatin Cell shrinkage, Chromatin Segmentation Apoptotic Phagocytosis:
condensation zeiosis margination of the nucleus, bodies no
DNA fragmentation inflammation
A. Differences between necrosis and apoptosis

Oxidants Bax Calcium

Apo-1/FAS antigen
Ceramide Active
CD95 caspases
Glucocorticoid T/B-

"
receptor antigen receptor Mitochondrion
Cytochrome c
O2, H2O2 release
i

DNA
OH, NO damage
(UV light, Apaf-1
Loss of cell- irradiation) pro-caspase 9
cell contact
Granzyme
Deprivation of Activation of further caspases, apoptosis
Hyperthermia growth factor

Effector genes C. Caspase activation by mitochondria

-p53 Apoptotic
-nur 77
cell
-c-myc
-ICE
Apoptosis- Apoptosis TSP
inhibiting promoting Vitronectin
genes genes receptor
-bcl-2 -bax CD36
-bcl-xL -bad PS
-Rb -bcl-xS
Scavenger
CD14 receptor-A

Actin

!
polymerization Actin
Anti-inflammatory response
Actin
TNF-" IL-1! MCP-1 IL-8
Survival Apoptosis
B. Regulation of apoptosis D. Phagocytosis of apoptotic cells
@B

"
! !1.%*$1B!1.%(0&C =1.$)/,.%017

!" #$%&$'($)*$) +)$,%-%./.%01 23)4$

!"#$%&%'('%)* '#$+*%,-#. ("# -.#/ ') 0#(.-"#
(*'%1#* )" (*'%2)/3 $)*$#*'"('%)*.4 5+# '#.'.
'(%* '%0# %. -.#/ (. '+# 0#(.-"# )6 (*'%1#* $)*9
$#*'"('%)*4
6#&7#/)4#'"5, 5+%. '#$+*%,-# %. (7.) 2(.#/
)* '+# "#($'%)* &"%*$%&7# )6 %00-*# $)0&7#>
$(* 2# &#"6)"0#/ %* .)7%/ &+(.# 8"(/%(7 %00-9
6)"0('%)* /-# ') (*'%1#*I(*'%2)/3 %*'#"($'%)*4
*)/%66-.%)*: %00-*)#7#$'")&+)"#.%.; )" 7%,-%/
5+# $-B#''# %. %""(/%('#/ <%'+ 7(.#" 7%1+': <+%$+
&+(.# .3.'#0. 8'-"2%/%0#'"3: *#&+#7)0#'"3;4
.$(''#". 6")0 '+# %00-*# $)0&7#>#.4 J#*.#.
5+# !"#$"%&"'("' )'"*#)#+,+#-. */'0" $(* 2#
("# -.#/ ') 6)$-. '+# .$(''#"#/ 7%1+' )*') (
/#.$"%2#/ (. 6)77)<.4 =)7-27# %00-*# $)09
&+)')0#'#"4 K.%*1 '+# 0#(.-"#/ .%1*(7.: '+#
&7#>#. 6)"0 %* '+# (*'%2)/3 #>$#.. ?)*# 87)<
-*D*)<* (*'%1#* $)*$#*'"('%)* $(* '+#* 2#
@1A@2 "('%); )6 '+# $-"B#4 5+# (0)-*' )6 $)09
/#'#"0%*#/ 6")0 ( .'(*/("/ $-"B#4
&7#>#. 6)"0#/ %. &")&)"'%)*(7 ') '+# (*'%1#*
$)*$#*'"('%)*4 5+# "#1%)* )6 #,-%B(7#*$# %. :" ;%<-'$ 6/&%/' =<<310&%>>37%01
"#($+#/ (. %*$"#(.%*1 $)*$#*'"('%)*. )6 '+#
?@/1,%1% @$.90&A
D/(0)/.0)C !--'%,/.%017

(*'%1#* ("# (//#/4 @ B%.-(7%?(27# &"#$%&%'('#

0(/# )6 %*.)7-27# %00-*# $)0&7#>#. 6)"0.
(' #,-%B(7#*$#4 C(%*73 .)7-27# %00-*# $)09
&7#>#. ("# &"#.#*' %* '+# .-2.#,-#*' "#1%)*
)6 (*'%1#* #>$#..4 5+# $)*$#*'"('%)* )6 '+#
$)0&7#>#. %*$"#(.#. (. '+# (*'%1#* $)*$#*'"(9
'%)* "%.#.4 5+%. .%0-7('#. (* (*'%1#* $)*$#*'"(9
'%)* '+(' %. ')) 7)<4 5+# '#.' .(0&7# 0-.' '+#"#9
6)"# 2# /%7-'#/ %* )"/#" ') D##& '+# (*'%1#*
$)*$#*'"('%)* %* '+# (.$#*/%*1 &("' )6 '+#
$-"B# ') #*.-"# '+(' '+# "#.-7'. ("# &")&)"'%)*(7
') '+# (*'%1#* $)*$#*'"('%)*4
E* '+%. '#.': (* (1(" &7('# %. +)0)1#*#)-.73
$)('#/ <%'+ ( 1#7 $)*'(%*%*1 '+# (&&")&"%('#
(*'%2)/34 5+# (*'%1#* .(0&7# %. &7($#/ %* <#77.
)6 '+# &7('#4 5+# (*'%2)/3 /%66-.#. "(/%(773 %*')
'+# 1#7 (*/ %. '+#"#23 /%7-'#/4 E00-*# $)09
&7#>#. 6)"0 &"#$%&%'('#. %* '+# "#1%)* )6 #,-%B(9
7#*$#4 E* '+# C(*$%*% 0#'+)/: '+# (*'%1#* $)*9
$#*'"('%)* %. .(%/ ') 2# &")&)"'%)*(7 ') '+#
.,-("# )6 '+# /%(0#'#" 8$L; )6 '+# "%*1 )6 &"#$%9
&%'('%)*4 5+# -*D*)<* (*'%1#* $)*$#*'"('%)* %.
/#'#"0%*#/ 6")0 ( .'(*/("/ $-"B# )2'(%*#/

"
<%'+ D*)<* $)*$#*'"('%)*. )6 '+# (*'%1#*4
5" +)$,%-%./.%01 /1& !**'3.%1/.%01
!"#$%&%'('%)* "#($'%)*+, E00-*# $)0&7#>#.
6)"0 /-# ') %*'#"($'%)* 2#'<##* (* (*'%2)/3
(*/ 0)7#$-7(" (*'%1#*.4 E* %00-*# &"#$%&%'(9
'%)*: '+# (*'%1#* %. /%7-'#/ 23 /%66-.%)* %* (
.(0&7# <%'+ ( D*)<* (*'%2)/3 $)*$#*'"('%)*
-*'%7 '+# &)%*' )6 &"#$%&%'('%)* )$$-".: %4#4: -*'%7
'+# (*'%1#*A(*'%2)/3 "('%) "#($+#. '+# #,-%B(9
7#*$# ?)*#4
-../0'%*('%)* "#($'%)*+, E00-*# $)09
&7#>#. 6)"0 /-# ') %*'#"($'%)* 2#'<##* (* (*'%9
2)/3 (*/ &("'%$-7('# (*'%1#*.4 @ /%.'%*$'%)* %.
0(/# 2#'<##* /%"#$' (117-'%*('%)* 8#414: +#9
0(117-'%*('%)* '#.' 6)" /#'#"0%*('%)* )6 27))/
'3&# (*/ F%/(7G. 2($'#"%(7 (117-'%*('%)* '#.';
(*/ %*/%"#$' (117-'%*('%)* '#.'. 8#414: 7('#> (19
17-'%*('%)* '#.' (*/ H)3/#*G. &(..%B# +#0(19
17-'%*('%)* '#.';4

2" +)$,%-%./.%01 6$/,.%017 %1 8'3%& +9/7$

10"2%3%4#'"5, @* (*'%1#* .(0&7# %. &7($#/ %* (

!
$-B#''# (*/ (77)<#/ ') "#($' <%'+ (* #>$#.. )6
(* (*'%.#"-0 $)*'(%*%*1 '+# $)""#.&)*/%*1
(*'%2)/34 =)7-27# %00-*# $)0&7#>#. 6)"04
5+# $+(*1# %* '-"2%/%'3 %* '+# $-B#''# %. 0#(9
.-"#/ 23 &+)')0#'"34 5) /#'#"0%*# '+# #*/
EF &)%*': '+# %*$"#(.# %* (2.)"&'%)* <%'+%* ( $#"9
 :$>%1%.%017 /1& +)$,%-%./.%01 G$,91%H3$7
!
Size of Immune complex
immune formation with
complexes molecular
(precipitate antigens
mass)

Precipitation
Ag : Ab ratio
Ag surplus Equivalence range Ab surplus
Immune complex
formation with
Ag Ab antigenic particles
(e g. erythrocytes,

D/(0)/.0)C !--'%,/.%017
latex particles)

Agglutination

A. Heidelberg curve B. Precipitation and agglutination

Turbidimetry
(Extraction measurement)

Laser/
quartz lamp
Cuvette
Photodetector

Scattered light detector

"
Nephelometry
(Scattered light measurement)

C. Precipitation techniques in fluid phase

Gel with antibodies

Ag-concentration C

in solution
!
Spot for antigen C ~ d2
to be tested 4
Standard
curve
Precipitate rings

!
(equivalence range)

d d
Relationship between diameter d of
precipitate ring and antigen concentration
D. Simple radial immunodiffusion (RID) according to Mancini
EE

"
! !/6&A,/C!/6&+)%8 -/6,7$46&)/1

!" #$%&$' ()*+', -..*/)%&00*1&)/

23*456,7')/8 9,65)%:
!" #$%& #'&#( )*#$ +"#%,'" +"- +"#%)*-. -%//0&'
1+-%+22. #*3+1- '+4$ *#$'1 %" +50'*0& +,+1*&'
,'26 7%&%)2' )+"-& */ 81'4%8%#+#%*" /*19 +# #$'
&%#'& 3$'1' #$' +"#%,'" +"- +"#%)*-. 9''#6
:$%& 9'#$*- %& + ;'1. '//'4#%;' 3+. #* #'&#
#$' %-'"#%#. */ 0"<"*3" +"#%,'"& )+&'- *"
#$' &.99'#1. */ 81'4%8%#+#%*" 8+##'1"&6 !-'"#%#.
*/ #3* +"#%&'1+ =3%#$ 1'&8'4# #* #$' 0"<"*3"
+"#%,'"> *4401& 3$'" #$' #3* )+"-& */ 81'4%8%?
#+#%*" /0&' #* /*19 + &%",2' 2%"'6 :$' )+"-& 41*&&
3$'" #$'1' %& "*"%-'"#%#.( +"- + &*?4+22'- &801
D$+)7$6)78 !>>'&4$6&)/1
(" #)4?,6 <',467)>5)7,1&1 2<',467)>5)7@
,1&1 &/ !/6&+)%8@4)/6$&/&/A B,':
!" #$%& #'4$"%50'( +"#%,'"& 9%,1+#' #$1*0,$ +
,'2 4*"#+%"%", +" +"#%)*-. #*3+1- +" +"*-'6
:$%& 2'+-& #* #$' /*19+#%*" */ 2*",( 1*4<'#?
&$+8'- 81'4%8%#+#'& =1*4<'#&> #$+# 4+" )' ;%&0+?
2%K'- ). &#+%"%",6 :$%& 9'#$*- 8'19%#& 50+"#%?
#+#%*" */ #$' +"#%,'" 4*"4'"#1+#%*" ). 4*98+1?
%", #$' #'&# &8'4%9'" #* + &%902#+"'*0&2.
9'+&01'- &#+"-+1-6

/*19& %" 8+1#%+2 %-'"#%#.6

;" <',467)&..*/)%&00*1&)/
2=)*/6,74*77,/6 <',467)>5)7,1&1:
@$'" + &+982' %& +-A0&#'- #* + ,%;'" 8B ='6,6(
8B C6D /*1 #$' #'&# +"#%,'"E 'F#1+4#+)2' "042'+1
+"#%,'"&( GHI>( #$' +"#%,'" +"- +"#%)*-. 9%?
,1+#' %" *88*&%#' -%1'4#%*"& #$1*0,$ #$' ,'2
-0' #* -%//'1'"4'& %" #$'%1 '2'4#1%4 4$+1,'&6
!990"' 4*982'F'& /*19 -01%", #$' #1+"&9%?
,1+#%*" 81*4'&& %/ #$' 4*11'&8*"-%", +"#%)*-.

"
%& 81'&'"# %" #$' 8+#%'"#J& &'1096 :$' %990"'
4*982'F'& /*19 2%"'& */ 81'4%8%#+#%*" #$+# 4+"
)' ;%&0+2%K'- ). &#+%"%",6

=" -..*/),',467)>5)7,1&1
!990"*'2'4#1*8$*1'&%& %& + 4*9)%"+#%*" */
81*#'%" '2'4#1*8$*1'&%& +"- %990"*81'4%8%#+?
#%*"6 :$' #'&# +"- 1'/'1'"4' &+982'& +1' /%1&#
&'8+1+#'- ). '2'4#1*8$*1'&%&6 :$' +"#%&'109
-%//0&'& 8'18'"-%402+12. #* #$' -%1'4#%*" */ &'?
8+1+#%*"6 L0' #* #$' /*19+#%*" */ 81'4%8%#+#%",
%990"' 4*982'F'&( &$+182. -'/%"'- 2%"'& */
81'4%8%#+#%*" /*19 %" #$' 1+",' */ '50%;+2'"4'6
M1*#'%"& 4+" )' %-'"#%/%'- )+&'- *" #$' %"#'"?
&%#.( &$+8'( +"- 8*&%#%*" */ #$' 81'4%8%#+#%*"
2%"'&6
!990"*'2'4#1*8$*1'&%& %& 0&'- %" 8+#%'"#&
3%#$ &0&8'4#'- 9*"*42*"+2 +"- 8*2.42*"+2
,+99*8+#$%'&6 M*2.42*"+2 %990"*,2*)02%"&
+1' 0"%/*192. -%&#1%)0#'- #$1*0,$*0# #$' ,+9?
9+?,2*)02%" /1+4#%*" +/#'1 '2'4#1*8$*1'#%4 &'?
8+1+#%*"6 N*"*42*"+2 %990"*,2*)02%"& /*19
+ 2*4+2 ,1+-%'"# %" #$' ,+99+?,2*)02%" /1+4#%*"

! EF
=N ,1+-%'"#>( 2'+-%", #* #$' /*19+#%*" */ + -%&?
#%"4#%;' %"-'"#+#%*" 8+##'1"6
Possible
G,45/&H*,1 )0 <',467)>5)7,1&1
!
precipitation Anti-!, " Anti-!, " Anti-!, "
patterns
of anti-!, "-
antiserum with x y x y x y
mixtures of the
antigens !, "
in spots x and y x y x y x y

Antigen ! ! ! " ! !"

or: !" !"
or: " "

D$+)7$6)78 !>>'&4$6&)/1
Identity No identity Partial identity
x=y x#y x y
A. Radial double diffusion (Ouchterlony)

Principle

Anode Cathode

Ab Ag Anti-ENA ENA
(anti-ENA) (ENA)

"
B. Transmigration electrophoresis ( countercurrent electrophoresis )

Start Serum
Anode Cathode

Electrophoresis

Alb !1 !2 " $

Antiserum/diffusion in gel

A n t i s e r u m
Precipitation
Immunoelectrophoresis

C. Immunoelectrophoresis (time course of procedure )

Cathode
Ag

Ag
Anode
Precipitation
line
D. Electrophoresis in antibody-containing gel (rocket electrophoresis)
!
EI

"
! !(&'#,(;!(&'6*7< =(&,>)-&'*(0

!" !##$%&'()&'*( +,-.('/%,0

! "#$%&&'()*+%)*,+! "#$#%$&'( ') *++,-$&(*$.
&(+ *($&/'"&#0 &( * 0#1-2 0*23,#4 !"#$%&'&
()'*+",*&- *1# &22-('+,'/-,&(0 ') $5# 6+7
%,*004 85#9 /&(" $' $5# *($&+#( "#$#12&(*($0
') 1#" /,''" %#,,0 *0 3#($*2#10 *(" &("-%#
*++,-$&(*$&'( ') $5# *($&+#(04 85#9 *1# %*,,#"
%'23,#$# :(*$-1*,; *($&/'"&#0 /#%*-0# $5#9
%*( &("-%# *++,-$&(*$&'( "-# $' $5#&1 3#($*.
2#1&% 0$1-%$-1#4 <($&/'"&#0 *+*&(0$ /,''"
+1'-3 *($&+#(0 *1# * $93# ') %'23,#$# *($&.
/'"&#04
.)/"#$%&'& ()'*+",*&- *,0' #=&0$ :6+> *($&/'.
?)6*>)&*>< !44$'-)&'*(0
%#,,0 %'*$#" C&$5 $#0$ *($&/'"&#0 :&22-(#
%'23,#=#0; *1# -0#" *0 $5# &("&%*$'1 090$#24
J5#( $5# $#0$ &0 3'0&$&F#D (' %'23,#2#($.
2#"&*$#" 5#2',90&0 ') $5# &("&%*$'1 090$#2
'%%-10 0&(%# $5# %'23,#2#($ C*0 %'(0-2#"4
6) $5# $#0$ &0 (#+*$&F#D %'23,#2#($ &0 0$&,, *F*&,.
*/,# $' &("-%# ,90&0 ') $5# $#0$ ?@A0 ') $5# &("&.
%*$'1 090$#24
K(# ') $5# "1*C/*%G0 ') $5&0 2#$5'" &0 )*,0#.
3'0&$&F# 1#0-,$0 "-#D )'1 #=*23,#D $' 0#,).&(5&/&.
$&'( ') 0#1-2 "-# $' 15#-2*$'&" )*%$'10D &2.
2-(# %'23,#=#0D #$%4 85&0 &0 1#),#%$#" *0 * 3'.
0&$&F# 1#*%$&'( ') $5# %'($1', 0*23,# :3*$&#($
0#1-2 *,'(# C&$5'-$ $5# *""&$&'( ') *($&+#(;4

"&#0;4 85#0# *($&/'"&#0 /&(" $' $5# *($&+#(

"#$#12&(*($ ') ?@A0 /-$ %*(('$ &("-%# *+. K$5#1 2*$#1&*,0 2*9 *,0' %'($*2&(*$# $5#
+,-$&(*$&'(4 B#2*++,-$&(*$&'( '%%-10 C5#( *($&+#( *(" )'12 &22-(# %'23,#=#0 C&$5
$5# "&0$*(%# /#$C##( 1#" /,''" %#,,0 &0 1#. $5# $*1+#$ *($&/'"9 &( $5# 3*$&#($H0 0#1-2D
"-%#" /9 *""&(+ * 0-33,#2#($ :*,/-2&(; $5-0 &("-%&(+ %'23,#2#($ /&("&(+4 85&0 &0
'1 * 0',-$&'( C&$5 * ,'C &'(&% %5*1+#D $5-0 *,0' 1#),#%$#" *0 * 3'0&$&F# 1#*%$&'( ') $5# %'(.
*,,'C&(+ $5# 6+> *($&/'"9 :&(%'23,#$# *($&. $1', *($&+#(4
/'"9; $' /1&"+# $5# +*3 /#$C##( $5# %#,,04
85# )'12*$&'( ') *($&/'"&#0 *+*&(0$ ?5E
1#" /,''" %#,,0 &( ?5.(#+*$&F# 3*$&#($0D
#4+4D *)$#1 *( ?5.&(%'23*$&/,# /,''" $1*(0)-.
0&'(D &0 * +''" #=*23,#4

"
- .%)#/ %&&'()*+%)*,+! 6( $5&0 2#$5'"D * ,*$#=
3*1$&%,# &0 *,,'C#" $' 1#*%$ C&$5 $5# -(.
G('C( *($&/'"94 6( $5# &,,-0$1*$#" #=*23,#
:15#-2*$'&" )*%$'1 0%1##(&(+;D 6+> /&("0 $'
$5# ,*$#= 3*1$&%,#4 <++,-$&(*$&'( ') $5# ,*$#=
3*1$&%,# '%%-10 &) 15#-2*$'&" )*%$'1 :6+7
*($&.6+>; &0 31#0#($ &( $5# 0#1-2 0*23,# :3'.
0&$&F# 1#*%$&'(;4
0%1)#2*%' %&&'()*+%)*,+ :('$ &,,-0$1*$#";4 0)'*1
+",2 ,&'&/'*") :3*,(% #&'4",;! @*%$#1&*, 0-0.
3#(0&'(0 &(%-/*$#" &( 0#1&*, "&,-$&'(0 ') $5#
3*$&#($H0 0#1-2 0#1F# *0 $5# *($&+#(4 <++,-$&(*.
$&'( '%%-10 &) $5# *($&/'"9 %'11#03'("&(+ $'
$5# *($&+#( &0 31#0#($ &( $5# 3*$&#($H0 0#1-24
0)'*5&) ,&'&/'*") :>1-/#1 2#$5'";! @*%$#1&*,
%-,$-1#0 *1# &(%-/*$#" C&$5 %,*00.03#%&)&% *("
$93#.03#%&)&% *($&/'"&#04 85&0 2#$5'" &0 -0#"
)'1 /*%$#1&*, $93# "#$#12&(*$&'(4

1" 2*34$,3,(&56'(7'(# 8,)-&'*( 9218:

85&0 2#$5'" &(F',F#0 $5# /&("&(+ *(" *%$&F*.
$&'( ') %'23,#2#($ /9 *($&+#(I*($&/'"9 %'2.
3,#=#0 )'1 "#$#12&(*$&'( ') *($&/'"&#0 &( 0#1-2

! @A
'1 %#1#/1'03&(*, ),-&"4 <($&+#( *(" %'23,#.
2#($ %'11#03'("&(+ $' $5# $*1+#$ *($&/'"9
*1# *""#" $' $5# 0#1-2 0*23,# :%'23,#.
2#($.)1## "-# $' &(*%$&F*$&'(;4 A'23,#2#($
C&,, /# /'-(" *(" %'(0-2#" &) $5# *($&/'"9
&0 31#0#($ &( $5# 0#1-2 0*23,#4 8#0$ 1#" /,''"
 !##$%&'()&'*( +,-.('/%,0B2*34$,3,(&56'(7'(# 8,)-&'*(

Before: chemical
!
Agglutination of binding
Sheep
Ag-loaded test erythrocytes
Ag erythrocyte
in the presence of specific
antibodies in patient serum

1. Hemagglutination

RF
(IgM anti-IgG)

IgG

?)6*>)&*>< !44$'-)&'*(0
Agglutination =
positive test reaction
Latex IgM-RF in
particle patient serum

2. Latex agglutination in rheumatoid factor screening

A. Agglutination techniques

Principle: competition between test system(Ag + Ab) and indicator system

(erythrocytes loaded with test Ab) for complement

Complement

Ag
Ab
Pre-incubation

Test system
+

Test system
Indicator system
(test erythrocytes,
loaded with test Ab)
"
Complement Positive
Ag (exogenously added) result No
Ab (patient serum) (complement hemolysis
bound by antigen-
antibody complex)

Negative
result
(complement Hemolysis
available for lysis
of test erythrocytes

Complement

Test system
(no specific
Ab present)
B. Complement-binding reaction (CBR)
+

Test system Indicator system

!
@C

"
! !$4+D($F!$4+30-& .$4(25A4+0$1

!" #$%&'()*+$,(- .''/$01023($4 !115&

6#*.7!8
!"# #$%&'# ('')$*+,,+& (, + '#-"*. */
0)+$-(-+-(1# +$+2&,(, ($ 3"(4" *$# */ -"# 5#6
+7#$-, (, 2+8#2#. 3(-" +$ #$%&'#9 !"(, '+&
8# #(-"#5 -"# +$-(7#$ *5 -"# +$-(8*.&9
:$ -"# (22),-5+-#. #;+'<2#= + 3#22 */ -"# 4+56
5(#5 '#.()' >),)+22& + '(45*-(-#5 <2+-#? (,
4*+-#. 3(-" -"# +$-(7#$ 4*55#,<*$.($7 -* -"#
-+57#- +$-(8*.&9 :/ -"(, +$-(8*.& (, <5#,#$- ($
-"# -#,- ,+'<2# >#979= ,#5)'?= (- 3(22 8($. -*
-"# +$-(7#$9 @$ #$%&'#64*$A)7+-#. ,#4*$.+5&
+$-(8*.& >#979= ,"##< +$-(6")'+$ :7B= C+8 /5+76
*53025402& !GG=+A54+0$1
+$-(8*.(#, +82# -* 8($. -* -"# +$-(7#$9 H#$4#=
-"# '#+,)5#. 5+.(*+4-(1(-& 3(22 8# 2*3 3"#$
-"# ,#5)' +$-(8*.& -(-#5 (, "(7" +$. 1(4# 1#5,+9
C" .''/$03=044+$D 6E(14(2$ 9=048
:$ I#,-#5$ 82*--($7= <5*-#($, +5# ,#<+5+-#. +46
4*5.($7 -* '*2#4)2+5 3#(7"- 8& '#+$, */ ,*6
.()' .*.#4&2 ,)2/+-# >JKJ?L<*2&+45&2+'(.#
7#2 #2#4-5*<"*5#,(, >JKJ6M@BN?9 @22 <5*-#($,
*8-+($ + $#7+-(1# 4"+57# .)# -* -"# <5#,#$4#
*/ JKJ >JKJ 8($.($7?9 !"# +..(-(*$ */ O6'#56
4+<-*#-"+$*2 .('($(,"#, ($-#5$+2 .(,)2/(.#
8*$.,9 J($4# -"#& 2*,# -"#(5 4"+5+4-#5(,-(4

'#$-? 8($., -* -"# -+57#- +$-(8*.& ($ -"# ,)86
,#0)#$- 5#+4-(*$ ,-#<9 :$ -"# <5#,#$4# */ -"# #$6
%&'#= -"# ,)8,-5+-# (, -5+$,/*5'#. ($ + 4*2*5
,-+($($7 5#+4-(*$9 !"# +$-(8*.& 4*$4#$-5+-(*$
($ -"# -#,- ,+'<2# 4+$ 8# .#-#5'($#. 8& 4*'6
<+5($7 -"# 4*2*5 5#+4-(*$ <5*.)4- 3(-" -"+- */
,-+$.+5., */ D$*3$ 4*$4#$-5+-(*$9
!"#$%&'( )*+!, (, + '#-"*. */ +$-(7#$ .#-#56
'($+-(*$9 !"# +$-(8*.& /*5 -"# -+57#- +$-(7#$ (,
8*)$. -* -"# ,*2(. <"+,# */ + '(45*-(-#5 3#229
!"# +'*)$- */ 8*)$. +$-(7#$ ($ -"# ,+'<2#
(, .#-#5'($#. 8& +..($7 +$ #$%&'#64*$A)6
4"+57# +$. /*5' .)5($7 #2#4-5*<"*5#-(4 ,#<+6
5+-(*$= -"# <5*-#($, +5# ,#<+5+-#. +44*5.($7
-* -"#(5 '*2#4)2+5 3#(7"-9
!"# <5*-#($, +5# -"#$ P82*--#.=Q -"+- (,= -5+$,6
/#55#. /5*' -"# 7#2 -* +$ (''*8(2(%($7 $(-5*6
4#22)2*,# >RE? '#'85+$#= 3"#5# -"#& 4+$ 8#
5#4*7$(%#. 8& ,<#4(/(4 +$-(8*.(#, ($ -"# '#'6
85+$#9 @$-(8*.(#, +7+($,- -.//01&" 23/4$./50/&
+5# ),#. ($ -"# #;+'<2#9 S$# */ -"# '+($ +.6
1+$-+7#, */ I#,-#5$ 82*--($7 (, (-, +8(2(-& -*
(.#$-(/& + ,<#4(/(4 +$-(8*.& +/-#5 <5*-#($ ,#<+5+6
-(*$9

"
7+-#. ,#4*$.+5& +$-(8*.&9 !"# ,#4*$.+5& +$-(6
8*.& /*5', + ,+$.3(4" 4*'<2#; +$. 8($., -*
-"# +$-(7#$9

9" :;< 70=+-)>?51( #*.7!

:$ -"(, '#-"*.= EF0 (, 4*1+2#$-2& 8*)$. -* 4"#6
'(4+22& +4-(1+-#. <*2&,-&5#$# '(45*-(-#5 ,-5(<,9
E(54)2+-($7 ('')$# 4*'<2#;#, ($ -"# ,+'<2#
>#979= ,#5)'? 8($. -* EF09 @$ #$%&'#62+8#2#.
+$-(8*.& +7+($,- ")'+$ :7B (, ),#. -* .#-#4-
-"# ('')$# 4*'<2#;#,9 @ 4*2*5 ,-+($($7 5#+46
-(*$ *44)5, +/-#5 +..(-(*$ */ + 4*55#,<*$.($7
,)8,-5+-#9 !"# ($-#$,(-& */ -"# 5#+4-(*$ (, <5*6
<*5-(*$+2 -* -"# 4*$4#$-5+-(*$ */ 4(54)2+-($7 ('6
')$# 4*'<2#;#, ($ -"# ,+'<2#9

:" @5-+0+''/$05115& 6:=511+A5= B(4?0-8

!"# 42+,,(4+2 5+.(*('')$*+,,+& >G:@? (, 8+,#.
*$ -"# <5($4(<2# */ 4*'<#-(-(1# 8($.($79 :$ -"#
(22),-5+-#. #;+'<2#= -"# +$-(7#$ 4*55#,<*$.($7
-* -"# -+57#- +$-(8*.& (, (''*8(2(%#. ($ -"# ,*6
2(. <"+,# */ -"# '(45*-(-#5 3#229 !"# )$2+8#2#.

!
+$-(8*.(#, ($ -"# ,#5)' ,+'<2# +$. -"# 5+.(*6
+4-(1#2& 2+8#2#. +$-(8*.(#, $*3 4*'<#-# /*5
+$-(7#$ 8($.($7 ,(-#,9 @$-(8*.& ,-(22 /5## ($ ,*6
2)-(*$ (, ,)8,#0)#$-2& 5#'*1#. 8& 3+,"($79
!"# "(7"#5 -"# $)'8#5 */ )$2+8#2#. +$-(8*.(#,
HI ($ -"# ,#5)'= -"# 2*3#5 -"# $)'8#5 */ 2+8#2#.
Indicator (no color)
+ substrate
Indicator-H (colored)
+ H2O
#*.7!J @.!J 5$- .''/$03=044+$D
!
(H2O2)
Color reaction

E E
E E Anti-mouse
antibody
Monoclonal Ig
E E
Antigen
Polyclonal Ig
(e.g. rabbit-
anti- xy)

*53025402& !GG=+A54+0$1
Detection of specific antibodies directed Sandwich ELISA
against an antigen by enzyme-labeled for sensitive antigen detection
secondary antibodies ( conjugate ) (e.g. cytokines)
E

Antibody Antigen Secondary antibody, enzyme linked

A. Enzyme-linked immunosorbent assay (ELISA)

High titer: Low titer:

low high
radioactivity radioactivity

* * *
"
Test Ab Measurement of radioactivity
Serum + tracer

E Patient

C1q
Ig
antibodies
* * *
Anti-human Ig
Antigen at solid phase
with subsequent
color reaction Principle: antibody in patient serum competes with radioactively
labeled test antibody
B. C1q solid-phase ELISA C. Radioimmunoassay (classical method)
1. SDS-PAGE 2. Transfer 3. Staining
PAG NC
MW (kDa)
100
AP
80

50
41
31

10

Mouse Ab against human Ig

Human Ab against B. burgdorferi

D. Immunoblotting (Western blot)

AP Alkaline phosphatase

B. burgdorferi proteins Immunoblot !

HK

"
! !+4-7(+9!+4-:&;3 /+4('8*4-&+)

!" #$%&'()*(+*( (,-))-&+

!"#$%&' (%$"#&%)* +%," $+" -#.-"#$/ .0 %1*.#12
&'3 "'"#3/ 4+"' "5-.*"6 $. )&3+$ .0 % 3&,"'
4%,")"'3$+7 8+" )&3+$ $+%$ &* "(&$$"6 +%* %
).4"# "'"#3/ %'6 $+"#"0.#" % 6&00"#"'$ 9.).#
$+%' $+" &'9&6"'$ )&3+$7 8+" "(&$$"6 )&3+$ &*
9%))"6 0):.#"*9"'9"7 ;):.#"*9"&' &*.$+&.9/%'%$"
<;=8!> &* $+" (.*$ 9.((.')/ :*"6 0):.#"*9"'$
6/"7 ;=8! &* *$&(:)%$"6 1/ +&3+2"'"#3/ 1):"
)&3+$ %$ 4%,")"'3$+* .0 ?@AB@AA '( %'6 "(&$*
/")).423#""' 0):.#"*9"'9" %$ % ).4"# 4%,"2
)"'3$+ <@AAB@@A '(>7
8+" "59&$"# 0&)$"# .' % 0):.#"*9"'9" (&9#.2
<8:&'84&'3 !==$-*84-&+)
8+&* ("$+.6 -"#(&$* 6&00"#"'$&%$&.' 1"$4""'
)%#3" 9"))* 4&$+ % +&3+ -)%*(%O':9)":* #%$&.
%'6 % 3#%':)%# 9/$.-)%*( <3#%':).9/$"*> %'6
*(%)) 9"))* 4&$+ % )%#3" ':9)":* <)/(-+.9/$"*>7
K.'.9/$"* +%," &'$"#("6&%$" -#.-"#$&"* <$"#>7
5" #$&2 134&,(4'3 6-)4&7'8,)
8+" *.#$"6 9")) -.-:)%$&.'* 9%' %)*. 1" %'%2
)/I"6 0.# .$+"# -%#%("$"#*C *:9+ %* 0):.#"*2
9"'9"7 8+" &((:'.0):.#"*9"'9" .0 )/(-+.2
9/$"* %'6 (.'.9/$"* &' $+" *%(-)" 9%' 1"
*"-%#%$")/ %'%)/I"67 8+" &'$"'*&$/ .0 9")) 0):.#2
"*9"'9" #.:3+)/ 9.##")%$"* 4&$+ $+" %'$&3"'

*9.-" #"*$#&9$* $+" -%**%3" .0 )&3+$ $. % 6"2
0&'"6 4%,")"'3$+ <"737C ?DA '(>7 8+" 0&)$"#"6
)&3+$ &* -#.E"9$"6 .'$. $+" 0):.#"*9"'$ *%(-)"7
;):.#"*9"'$ )&3+$ "(&$$"6 %$ 4%,")"'3$+* .0
@FAB@@A '( &* $+"' -%**"6 $+.:3+ % 6&9+#.&9
(&##.# %'6 % 1%'6-%** 1%##&"# 0&)$"#C $+"#"1/
(%G&'3 &$ ,&*&1)" :'6"# $+" (&9#.*9.-"7
." /,,%+&0$%&'()*(+*(
=' !"#$%& "''()*+,(*#$-%$)%$C $+" %'$&1.6&"*
%#" %)#"%6/ 9.'E:3%$"6 4&$+ % 0):.#"*9"'$
6/"7 =' ")!"#$%& +,(*#$-%$)%$C .' $+" .$+"#
6"'*&$/ .' $+" 9")) *:#0%9" %'6 9%' 1" P:%'$&2
0&"6 :*&'3 % -+.$.(:)$&-)&"# $:1" <JK8> 6"$"92
$.# <&"%>7
Q ':(1"# .0 %'$&1.6&"* 6&#"9$"6 %3%&'*$ 6&02
0"#"'$ %'$&3"'* %'6 9.'E:3%$"6 $. 6&00"#"'$
0):.#"*9"'$ 6/"* 9%' 1" %'%)/I"6 *&(:)$%2
'".:*)/7 L.(" .0 $+" (.*$ 9.((.' 6/"*
:*"6 &' 0).4 9/$.("$#/ %#" 0):.#"*9"&' &*.$+&.2
9/%'%$" <;=8!> %'6 -+/9."#/$+#&' <JR>7 S.$+
6/"* %#" "59&$"6 1/ )%*"# )&3+$ %$ % 4%,")"'3$+
.0 ?TT '(C 1:$ $+"&# 0):.#"*9"'9" "(&**&.'*
-"%G* ,%#/7 ;=8! -"%G* &' $+" 3#""' "(&**&.'

"
#%'3"C 4+"#"%* JR -"%G* &' $+" #"6 "(&**&.'
+%'6C % 0):.#.9+#.("2)%1")"6 *"9.'6%#/ %'$&2
#%'3"7 Q**:(&'3 $+"#" %#" $4. $%#3"$ %'$&3"'*
1.6/ &* %66"6 &' % *"9.'6 *$"- %0$"# $+" %'$&2
.0 &'$"#"*$C 0):.#"*9"'$ 6/"* 9%' 1" :*"6 $.
3"'2*-"9&0&9 -#&(%#/ %'$&1.6/ +%* 1""' 1.:'67
6&00"#"'$&%$" %'6 &6"'$&0/ %'$&3"'2-.*&$&," 9"))
H&#"9$ &((:'.0):.#"*9"'9" 9%' 1" :*"6 $.
-.-:)%$&.'* $+%$ "5-#"** 1.$+ .0 $+" $%#3"$ %'$&2
*$:6/ $4. .# (.#" %'$&3"'* %$ % $&("7 ='6&#"9$
3"'* <"(&$ 1.$+ #"6 %'6 3#""' 0):.#"*9"'9">
&((:'.0):.#"*9"'9" &(-#.,"* $+" ,&*:%)&I%2
.# .')/ .'" .0 $+" $%#3"$ %'$&3"'* <"&$+"# #"6
$&.' .0 4"%G)/ "5-#"**"6 %'$&3"'* 1"9%:*"
.# 3#""'>C %'6 &6"'$&0/ %'$&3"'2'"3%$&," 9"))
*","#%) (.)"9:)"* .0 $+" )%1")"6 %'$&1.6/ 9%'
-.-:)%$&.'* $+%$ 6. '.$ "5-#"** "&$+"# .0 $+"
1&'6 $. $+" -#&(%#/ %'$&1.6/7 8+" *%(-)" 9%'
%'$&3"'* <'. 0):.#"*9"'9">C %* *+.4' &' $+"
1" 0&5"6 $. (%G" $+" 9")) ("(1#%'" -"#("%1)"
#&3+$ -%'")7 8+" "5%(-)" *+.4* 6.:1)" *$%&'&'3
"'.:3+ 0.# &6"'$&0&9%$&.' .0 &'$#%9/$.-)%*(&9
0.# !HU %'6 !H?7 ;.:# -.-:)%$&.'* 9%' 1"
%'$&3"'*7 8+&* &* %)*. %' "00"9$&," 4%/ $.
6"$"9$"6V !H?! 8 9"))* <+")-"# 8 )/(-+.9/$"*>C
*$%&' 9"))* &' *:*-"'*&.'C $&**:" *"9$&.'*C .#
!H?" 8 9"))* <(.*$ 4&)) 1" !HT2-.*&$&," )/(2
9/$.*-&'*7 <!"#>
-+.9/$"*>C !H?! !HU" 9"))* <(.*$ 4&)) 1"
(.'.9/$"*>C %'6 6.:1)" '"3%$&," 9"))*C &'9):$2
1" #$&2 134&,(4'3
&'3 S )/(-+.9/$"*C WX 9"))*C %'6 *.(" (.'.2
=' 0).4 9/$.("$#/ <$"%>C 9")) *:*-"'*&.'* %#" 9/$"*7
).%6"6 &' % ,&1#%$&'3 0).4 9+%(1"# 4&$+ %
'.II)" $+%$ "5-")* $+"( &' 6#.-)"$*C "%9+ 9.'2
$%&'&'3 % *&'3)" 9"))7 8+" 6#.-)"$* -%** % )%*"#
1"%( %'6 *9%$$"# )&3+$ %* $+" 1"%( *$#&G"*
$+"(7 8+&* *9%$$"#&'3 &* ("%*:#"6 1/ % -+.$.2

!
(:)$&-)&"# $:1" <JK8> 6"$"9$.#7 .*#/0#!10)2,$
,"23& -%0&&$# <;L!> 9.##")%$"* 4&$+ 9")) *&I"7
4#&3*2*)0, ,"23& -%0&&$# .# *&6" *9%$$"#C 6"0&'"6
%* MA! )&3+$ *9%$$"# <MA!NL> 4&$+ #"*-"9$ $. $+"
1"%( %5&*C 9.##")%$"* 4&$+ 9")):)%# 3#%':)%#&$/
>? %'6 4&$+ $+" -)%*(%O':9)":* #%$&. .0 $+" 9"))*7
 UV radiation
Fluorescing FITC FITC Exciter
/,,%+&0$%&'()*(+*(
!
substrate excitation fluorescence filter
365 450- 520-
(Invisible) 490 nm 560 nm
400
Energy Band-
Energy (nm)

pass
decrease
500 filter
Green
555 Dichroic
(visible)
600 mirror
Fluorescence Light >510 nm

700
300 400 500 600
![nm]
1. Generation 2. Absorption/emission- 3. Fluorescence microscope

<8:&'84&'3 !==$-*84-&+)
2. spectrum of FITC
A. Fluorescence

Fluorescing FITC- PE-conjugated

antibody antibody

1. Direct immunofluorescence 2. Double fluorescence

Fluorescing
Primary antibody anti-Ig antibody
(mouse anti-human) (anti-mouse)

"
4. Intracytoplasmic
3. Indirect immunofluorescence 4. fluorescence
B. Immunfluorescence

Cells in Side Photomultiplier

suspension scatter
530 – 550 nm Granulocytes Monocytes
(green)
Side scatter

560 – 580 nm (red) Light-

sensitive Lymphocytes
diode
Forward scatter
1. Principle Forward scatter
C. Flow cytometry 2. Separation of cell fractions

Negative control 75% positive CD3+ CD3+

No fluorescing cells CD4- CD4+
cells
Anti-CD3
antibody
CD3-FlTC

Negative Positive
Cell count

Cell count

1. Histograms
Fluorescence intensity

D. Flow cytometry: Histograms

Fluorescence intensity
CD3-
CD4-
CD4-PE
2. Dot plot, two-color analysis
CD3-
CD4+

!
>@

"
! !&+)-4&D!&+)8'97 #&+43/.+)'&*

!" #$$%&'()*+','-)./, 0+/)&)&-

!"##$% #&'()%# *+, -"#.+)+/"0&) &1&)2#"# &,%
,+$."1%)2 *"3%4 "1 *+,'&)"15 6"10% *+,'&)"1 *"3&7
.$,%4 92 .,%&."1/ .-% .%#. #(%0"'%1# >".- -%&.8
0-%'"0&)#8 +, #+)$."+1# >".- &1 &):&)"1% (S5
ITG (,+9%# 4",%0.%4 &/&"1#. #(%0"*"0 ITG #%7
M$%10%# &,% $#%45 ITG (,+9%# &,% 0+'()%'%17
."+1 '&2 &).%, .-% &1."/%1 4%.%,'"1&1.# +*
.&,2 ITG #%M$%10%# )&9%)%4 >".- & '&,:%, '+7
'&12 0%))$)&, #.,$0.$,%#8 #(%0"'%1# '$#. 9%
)%0$)%5 !-% ITG (,+9%# -29,"4";% >".- ITG "1
#-+0: *,+;%1 .+ 2"%)4 0,2+#.&. #%0."+1# '+,%
.-% #&'()%8 &14 .-% '&,:%, '+)%0$)% +1 .-%
#$".&9)% *+, "''$1+-"#.+0-%'"0&) #.&"1"1/5
(,+9% ,%14%,# -29,"4";&."+1 ="#"9)%5
<,2+(,%#%,=%4 #%0."+1# &,% "10$9&.%4 >".-
6(%0"*"0 UTG (,+9%# &,% &)#+ &=&")&9)%5 !-%#%
&1."9+4"%# &/&"1#. .-% .&,/%. &1."/%1 *+, ?@A
(,+9%# (%,'". .-% "4%1."*"0&."+1 +* UTG *+, #(%7
B@ '"1$.%# &. CD !<5 E+$#% '+1+0)+1&) &1."9+7
0"*"0 0%)) (,+4$0.#8 #$0- &# 02.+:"1%#8 &. .-% #"17
4"%# &,% '+#. 0+''+1)2 $#%45 !-% #(%0"'%1#
/)%70%)) )%=%)5 !-% '+#. 0+''+1 '&,:%, #$97
&,% .-%1 >&#-%48 &14 & #%0+14&,2 &1."9+42
#.&10%# &,% *)$+,%#0%"1 &14 9"+."18 9$. +.-%,
&/&"1#. '+$#% "''$1+/)+9$)"1 "# &44%45 !-%
"''$1% 0+'()%3%# H%5/58 4"/+3"/%1"1A&1."74"7
E/8'3/+'37 !>>,)./+)'&*

#%0+14&,2 &1."9+4"%# &,% +*.%1 9"+."12)&.%48

.-&. "#8 0+1F$/&.%4 .+ 9"+."18 & =".&'"1 >".-
&1 %3.,%'%)2 -"/- &**"1".2 *+, .-% (,+.%"1 #.,%(7
.&="4"15 G 0+'()%3 '&4% +* #.,%(.&="4"1 &14 .-%
%1;2'% (%,+3"4&#% "# $#%4 *+, #.&"1"1/5 !-% %17
;2'% .-%,%*+,% 0+'%# "1.+ 0)+#% (,+3"'".2 .+
.-% .&,/%. &1."/%15 !-% &44"."+1 +* & 0-,+'+7
/%1"0 #$9#.,&.%8 #$0- &# 4"&'"1+9%1;"4"1%
HIGJK +, &'"1+%.-2)0&,9&;+)% HGL<K8 )%&4# .+
& 0+)+, #.&"1"1/ ,%&0."+1 .-&. &00$,&.%)2 ,%*)%0.#
.-% 4"#.,"9$."+1 +* .-% .&,/%. &1."/%1 "1 .-% ."#7
#$% #&'()%5
/+3"/%1"1 &1."9+4"%#K &,% &)#+ $#%45
;" <=/$>,4? 2#06 0+/)&)&- )&
@?AB C3/&*,'./+)'&
N1 .-% "1.%,(-&#%8 .-% L!V /%1% +1 0-,+'+7
#+'% W &14 .-% GEX7Y /%1% +1 0-,+'+#+'%
?Y +* 1+,'&) 0%))# 0&1 9% ="#$&)";%4 $#"1/
ITG (,+9%# )&9%)%4 >".- RN!< +, QL ,%#(%07
."=%)25
!,&1#)+0&."+1 +* & #'&)) #%/'%1. +* 0-,+'+7
#+'% ?Y .+ 0-,+'+#+'% W &14 ="0% =%,#&

"
!-% !"!!" #$%&'( "# &1+.-%, 0+''+1 "'7 +00$,# "1 #+'% 0&#%# +* &0$.% '2%)+"4 )%$:%'"&
'$1+-"#.+0-%'"0&) #.&"1"1/ .%0-1"M$%5 !-% H#%% (5 Y?WK5 G #%/'%1. +* .-% RN!<7)&9%)%4
(,"'&,2 &1."9+42 H$#$&))2 & '$,"1% &1."9+42K GEX7Y /%1% "# 9,+$/-. 1%3. .+ .-% QL7)&9%)%4
9"14# .+ .-% .&,/%. &1."/%15 G1 &1."7'+$#% N/ L!V /%1%5 !-% *$#"+1 +* .-% .>+ /%1%# 0&1 9%
&1."9+42 HO9,"4/"1/P &1."9+42K "# .-%1 &44%48 ="#$&)";%4 4$% .+ .-% F$3.&(+#"."+1 +* .-% ,%4
*+))+>%4 92 & 0+'()%3 0+1#"#."1/ +* &):&)"1% &14 /,%%1 *)$+,%#0%10%5
(-+#(-&.&#% HGQK &14 & '+1+0)+1&) '+$#%
&1."9+42 4",%0.%4 &/&"1#. &):&)"1% (-+#(-&.&#%5
!-% )&..%, &1."9+42 "# ,%*%,,%4 .+ &# &1 &1."7GQ
HGGQK &1."9+425 !-% GQAGGQ 0+'()%3 9"14# .+
.-% .&,/%. &1."/%1 ="& 9,"4/"1/ &1."9+4"%#5 !-%
#$9#%M$%1. %1;2'&."0 ,%&0."+1 >".- & 0-,+'+7
/%1"0 #$9#.,&.% )%&4# .+ &1."/%174%(%14%1.
(,%0"(".&."+1 +* 42% "1 .-% #&'()%5 !-% #%1#"."=7
".2 +* GQGGQ #.&"1"1/ 0&1 9% %1-&10%4 92 ,%7
(%&."1/ .-% 9,"4/"1/ ,%&0."+15 L3&'()%# +*
.-"# "''$1+-"#.+0-%'"0&) #.&"1"1/ .%0-1"M$%
&,% #-+>1 "1 "))$#.,&."+1# H!K &14 H"K5 N1 H!K8 &
#"1/)% .$'+, 0%)) 0&1 9% ="#$&)";%4 &'+1/ 1%7
/&."=% 9+1% '&,,+> 0%))# $#"1/ &1 &1."9+42
&/&"1#. %(".-%)"&) 0%))#5 N1 H"K8 <I?? &1."9+4"%#
(,+4$0% &1 %30%))%1. #.&"1 +* J )2'(-+02.%# "1
.-% *+))"0)% '&1.)%8 .-$# '&:"1/ ". (+##"9)% .+

! @F
="#$&)";% .-% #.,$0.$,% +* .-% /%,'"1&) 0%1.%,5

1" 2,%'34*.4&.4 #&5*)+% 6783)9):/+)'&

R)$+,%#0%10% "17#".$ -29,"4";&."+1 HRN6SK "#
$#%4 .+ "4%1."*2 '+)%0$)&, #.,$0.$,%# +1 .-%
ITG +, UTG )%=%)5 !-% ITG 4+$9)% -%)"3 "# ,$(7
 #$$%&'()*+','-7
!
E.g.
lymph node
or spleen or N2
tumor tissue – Heat Rupture of
Surgical specimen Shock freeze – Formamidase H-bonds:
– Alkaline solutions single-strand DNA

Hybridization

Thin sections ( 4-8 µm) on Cryostat

microscope slides sections Fluorochrome-

E/8'3/+'37 !>>,)./+)'&*
labeled
1. Preparation of samples complementary
1. With DNA probes DNA-probe
3 Streptavidin/peroxidase
2 Antibody + Comple-
B S POX
(rabbit mentary
anti-mouse, + RNA RNA probe,
Chromogenic
biotin- substrate digoxigenin-
conjugated ) (DAB: diamino- labeled Hybridization
1 Antibody benzidine)
(murine) Mild fixation

Section with antigen F

"
F F F F

2. Biotin–avidin/peroxidase staining
+ FITC-labeled
anti-
Alkaline digoxigenin
phosphatase RNA-specific fluorescence Ab
3 AP–AAP + Chromo-
complex genic 2. With RNA probes
(mouse Ab) substrate B. Fluorescence in-situ hybridization
1 Primary 2 Bridging B. methods
antibody antibody
(mouse) (rabbit) Chromosome 8 Chromosome 8q-
Chromosome 21 Chromosome 21q+

3. APAAP staining

ETO gene AML 1 gene

t(8:21)

4. Detection of
tumor cells in
the bone marrow
5. Staining of the
follicle mantle
with CD22 Abs
A. Immunohistological staining
Normal cell
Interphase cytogenetics
C. Example of FISH staining in 8:21
C. translocation
t(8:21) cell

!
@G

"
! 1/&&-&'0 #22-*)(;

!" #$%&'()%* %+ ,%*%*-.&/'0 1/&&$ +0%2

3/0)45/0'& 6&%%7
!"#"#$%&'() %'&&* +# ,-' .')+.-')(& /&""0 %(#
/' *'.()(,'0 1)"2 ",-') %'&&* /3 0'#*+,3 4)(0+5
'#, %'#,)+1$4(,+"#6 7 8+%"&&593.(:$' *"&$,+"#
;0'#*+,3 "1 <6=>> 4?@A +* .&(%'0 +# ( ,'*, ,$/'B
(#0 0+&$,'0 -'.()+#+C'0 /&""0 +* &(3')'0 "#
,".6 D-' ,$/' +* ,-'# %'#,)+1$4'06 @"E50'#*+,3
%'&&* ;&32.-"%3,'* (#0 2"#"%3,'*A #"E 1&"(,
"# ,". "1 ,-' *"&$,+"#B (#0 (&& ",-') /&""0 %"25
."#'#,* 1")2 ( .'&&', (, ,-' /",,"2 "1 ,-' ,$/'6
D-' 2"#"#$%&'() %'&&* (, ,-' 8+%"&&F.&(*2( +#5
,')1(%' %(# /' )'2"G'0 E+,- ( .+.',,'6 71,') +#5
:'@%0'(%0; !44&).'()%*$
(#,+4'#5#'4(,+G' %'&& 1)(%,+"#*6 D-+* 2',-"0 +*
%(&&'0 $&&'#(&"%#)*$+ ,)!"-"*$(#6 7 2(4#',
,-(, (,,)(%,* ,-' +)"#5&"(0'0 %'&&* +* $*'0 ," *'5
.()(,' (#,+4'#5/'()+#4 %'&&*6 D-+* +* ( G')3 '15
1'%,+G' 2',-"0 1") )'2"G+#4 $#E(#,'0 %'&&*
1)"2 ( *"&$,+"#6 7* &+,,&' (* ( *+#4&' %"#,(2+#(,5
+#4 ,$2") %'&& %(# /' *'.()(,'0 1)"2 <=== #")5
2(& %'&&* /3 +22$#"2(4#',+% *'.()(,+"#6 Y#
",-') E")0*B ( MFZ &"4 0'.&',+"# "1 $#E(#,'0
%'&&* %(# /' (%-+'G'06
B" 1/&& 8/4'0'()%* @; >&%C 1;(%2/(0;
[")2(& 1&"E %3,"2',)3 E(* 0'*%)+/'0 "#

%$/(,+"# "1 ,-' %'&& 2(,')+(& +# %$&,$)' 1&(*H*B
,-' 2"#"%3,'* (0-')' ," ,-' .&(*,+% E(&&* "1
,-' /",,&'6 D-+* 2(H'* +, ."**+/&' ," %(.,$)'
&32.-"%3,'* *'&'%,+G'&36
6" 8/4'0'()%* %+ 9 '*7 6 :;245%.;(/$
<=%$/((/ >%02'()%*?
D &32.-"%3,'* 'I.)'** (0-'*+"# 2"&'%$&'*B
*$%- (* ,-' JKL 2"&'%$&'6 JKL +#,')(%,* E+,-
@875M ;JKNOA "# ,-' *$)1(%' "1 *-''. )'0 /&""0
%'&&* ;PQRJA6 71,') ,)'(,2'#, E+,- (# '#C32'B
.(4' OZ6 7 ./'(-),+)#+)0"+*$1"*)2 +)// ,(-*)-
;87JPA +* ( *.'%+(&+C'0 1&"E 2',') +# E-+%-
,-' 1+#' %'&&5%"#,(+#+#4 0)".&',* ()' '&'%,)+%(&&3
%-()4'0 $#0') %"2.$,') 4$+0(#%'6 K)".&',*
E+,- 1&$")'*%'#, %'&&* ()' ."*+,+G'&3 %-()4'0B
(#0 ,-"*' E+,- #"#1&$")'*%'#, %'&&* ;'646B (#,+5
4'#5#'4(,+G' %'&&*A ()' #'4(,+G'&3 %-()4'06 D-'
*,)'(2 "1 %'&&* +* 4$+0'0 ,-)"$4- '&'%,)+% 0'1&'%5
,+"# .&(,'*B E-')' ,-' (#,+4'#5."*+,+G' (#0
(#,+4'#5#'4(,+G' %'&&* ()' *'.()(,'0B ,-'#
4$+0'0 +#," *'.()(,' %"&&'%,+"# ,$/'*6 D-' .$)5
+,3 "1 %'&&* *'.()(,'0 /3 87JP +* $. ," VV W6

"
*$%- (* #'$)(2+#+0(*' ") L5(2+#"',-3&+5
*",-+"$)"#+$2 /)"2+0' ;7SDAB ,-' (0-'*+"#
2"&'%$&' "# ,-' QRJ *$)1(%' 2")' )'(0+&3 +#,')5
(%,* E+,- D &32.-"%3,'*6 P'G')(& PQRJ %(# /+#0
," ( *+#4&' D %'&&B ,-')'/3 1")2+#4 T)"*',,'*6U Q"5
*',,'51")2+#4 %'&&* %(# /' +*"&(,'0 /3 0'#*+,3
4)(0+'#, %'#,)+1$4(,+"# "# 8+%"&&6 7 1)(%,+"# "1
(..)"I+2(,'&3 VNW .$)' D &32.-"%3,'* %(#
/' +*"&(,'0 (1,') -3.","#+% &3*+* "1 ,-' )'0 /&""0
%'&&*6
J'&&* ,-(, 0" #", 1")2 )"*',,'* 1&"(, "# ,".
"1 ,-' 8+%"&& &(3') (#0 %(# (&*" /' +*"&(,'06
D-'*' %'&&* .)+2()+&3 %"#*+*, "1 R %'&&* (#0 ",-')
#"#5D %'&&*6

1" !*()@%7;A,/7)'(/7 8/4'0'()%* %+

1/&& >0'.()%*$
J$&,$)' 1&(*H* ") .&(*,+% 0+*-'* %(# /' %"(,'0
E+,- (#,+/"0+'* (, (# (&H(&+#' .9 ;!"##$#%A6
X-'# ( %'&& 2+I,$)' +* +#%$/(,'0 "# ,". "1
,-' (#,+/"035%"(,'0 *$)1(%'B ,-' %'&&* ,-(, 'I5
.)'** ,-' ,()4', (#,+4'# E+&& (0-')' ," ,-' .&(*5
,+% E(&&* "1 ,-' /",,&' ") 0+*-6 7#,+4'#5#'4(,+G'

! DD
%'&&* %(# '(*+&3 /' )'2"G'0 /3 0'%(#,+#46
D-' (#,+4'#5."*+,+G' %'&&* %(# /' )'2"G'0 /3
2'%-(#+%(& 2'(#* ") /3 '#C32(,+% 0+4'*,+"#6
R3 %"(,+#4 (#,+/"0+'* "#," *2(&& /'(0* ,-(,
%"#,(+# +)"# ;(G(+&(/&' +# 0+11')'#, *+C'*AB +, +*
."**+/&' ," %(.,$)' '+,-') (#,+4'#5."*+,+G' ")
 Centrifuge
1/&& #$%&'()%* 9/.5*)E-/$
!
Mononuclear
cell fraction
Ficoll

Diluted Ficoll Granulocytes,

blood (density: 1.077) erythrocytes,
platelets
A. Isolation of mononuclear cells from peripheral blood

Non-T fraction
Sheep (B lymphocytes,

:'@%0'(%0; !44&).'()%*$
erythrocytes monocytes
T lymphocytes,
Centrifuge Ficoll sheep
erythrocytes
Mononuclear cells Binding of sheep erythrocytes
to T cells: rosette formation
B. Separation of T and B lymphocytes: Rosette formation

Plastic surface Antibody

coated with labeled with
antibodies iron beads

Antigen-
bearing
Antigen-
negative
Antigen-
bearing Antigen-
"
Magnet

cells cells cells negative

adhere attracted by cells
magnet
1. Panning method 2. Immunomagnetic separation
C. Antibody-mediated separation of cell fractions

Cells in suspension Photomultiplier

Vibrating cuvette for side-scattered Photomultiplier for
light light
530–550 nm (green)

Bandpass filter Photomultiplier

for light
560–580 nm (red)

Laser Dichroic mirrors

Light-sensitive
photodiode
– + Forward scatter

Positive cells
+
+ –

D. Cell separation by flow cytometry

–

Negative cells
!
DF

"
! 2+0040'/ 5;;4)%$<

!" !#$%&'$%() *+,$,

! "#$$% &'# &"()*&(#+ &,+ ),+-"#+ (. /'.$)0#'&(#
., ".,(&"( 1)(2 %/#")0)" &,()3#,%4 5, (2# /#')/26
'&+).&"()*# (')()-? )% ),".'/.'&(#+ ),(. (2#
BM@ .0 (2# +)*)+),3 "#$$%4
@0(#' 0-'(2#' ;PUKL 2.-'% .0 "-$()*&().,8
(2# "#$$% &'# Y2&'*#%(#+Z ., &-(.?&(#+ #[-)/6
#'&$ 7$..+8 .,$9 & ,#3$)3)7$# /#'"#,(&3# .0 !"#$$%
?#,(4 5, .(2#' 1.'+%8 (2#9 &'# '),%#+ .-( .0
:., (2# .'+#' .0 ;<;= === "#$$% .' $#%%> '#&"(
(2# 1#$$% .0 (2# "-$(-'# /$&(# &,+ /&%%#+
1)(2 & %/#")0)" &,()3#,4 5, *)('. (#%(% .0 !6"#$$
(2'.-32 & 3$&%% 0)7#' 0)$(#'4 !2# "#$$%8 (2&( )%8
0-,"()., &'# (2#'#0.'# /#'0.'?#+ -%),3 %-76
2)326?.$#"-$&'61#)32( BM@ ?.$#"-$#%8 &'#
%(&,"#% (2&( %()?-$&(# &$$ ! "#$$% '#3&'+$#%% .0
"&-32( ), (2# 0)$(#'8 12)$# -,7.-,+ (29?)+),#
(2# &,()3#,6%/#")0)" '#"#/(.'4 !2#%# %-7%(&,"#%
)% 1&%2#+ .-(4 @ 7#(& ".-,(#' )% -%#+ (. ?#&6
&'# "&$$#+ !"#$%#"&'# '%()*'("+, :#4348 /29(.2#6
%-'# (2# '&+).&"()*)(9 ), (2# 0)$(#'8 12)"2 ".''#6
?&33$-(),), &,+ ".,"&,&*&$), @>4
$&(#% 1)(2 (2# #D(#,( .0 BM@ '#/$)"&()., &,+
@,()7.+)#% &3&),%( (2# ABC ".?/$#D .0 (2#
/'.$)0#'&().,4
!6"#$$ '#"#/(.' "&, $#&+ (. "'.%%6$),E&3# .0
='>(/'$(/< !??0%#'$%(),

(2# ABC ?.$#"-$#4 !2)% )?)(&(#% /29%).$.3)"&$
&,()3#, 7),+),38 12)"2 %()?-$&(#% ?.%( ! "#$$%4
A9(.E),#% :#4348 FG6AHI8 5J6K8 5J6L8 &,+ 5IM6!> ),
%-/#',&(&,( &'# (2#, ?#&%-'#+ &% /&'&?#(#'%
.0 !6"#$$ &"()*&().,4 !2# ),('&"9(./$&%?)" "&$6
")-? )., ".,"#,('&()., )% & *#'9 #&'$9 /&'&6
?#(#' .0 &"()*&().,N )( "&, 7# +#(#"(#+ 1)(2),
& 0#1 %#".,+% &0(#' "'.%%6$),E&3# .0 (2# &,()3#,
'#"#/(.' :%## /4 ;O>4 H/#")&$ +9#% (2&( "2&,3#
(2#)' 0$-.'#%"#,"# #?)%%)., %/#"('-? 12#,
(2#9 7),+ (. "&$")-? :#4348 5,+.6;> &'# -%#+ (.
?#&%-'# (2# ),"'#&%# ), (2# ),('&"9(./$&%?)"
2" * 2+00 34)#$%() 5) 6%&(7
8+9/%+4: 840$%$+,$
!2# G#\')#-D ?-$()(#%( )% & ".??#'")&$ (#%(
".?/')%),3 #)32( (),#% 1)(2 ()/% ".,(&),),3 *&'6
).-% 7&"(#')&$ .' 0-,3&$ &,()3#,% +)%%.$*#+ ),
3#$&(),4 G.%( ),+)*)+-&$% 2&*# 7##, #D/.%#+
(. (2#%# &,()3#,%4 !2# (),#% &'# /'#%%#+ ),(.
(2# %E), 0.' ),('&"-(&,#.-% +#$)*#'94 !2# %E),
)% "2#"E#+ &//'.D)?&(#$9 LW 2.-'% $&(#' 0.' +#6
$&9#+ 29/#'%#,%)()*)(9 '#&"().,% :%## /4 SO!>4
!2# (#%( )% ".,%)+#'#+ /.%)()*# )0 & %E), ),+-'&6

"
/.(&%%)-? ".,"#,('&().,4 !2# %2)0( ), 0$-.'#%6 ()., .0 !K ?? ), +)&?#(#' )% +#(#"(#+4
"#,"# "&, 7# /'#")%#$9 ?#&%-'#+ -%),3 & 0$.1
"9(.?#(#' :%## /4 OL>4
!2# #D/'#%%)., .0 &"()*&().,6+#/#,+#,( %-'6
0&"# &,()3#,% "&, &$%. 7# ?#&%-'#+ 79 0$.1 "96
(.?#('94 G.$#"-$#% %-"2 &% ABPQ .' (2# ('&,%6
0#''), '#"#/(.' ABO; &'# -/'#3-$&(#+ ., (2# "#$$
?#?7'&,# 1)(2), & 0#1 2.-'% &0(#' &"()*&().,4
R(2#'%8 %-"2 &% ABKS .' GTA ?.$#"-$#%8 &'# ,.(
-/'#3-$&(#+ 7#0.'# ;UC +&9%4
-.## %$%#. '&'#$,), :AA@> )% &,.(2#' 1&9 (. (#%(
0.' "#$$ &"()*&().,4 AA@ ?&E#% )( /.%%)7$# (. /'#6
")%#$9 ".-,( (2# ,-?7#' .0 +.'?&,(8 &"()*&(#+8
&,+ /'.$)0#'&(),3 "#$$%4

-" ./(0%1+/'$%() *+,$

!2# /'.$)0#'&()*# "&/&")(9 )% .0(#, -%#+ &% &
/&'&?#(#' 0.' &%%#%%?#,( .0 !6"#$$ 0-,"().,
:#$/!0"%$(. ,()/1#'()"& (.,( .' (+'&,2"+/'()"&
(.,(>4
!2# "#$$% &'# "-$()*&(#+ ), S V ARK ), &, ),"-6
7&(.' 0.' OKUQP 2.-'% &( CO !A ), (2# /'#%#,"# .0

!
+)00#'#,( %()?-$)4 !2# /'."#%% .0 "#$$ +)*)%).,8
12)"2 )% &%%.")&(#+ 1)(2 & +.-7$),3 .0 (2#
BM@ ".,(#,(8 %(&'(% &0(#' &'.-,+ LW 2.-'%4 X#6
"&-%# .0 (2# &++)()., .0 '&+).&"()*#$9 $&7#$#+
(29?)+),# ), "-$(-'# ?#+)-? :&, T6/.%)().,
@A .0 (2# ?.$#"-$# )% .""-/)#+ 79 CT8 (')()-?>8
 Stimulus Stimulus
*+,$, (1 *B2+00 34)#$%()

T0 4 12 24 h
!
CD69

CD71

[Ca2+]i
CD25
GM-CSF
IL-2, IL-4 HLA-DR
IFN-! 0 2 4 6 8 10 min
1. Cytokine measurement 2. Flow cytometry [Ca2+]i 3. Expression of
1. (ELISA) 3. activation antigens
A. Activation assays

='>(/'$(/< !??0%#'$%(),
Dist. Glass fiber filter
3 H2O
H-thymidine = Radioactive captures cells

16 h, 37 ˚C, 5%CO2
48 h
Scintillation
37˚C
5% CO2

– Mononuclear cells
– Stimulus (lectins, antigens)
Cell division: DNA synthesis
incorporation of 3H-thymidine
in new DNA strands
Vacuum
fluid

"-counter "
– Growth factors cpm (counts
Waste
B. Proliferation assay per minute)

Proximal
Proteus 8 1 Tetanus
Trichophyton 7 2 Diphtheria
Candida 6 3 Streptococcus
Control 5 4 Tuberculin
(glycerin)
Distal

C. T-cell function in vivo: Mérieux multitest

!
@C

"
! 3$22;2'& >::;%)(6

!" #$%$&'()*% *+ !%(),$%-./$0)+)0 1-0$22

32*%$4
!"#$%&" &'"%( )*+ ,-./"(# %, &'" $"(%$'"(0)
/)**1 2-#-0))3 4(*. 5657 777 &* 56577 77789
0,&%:",;#$"<%4%< = <"))# <0, /" %#*)0&"1 0,1 ">;
$0,1"1 %, ?%&(*@ ='%# %# 1*," /3 <-)&-(%,: &'"
<"))# %, &'" $("#",<" *4 &'" &0(:"& 0,&%:",9
AB;C9 0,1 %((01%0&"1 0-&*)*:*-# .*,*,-<)"0(
<"))# 0# 4""1"( <"))#@ A, &'%# <0#"9 &'" .*,*,-<;
)"0( <"))# #"(?" 0# 0,&%:",;$("#",&%,: <"))#@ ='"
0,&%:", 0,1 0,&%:",;$("#",&%,: <"))# 0(" 0:0%,
011"1 0(*-,1 #"?", 103# )0&"(@ ='%# &3$" *4
#&%.-)0&%*, %# ("$"0&"1 #"?"(0) &%."# 0& +""D)3
?'@*&'(*&6 !//2)0'()*%4
<"))# 0,1 <0, /" 1"&"(.%,"1 -#%,: 0 #%.$)"
4*(.-)0@ ='" 1%#01?0,&0:" %# &'0& <"))# &'0&
1%" 1-" &* 0$*$&*#%# 0(" ,*& <*(("<&)3 ."0#-("1
%, &'" &"#& 2#"" /")*+8@
3" 36(*(*7)0)(6 1$4(8 =': 1$4(
='" <'(*.%-. (")"0#" 0##03 *4&", -,1"("#&%;
.0&"# &'" D%))%,: "44%<0<3 *4 "44"<&*( <"))#@
Y*." *4 &'" <"))# 0(" D%))"1 ,*& /3 )3#%# /-&
/3 0$*$&*#%#@ ='" 0##03 1*"# ,*& 1"&"<& <"))#
D%))"1 /3 0$*$&*#%# /"<0-#" 0$*$&*&%< ?"#%<)"#
'0?" 0, %,&0<& <")) ."./(0," 0,19 &'-#9 1*
,*& (")"0#" O5H(@

%,&"(?0)#@ E,1"( &'"#" <*,1%&%*,#9 &'" 4"+ 0,&%;
:",;#$"<%4%< = <"))# $("#",& %, &'" #&0(&%,:
<-)&-(" 1* $(*)%4"(0&"9 /-& &'"3 0(" #&%)) 1%)-&"1
%, 0 )0(:" .0F*(%&3 *4 ,*,;0,&%:",;#$"<%4%<
=<"))#@ G !"#"$"%& '"!($")% %# &'"("4*(" $"(4*(."1
%, &'" <-)&-("# +%&' .0<(*#<*$%<0))3 ?%#%/)" <"))
:(*+&' 2#*." *4 &'" $(*)%4"(0&%,: <"))# 4*(.
'-:" <")) 0::(":0&"#8@ G# 0 ("#-)&9 #*." *4 &'"
<0?%&%"# %, &'" <-)&-(" $)0&" <*,&0%, *,)3 0 #%,:)"
= <"))@ H)*,0) ">$0,#%*, *4 &'" 0,&%:",;#$"<%4%< =
<"))# %, &'"#" +"))# %# 0<'%"?"1 /3 011%,: AB;C
0,1 &'" &0(:"& 0,&%:",@
A, &'" #*;<0))"1 1.# $-/$9 &'" &0(:"& <"))# 0("
4%(#& <-)&-("1 %, &'" $("#",<" *4 &(%&%-.;)0/")"1
&'3.%1%,"9 +'%<' %# %,<*($*(0&"1 %,&* &'" !JG
*4 &'" <"))#@ Z'", <"))# 1%" 1-" &* 0$*$&*#%# 2#""
$@ NO89 &'"%( !JG %# 4(0:.",&"1 %,&* &%,3 $%"<"#@
='" <-)&-("1 <"))# 0(" &'", $(*<"##"1 *, 0,
0-&*.0&"1 <")) '0(?"#&"(@ ='" '%:';.*)"<-)0(;
+"%:'& !JG *4 %,&0<& <"))# %# <0-:'& %, &'" 4%)&"(9
+'"("0# &'" )*+;.*)"<-)0(;+"%:'& !JG *4
0$*$&*&%< <"))# %# (".*?"1 +%&' &'" +0#'%,:
4)-%1@ ='" (0&" *4 )3#%# <0, /" <0)<-)0&"1 -#%,:
0, 0$$(*$(%0&" 4*(.-)0@

" 5" 36(*(*7)0)(6 1$4(8 39&*:);: <$2$'4$

!44'6
G,&%:",;#$"<%4%< <3&*&*>%< = )3.$'*<3&"# 2H=B8
<0, D%)) <"))# &'0& $("#",& &'" 0$$(*$(%0&" 0,&%;
:", %, &'"%( IBG .*)"<-)"#@ J0&-(0) D%))"( 2JK8
<"))#9 *, &'" *&'"( '0,19 D%)) <"))# &'0& "%&'"( 1*
,*& ">$("## LIH .*)"<-)"# *( ">$("## 4*("%:,
*( 0/"((0,& LIH .*)"<-)"# 2#"" $@ MN8@ ='"
*+,)#"(# ,-!-./- .//.0 %# &'" <)0##%<0) &"#& *4
JK <")) 4-,<&%*, 0,1 H=B 4-,<&%*,@ ='" &"#& %#
$"(4*(."1 /3 )0/")%,: &'" &0(:"& <"))# +%&'
(01%*0<&%?" <'(*.%-. 2O5H(89 +'%<' /%,1# &*
<3&*$)0#.%< $(*&"%,#@ P,)3 0 #.0)) 4(0<&%*, *4
&'" (01%*0<&%?%&3 %# #$*,&0,"*-#)3 (")"0#"1 /3
&'" <"))# 2#$*,&0,"*-# )3#%#9 /0<D:(*-,1 )3#%#8@
Q44"<&*( <"))# 0(" 011"1 0& ?0(%*-# <*,<",&(0;
&%*,# 4*( RSN '*-(#9 +'%<' )"01# &* )3#%# *4
&'" &0(:"& <"))#@ T-$&-(%,: *4 &'" <")) .".;
/(0,"9 +'%<' %# %,1-<"1 /3 $"(4*(%,# 0,1 :(0,;
U3."# 2#"" $@ MV!89 )"01# &* &'" (")"0#" *4 (01%*;
0<&%?" <'(*.%-.9 +'%<' <0, /" ."0#-("1 %,

!
&'" #-$"(,0&0,&@ ='%# &3$" *4 )3#%# %# 0)#*
("4"(("1 &* 0# WD%))%,:@X ='" .*(" "44"<&%?" &'"
)3#%#9 &'" '%:'"( &'" 0.*-,& *4 <'(*.%-. (";
)"0#"1@ L0>%.0) <'(*.%-. (")"0#" %# 0<'%"?"1
/3 )3#%,: 0)) *4 &'" <"))# %, 0 #-%&0/)" 1"&"(:",&
AB 2"@:@9 =(%&*,8@ ='" "44%<0<3 *4 <")) )3#%# %# $0(&%0))3
1"$",1",& *, &'" (0&%* *4 "44"<&*( <"))# &* &0(:"&
 + Irradiated
autologous MNC
!%(),$%-4/$0)+)0 1$4(4

Limiting dilution
!
Cell 1000 cells/well
+ Antigen growth 100 cells/well
+IL-2 10 cells/well
1 cell/well
4-7 days 7 days 0.3 cell/well
37°C 37°C
5% CO2 5% CO2
Repeat 3 – 4x
– Mononuclear cells (MNC)
– Antigen + Antigen
– Human AB serum + IL-2
A. Generatiion of antigen-specific T cell clones

?'@*&'(*&6 !//2)0'()*%4
No
Medium effector cells =
background
Effector/target
ratio1 : 1

Washing Effector/target
ratio 5 : 1
Binds to
intracellular
proteins Effector/target
ratio 20 : 1

+ Triton
Maximal cell lysis

cpm probe – cpm background

cpm maximum – cpm background
x 100
"
B. Cytotoxicity assay: Chromium release assay

Target cell Effector Target cell

+ 3H-thymidine cell apoptosis

Labeled
DNA
1. 2. Fragmented DNA

Dist. !-counter
H2O
Lysis in %

cpm without cpm probe

effector cell
Only x 100

3.
Filter

C. Cytotoxicity assay: Jam test

waste
intact
DNA
sticks
to
filter 4.
cpm without effector cells

cpm = counts per min

!
AC

"
! 63445410 #>>5.:/7

!" #$%&! '(#)*+,

!"# $%&'()! *#+,-.#/01+2#3 1..4+56578#+9
6:59 ;66;-< 16 46#3 95 3#9#7.1+# 9"# =7#>4#+?-
13#+91=- JRHV 57 JRIV ! ?#006 ;+3 9"#17 ?-9521+#
:;99#7+6A

6" 67/89:.3 )3203/:8. !<<17

5= ;+91@#+/6:#?1=1? ! ?#006 1+ ?#00 ?40947#6A B+91/
@#+/691.40;9#3 ?-9521+# :7534?915+ 16 .#;/
647#3 95 3#9#7.1+# 9"# 3#@7## 5= ;+91@#+ 6:#/
?1=1?19-A !"# ;+91@#+C ;+91@#+/:7#6#+91+@ ?#006C
;+3 ! ?#006 ;7# :0;?#3 95@#9"#7 1+ ; D#00 *5= ;
.#.87;+#/?5;9#3 .1?75919#7 :0;9#< ?5;9#3
D19" ;+918531#6 ;@;1+69 9"# 9;7@#9 ?-9521+#
*#A@AC &EF/!< ;+3 1+?48;9#3 =57 GH 95 HI "5476A
J#006 691.40;9#3 8- 9"# ;+91@#+ :7534?#
&EF/!C D"1?" 16 854+3 5+ 9"# 6:59 8- 9"# .#./
(1?801/807 !@@4:21/:8.<
B 816:#?1=1? ;+91853- *?;9?" 7#;@#+9C W109#+-1<
.;2#6 19 :566180# 95 81+3 ?-9521+#6 6#?7#9#3
8- ;?91K;9#3 ! ?#006 317#?90- 5+ 9"# ?#00 647=;?#A
!"# ;+91853- 1+191;00- 81+36 95 JRHUC ; 481>41/
9546 647=;?# .;72#7A !"# 6#?7#9#3 ?-9521+#
*#A@AC &EF/!< 16 854+3 95 9"# ?#00 647=;?#C D"#7#
19 16 7#?5@+1,#3 8- ; 6#?5+3 =0457#6?#+?#/0;/
8#0#3 ;+91853-A ! ?#006 69;1+#3 1+ 9"# :75?#66
?;+ 9"#+ 8# 1650;9#3 1+ ; EBJ' 6579#7 57 1+ ;

87;+#/854+3 ;+918531#6A B=9#7 1+?48;915+C 9"#
?#006 ;7# 7#.5K#3 8- ?;7#=40 D;6"1+@ ;+3 1+?4/
8;9#3 D19" ; 81591+/?5+L4@;9#3 6#?5+3 ;+91/
853- ;@;1+69 &EF/!A &+ 9"# 9"173 69#:C 697#:9;/
K131+ 81+36 95 9"# ;+91853-/854+3 81591+A !"#
#+,-.# ;99;?"#3 95 697#:9;K131+ ;?91K;9#6 ;
?"75.5@#+1? 648697;9# 9";9 69;1+6 9"# 6:596
D"#7# 9"# 691.40;9#3 ! ?#006 :7534?#3 &EF/!A
!"# +4.8#7 5= 6:596 1+31?;9#6 9"# =7#>4#+?-
5= ?-9521+#/:7534?1+@ ?#006C D"1?" 16 #M:7#66#3
;6 9"# +4.8#7 5= 6:59/=57.1+@ ?#006 *'EJ< :#7
NOO OOO ?#006A
.;@+#91? =1#03 *WBJ'< D19" 9"# ;13 5= 175+/?5+/
L4@;9#3 ;+918531#6A !"# ;3K;+9;@# 5K#7 1+97;/
?#0040;7 ?-9521+# 69;1+1+@ 16 9";9 9"# ?#006 7#/
.;1+ 1+9;?9 ;+3 ?;+ 8# =479"#7 ;+;0-,#3 8-
=4+?915+;0 ;66;-6A
=" ,3/01>30 )/1:.:.;
!#97;.#7 69;1+1+@ 16 46#3 =57 317#?9 69;1+1+@ 5=
;+91@#+/6:#?1=1? ! ?#006A E1769C 9"# "#;K- ?";1+6
5= WXJ ?0;66 & .50#?40#6 *#A@AC X%B/BG< ;7#
854+3 95 ; 9#97;.#7 0;8#0#3 D19" ; =04575/
?"75.# *($<A !"# 81+31+@ :5?2#96 5= 9"# WXJ

" -" #./0123445410 67/89:.3 )/1:.:.;

P+012# 9"# $%&'()! ;66;-C D"1?" ?;+ 5+0- 3#/
9#7.1+# 9"# =7#>4#+?- 5= ?-9521+#/:7534?1+@
! ?#006C 9"# 1+97;?#0040;7 69;1+1+@ 9#?"+1>4#
?;+ ;065 :7#?16#0- 13#+91=- 9"# 9-:# 5= ;?91K;9#3
?0;66 & .50#?40# ;7# 9"#+ 05;3#3 D19" ; *6-+/
9"#91?< :#:913#A !"16 :75?#347# ?;+ 8# 46#3
95 69;1+ 5+0- 9"56# ! ?#006 *JRIV< 9";9 7#?5@+1,#
9"# 7#6:#?91K# :#:913# 1+ ?5+L4+?915+ D19"
X%B/BGA !"# 0;8#0#3 ?#006 ?;+ 6486#>4#+90-
8# 74+ 9"754@" ; EBJ' 6579#7 95 @#+#7;9# ;+91/
! ?#006A )+?# 691.40;9#3 D19" 9"# ;+91@#+C 9"# @#+/6:#?1=1? !/?#00 01+#6A
?#00 ?40947# 16 1+?48;9#3 D19" Q7#=#031+ B 95
1+"1819 9"# #M974615+ 5= 1+97;?#0040;7 ?-9521+#A
!"16 7#64096 1+ 9"# ;??4.40;915+ 5= 0;7@#
>4;+9191#6 5= 9"# 6#?7#9#3 ?-9521+# D19"1+ 9"#
?#006A '47=;?# 69;1+1+@ 5= 9"# ?#006 16 :#7=57.#3
*#A@AC =57 JRH ;+3 JRI< =5005D#3 8- =1M;915+
D19" :;7;=57.;03#"-3#A '486#>4#+9 97#;9.#+9
D19" 9"# 3#9#7@#+9 6;:5+1+ :#7.#;8101,#6 9"#
?#00 .#.87;+#6 95 ;005D 9"# ;+918531#6 9";9
81+3 1+97;?#0040;7 ?-9521+#6 95 :;66 9"754@"
9"# .#.87;+#6A P6# 5= 9D5 0;8#0#3 ;+918531#6
*E&!J/0;8#0#3 &EF/! ;+918531#6 ;+3 ($/0;8#0#3
&%/H ;+918531#6< :#7.196 31==#7#+91;915+ 8#/
9D##+ ?#006 9";9 :7534?# &EF/! 57 &%/HA %;8#01+@
5= 647=;?# .;72#76 16 ;?"1#K#3 461+@ .4091:0#

!
7#3 #.1991+@ =04575?"75.#6 D19" D;K#0#+@9"6
9";9 ?;+ 8# 31==#7#+91;9#3 1+ ; 34;0 0;6#7 EBJ'
6579#7C =57 #M;.:0#AC 461+@ (#7J( *:#7131+#
?"0575:"-00 :759#1+C STU +.< =57 JRH ;+3
B(J *;005:"-?5?-;+1+C SSO +.< =57 JRIA !"16
AB :#7.196 9"# 61.409;+#546 13#+91=1?;915+ 5= ;00
=547 =0457#6?#+?#6 ;+3 .;2#6 19 :566180# 95
Coating Ab Over night
!<<17 *0823C503< D80 6E1012/30:F:.; !./:;3.&<@32:D:2 , 2344<

24–28 h
!
Wash
Antigen-presenting
cells, antigen, T cells
Detection Ab 1h
E E

Wash E Wash

Chromogenic substrate
E

(1?801/807 !@@4:21/:8.<
A. IFN-" ELISPOT
?
!-CD4- !-CD8-
PerCP AP 2

Surface staining
Intracellular
cytokines
Wash + Permeabilize
fixate with PFA

!-IL-4-
PE

Intracellular
!-IFN-"
FITC
with saponin

CD-8-APC IL-4-PE
"
staining
CD4-PerCP IFN-"-FITC
B. Intracellular IFN-" staining

CD45

Bispecific Ab, Restimulation,

!-CD45 ˜!-IFN-" IFN-" production
for 45 min

PE
FACS sorting

!-IFN-"-Ab PE PE

!-PE bead

C. Cytokine secretion assay PE

MACS sorting

!
AG

"
! 89:-0,' ;::9.*)6

!" #$%&'' !()*+,)*-.

!"# $%&'()(&()*# )++%',-.,/%.)' &00&1 )0 &
-,,2 3&4&+#(#4 ,5 )' *)*, 678#.. 5%'8(),'9 :,;7
0"##3 ,4 4&//)( )++%',-.,/%.)'0 &'2 8%.7
(%4#2 ;)(" 6 8#..0 ,' &-&4,0# -#.9 !#4+)'&..1
2)55#4#'()&(#2 6 8#..0 0#84#(# )++%',-.,/%7
.)' +,.#8%.#0< ;")8" 2)55%0# )'(, ("# -#. &'2
#*#4< )5 &'()/,21 2#5)8)#'8)#0 #=)0(< 5%'8(),'&.
5,4+ )++%'# 8,+3.#=#0 ;)(" ("# &'()7"%7
(#0(0 +%0( /# 3#45,4+#29
+&' )++%',-.,/%.)' &'()/,2)#0 ,' ("# 0%47
>'()/,2)#0 2)4#8(#2 &-&)'0( 0%45&8# )++%7
5&8# ,5 ("# '#&4/1 X6F09 F,+3.#+#'( )0
',-.,/%.)'0 .#&2 (, 84,007.)'?&-# ,5 ("# )++%7
&22#2< &'2 ("# X6F0 ("&( &4# )' 8.,0# 34,=)7
',-.,/%.)' +,.#8%.#0< ("#4#/1 )+)(&()'- 3"17
+)(1 (, ("# &'()/,2170#84#()'- 8#..0 &4#
0),.,-)8&. 0()+%.&(),' 2%# (, &'()-#'09 @)'8#
.10#29 !"# '%+/#4 ,5 "#+,.1()8 3.&$%#0 8,47
("# /)'2)'- ,5 )++%',-.,/%.)'0 (, A8 4#8#3(,40
4#03,'20 (, ("# '%+/#4 ,5 (#4+)'&..1 2)55#47
"&0 &' )'")/)(,41 #55#8(< A&/ 54&-+#'(0 54,+
#'()&(#2 6 8#..09
&'()7B-C &'()/,2)#0 &4# %0#29 D1,3").)E#2
!")0 +#(",2 8&' &.0, /# %0#2 (, 0(%21 0%/7
!"#$%&'()())*+ #*,-*+ /&8(#4)& ,5 ("# F,;&'
3,3%.&(),'0 ,5 &'()/,21734,2%8)'- 8#..09 !"#
<,4-0,)-06 !=='*(,)*-.>

F G@>FH -4,%3 &4# *#41 3,(#'( )'2%8(,40 ,5

%0# ,5 &'()7B-C7/#&4)'- 0"##3 4#2 /.,,2
84,007.)'?&-#9 >0 )' ! 8#..0< &'()-#' /)'2)'-
8#..0 #'0%4#0 ("&( ,'.1 (",0# 6 8#..0 ("&( 0#7
.#&20 (, & +#&0%4&/.# )'84#&0# )' ("# )'(4&7
84#(# B-C ;).. /# *)0%&.)E#29 61 &..,;)'- ("#
81(,3.&0+)8 8&.8)%+ 8,'8#'(4&(),' ;)(")' &
&'()-#' (, /)'2 (, ("# @X6F0< )( )0 3,00)/.# (,
5#; 0#8,'20< &'2 (, &' ,*#4#=34#00),' ,5 ("#
+#&0%4# 6 8#..0 ("&( 5,4+ &'()/,2)#0 &-&)'0(
&'()-#'0 FIJK &'2 FILM G(4&'05#44)' 4#8#3(,4H
& 03#8)5)8 &'()-#'9
;)(")' & 5#; ",%409 FINO &'2 FINP &'()-#'0 ,'
# 567!289 "-+"9 B' (")0 (#0(< ("# 6 8#..0 &4# 034#&2
("# 8#.. +#+/4&'# &4# %34#-%.&(#2 ;)(")' NQP
,'(, 8%.(%4# 2)0"#0 8,&(#2 ;)(" &' &334,34)7
2&109
&(# &'()-#'9 @3#8)5)8 &'()/,2)#0 34,2%8#2 /1
("# 6 8#..0 /)'2 (, ("# &'()-#'9 A4## &'()/,7
#" #$%&'' /0-'*1&0,)*-.
2)#0 &'2 8#..0 &4# 4#+,*#2 /1 ;&0")'-9 W'7
R'8# ("#1 "&*# /##' &8()*&(#2 2%# (, )++%',7 E1+#7/,%'2 &'()/,2)#0 &-&)'0( )++%',-.,7

" -.,/%.)' 84,007.)'?&-#< 6 8#..0 4#$%)4# & 0#8,'2

0()+%.%0 )' ,42#4 (, 34,.)5#4&(#9 !"#1 8&' /#
0()+%.&(#2 /1 81(,?)'#0< 0%8" &0 BD7N< BD7J<
BD7MS G678#.. -4,;(" 5&8(,4H< /1 0,.%/.# 4#8#37
(,40 G#9-9< /1 & 0,.%/.# 8.#&*&-# 34,2%8( ,5 ("#
0%45&8# &'()-#' FINPH< ,4 /1 /)'2)'- ,5 ("#
/%.)'0 &4# &22#2 /#5,4# ("# &22)(),' ,5 & -#.
8,'(&)')'- ("# 8,44#03,'2)'- 8"4,+,-#'9 >
03#8)5)8 8,.,4 4#&8(),' (&?#0 3.&8# ,'.1
;"#4# ("# 03#8)5)8 &'()/,2)#0 &4# /,%'29
!")0 34,2%8#0 8,.,4#2 03,(0 ("&( 8&' /#
8,%'(#2 (, 2#(#4+)'# ("# '%+/#4 ,5 &'()7
FIST .)-&'2 (, ("# FIST &'()-#'9 @)+).&4.1 (, /,21734,2%8)'- 8#..09
("# 34,8#00 )' ! 8#..0< ("# )'8,43,4&(),' ,5 (4)7
()%+7.&/#.#2 ("1+)2)'# )'(, 6 8#..0< &0 +#&7
0%4#2 )' LN7",%4 8%.(%4#0< )0 %0#2 &0 & 3&4&7
+#(#4 ,5 34,.)5#4&(),' G0## 39 UM!H9
V"#' ("# 84,007.)'?&-# ,5 )++%',-.,/%.)'0
)0 3&4()8%.&4.1 #55#8()*# G#9-9< ;"#' @>F /&8(#4)&
&4# %0#2H< ("# 6 8#..0 0,+#()+#0 34,2%8# &%(,7
84)'# -4,;(" 5&8(,40< +&?)'- ("# %0# ,5 5%4("#4
#=,-#',%0 0()+%.) %''#8#00&419

%" #$%&'' 2*11&0&.)*,)*-.3 !.)*4-56

7&(0&)*-.
6 8#..0 8&' 2)55#4#'()&(# )'(, 3.&0+& 8#..0 &5(#4
OQL 2&10 ,5 8#.. 8%.(%4#9 !"# WDB@> ,4 XB> 8&' /#
%0#2 (, $%&'()(&(# ("# '%+/#4 ,5 &'()/,2)#0 )'

!
("# 0%3#4'&(&'(< /%( ',( ("# &8(%&. '%+/#4 ,5 6
8#..0 ("&( 34,2%8# &'()/,2)#09 Y&4),%0 "#+,.17
()8 3.&$%#75,4+)'- 8#.. GZAFH (#0(0 8&' /# %0#2
(, ,/(&)' (")0 5)-%4#9
" .-/-,+- %-0('&"1) 234 #++#&9 @"##3 4#2 /.,,2
?@ 8#..0 G@X6FH &4# 8,'[%-&(#2 ;)(" &'()7"%+&'
Antigen Stimulus
A&>)> -1 #$%&'' B9.()*-.

Marker T0 4 24 h
!
CD69

CD71

[Ca2+]i
CD25 ( )

CD23 ( ) ( )

0 2 4 6 8 Min
Anti-IgM Cross-linkage Activated Increase in Expression of activation
antibody, of slg B cell intracytoplasmic calcium antigen
SAC

<,4-0,)-06 !=='*(,)*-.>
A. B-cell activation

IL-2 40
H-thymidine incorporation (cpm)

IL-14 (BCGF)
30
IL-4
20
sCD 23

10
Activated CD40 ligand,

"
B cell anti-CD40
antibody
3

Anti-IgM IL-14 SAC Anti-IgM Anti-IgM +

+ IL-14 anti-CD40
B. B-cell proliferation

Sheep erythrocytes
coated with anti-Ig
serum
+ Complement
Hemolytic
plaques
B
+

Agarose gel

1. Inverse plaque-forming cell assay

Antigen- E E E E EE EE
E E
coated EE EE
E

Petri dish
Washing Washing
+ +

!
E E E

Ab-producing Enzyme-linked Gel with chromogenic

B cells anti-Ig antibodies substrate
2. ELISPOT test
C. B-cell differentiation: Antibody secretion
?C

"
! <$,(7%,4) +-$,$.-74, <(&'$=5

!" #$%&'()* +,$&&-*.

!" #$%&'()" *+$&&,"-. /01 2)3-4("&5 3)( 5(637
)3&(8 *9 -(+ (+(:&)$6'$)(5,5 %5,"- :36,++3)9 $)
(+(:&)$6'$)(&,: 2$):(5 3"8 3)( &)3"52())(8
$"&$ 3" ,44$*,+,;,"- 4(4*)3"(< ='( 2)3-7
4("&5 3)( &'(" '9*),8,;(8 %5,"- 56(:,2,:
6)$*(5< /01 2)3-4("&5 $2 ,"&()(5& :3" *( -("7
()3&(8 2)$4 -("$4,: /01 *9 4(3"5 $2 )(5&),:7
&,>( (";943&,: 8,-(5&,$" $) *9 4(3"5 $2 3 6$+97
4()35( :'3," )(3:&,$" ?5(( !@< ='( /01
2)3-4("&5 3)( 8(&(:&(8 %5,"- ?)38,$3:&,>(+9 $)
"$")38,$3:&,>(+9@ +3*(+(8 '9*),8,;3&,$" 6)$*(5
&'3& *,"8 &$ :$46+(4("& 5(A%(":(5 >,3 '98)$7
>4?$)4&$)2 !@@,-74&-$*5
?346+,2,:3&(5@ :3" *( 5(63)3&(8 *9 -(+ (+(:&)$7
6'$)(5,5 3"8 >,5%3+,;(8 *9 (&',8,%4 *)$4,8(
,"&():3+3&,$" %"8() JK +,-'&<
:" :/! #(;%(*7-*.
='( 4$5& :$44$" 4(&'$8 $2 5(A%(":,"- /01
2)3-4("&5 ,5 (";943&,: 59"&'(5,5 $2 &'( 2)3-7
4("&5 ," 3 4(&'$8 *35(8 $" 3 /0'#(1.%"$#('.1
#(* "%'/.#-(< ='()( 3)( "$C 3 "%4*() $2 3%&$7
43&(8 5(A%(":,"- 595&(45 %5,"- 2"#$%"& $)
.%"$#('.-"& ?5$7:3++(8 :'3,"7&()4,"3&,"- 8,7
8($E9"%:+($&,8(5@ +3*(+(8 C,&' 2+%$)(5:("&
89(5< ='(5( 595&(45 %5( 2$%) 89(5 &'3& 2+%$)(5:(

-(" *$"85< #6(:,2,: 8(&(:&,$" $2 &'( +3*(+(8
6)$*(5 ,5 3:',(>(8 *9 3%&$)38,$-)36'9 $) :')$7
4$-("5<
+" /$)&'()* +,$&&-*.
0$)&'()" *+$&&,"- ,5 %5(8 2$) '9*),8,;3&,$" $2
B01 ?B01 2)3-4("&5@< !" &',5 4(&'$8. &'(
5,;( 3"8 "%4*() $2 56(:,2,: 4B01 4$+(:%+(5
3)( 8(&()4,"(8 32&() &'( 6)(63)3&,$" $2 &$&3+
B01 $) 6$+9?1@ B01< B01 4$+(:%+(5 3)( 5(637
)3&(8 *9 -(+ (+(:&)$6'$)(5,5 3"8 &)3"52())(8
$"&$ 3" ,44$*,+,;,"- 4(4*)3"(< ='( B01 5(7
3& 8,22()("& C3>(+("-&'5< ='( 8(&(:&$)5 $2 3"
3)-$" +35() )(-,5&() &'( 89(756(:,2,: 5,-"3+5 35
&'( 5346+(5 4,-)3&( &')$%-' -(+< ='( 83&3
3)( 3"3+9;(8 %5,"- 3 :')$4$-)34<
L"( $2 &'( 4$)( )(:("& 4(&'$85 ,5 5,"-+(7
5&)3"8 5(A%(":,"- %5,"- *,$&,"9+3&(8 6),4()5<
!" ,++%5&)3&,$" ". &'( 56(:,2,: 5(A%(":( ,5 +$:3&(8
," 3" ,"5()& $2 3 6'3-( ?!7-& !!@< ='( *,$&,"9+3&(8
6),4() ?3-"4'"5 2"#$%"@ :$"&3,"5 &'( 56(:,2,:
5(A%(":( ?5(A%(":( $2 ,"&()(5&@ 3"8 3 M! 5(7
A%(":( ,8("&,:3+ C,&' &'( %",>()53+ 5(A%(":,"-
6),4()< ='( "$"*,$&,"9+3&(8 6),4() ?"%6%"&%

"
2"#$%"@ :$"&3,"5 3 F! 5(A%(":( 3"8 3 M! 5(7
A%(":( $2 ,"&()(5& ,5 &'(" 8(&(:&(8 *9 '9*),8,7
A%(":( :$46+(4("&3)9 &$ &'( )(>()5( %",>()53+
;3&,$" C,&' +3*(+(8 6)$*(5<
6),4()< 12&() 346+,2,:3&,$" *9 4(3"5 $2 HIB
C,&' 6)$6$)&,$"3&( %5( $2 &()4,"3&$)5. &'(
0" 1$,23()45( 0'4-* 6(47&-$* 81069
56(:,2,: *,$&,"9+3&(8 346+,2,:3&(5 :3" &'(" *(
='( 6$+94()35( :'3," )(3:&,$" ,5 3 &(:'",A%( *$%"8 &$ 5&)(6&3>,8,"7:$3&(8 63)343-"(&,:
2$) (";943&,: 346+,2,:3&,$" $2 &'( 56(:,2,: "%7 *(385 3"8 (+%&(8 ," 3" 3+D3+,"( (">,)$"4("&<
:+(,: 3:,8 5(A%(":(5 6),$) &$ &'(,) 8(&(:&,$"< ='( *(385 :3" &'(" *( %5(8 2$) 5$+,876'35(
='( 6)$:(8%)( ,5 *35(8 $" &'( )(6(&,&,$" $2 3 5(A%(":,"-<
56(:,2,: )(3:&,$" 5(A%(":(. &'( ,"8,>,8%3+ 5&(65
$2 C',:' 3)( 6()2$)4(8 3& 3 6)(:,5(+9 8(2,"(8
&(46()3&%)(<
='( 8$%*+( 5&)3"85 $2 &'( /01 $2 ,"&()(5&
?$) :/01 $2 ,"&()(5& 32&() )(>()5( &)3"5:),6&,$"
$2 B01@ ,5 2,)5& 8("3&%)(8 ,"&$ 5,"-+( 5&)3"85<
!"#$%"& ?$+,-$"%:+($&,8(5 56(:,2,: 2$) &'( "%7
:+(,: 3:,8 5(A%(":( $2 ,"&()(5&@ "$C 5(&&+( $"
&'( 5,"-+( 5&)3"85 $2 /01 ," 3 6)$:(55 D"$C"
35 '((%')#(*< !" &'( "(E& 5&(6. &'( F! ("85 $2
&'( 6),4()5 3)( (E&("8(8 *9 388,&,$" $2 3 &'()7
4$5&3*+( 6$+94()35( ?(<-<. +', 6$+94()35(@
:$46+(4("&3)9 &$ &'( 43&),E ," 3 6)$:(55
)(2())(8 &$ 35 %)-(*'.#-(< ='( :9:+( $2 8("3&%)37

!
&,$". 3""(3+,"-. 3"8 (+$"-3&,$" ,5 )(6(3&(8 367
6)$E,43&(+9 FG &,4(5< ='( "%:+(,: 3:,8 5(7
A%(":( $2 ,"&()(5& ,5 346+,2,(8 (E6$"("&,3++9
*(:3%5( (3:' "%:+(,: 3:,8 5&)3"8 59"&'(5,;(8
*9 &'( 6$+94()35( :3" 2%":&,$" 35 3 "(C 43&),E
AB ," &'( 5%*5(A%("& )(3:&,$"< ='( 6)$8%:&5 $2 HIB
 Slot
!*4,2&-74, C(7'*-;%(5
!
15.8 kb
13.1 kb
9.0 kb
7.1 kb
6.5 kb
2.9 kb
1.0 kb
a b c
Agarose gel after DNA transfer filter Autoradiography film or
gel electrophoresis labeled enzymatic color reaction
75 V; 60 mA DNA probe xy
A. Southern blotting

>4?$)4&$)2 !@@,-74&-$*5
28S

18S

12S

5S

a b c

"
Agarose gel after RNA transfer filter Autoradiography film or
gel electrophoresis labeled enzyme color reaction
75 V; 60 mA cDNA-probe xy
B. Northern blotting

Region to amplify !-gt-11 !-gt-11

left arm right arm
Denaturation to DNA Insert
single strands
Hybridization with strand-
specific primers Biotin-conjugated
PCR mit primers
Nonconjugated
primers
Second heat denaturation,
hybridization with primers
and synthesis of comple-
Streptavidin- Separation of single strands
mentary strands
coated by streptavidin-linked
particle magnetic beads

A C G T
3'ddTACGGAGCTGATTA....
3'ddACGGAGCTGATTA....
3'ddCGGAGCTGATTA....
Sequence analysis

3'ddGGAGCTGATTA....

!
Direction 5'-3'

3'ddGAGCTGATTA....
Primer PCR cycle repeated 3'ddAGCTGATTA....
sequence 20–35 times 3'ddGCTGATTA....
3'ddCTGATTA....
3'ddTGATTA....
Millions of copies of DNA product
C. Polymerase chain reaction D. DNA sequencing
AA

"
" 8--0'.*)9&:&)':&)4

!" #$%&'()* !+,--,+%./0%&')-&,

!"#$%&'( )*)++)*#,-.#$%'+$)/ )#0, 1'2'11'( 3, )0
41.3,%50 )*)++)*#,-.#$%'+$)/ $0 )% !"#$%&'( 1'"
6'00$7' 681,+,0,+' ('2'63 6).0'( -9 *'%'3$6 +."
3)3$,% ,2 ) 4 6'##"0:'6$2$6 391,0$%' &$%)0'; <8' ('2'63
#')(0 3, ) 4 6'## +)3.1)3$,% ($0,1('1 68)1)63'1$='(
-9 )11'03'( 4 6'## ('7'#,:+'%3 )3 38' :1'"4 6'##
03)*'; >'6.11'%3 1'0:$1)3,19 31)63 $%2'63$,%0 )1'
38' +,03 6,++,% 6#$%$6)# +)%$2'03)3$,%0 ,2 38'
1'0.#3$%* ?*@ ('2$6$'%69; A'%$%*$3$0/ :9,('1+)/
)%( 0':0$0 +)9 )#0, ,66.1; <8'0' $%2'63$,%0 )1'
39:$6)##9 6).0'( -9 6):0.#'"2,1+$%* :9,*'%$6 -)6"
3'1$)/ 0.68 )0 03):89#,6,66$/ :%'.+,6,66$/ )%(
031':3,6,66$; B%'"38$1( ,2 38'0' 6)0'0 )1' )00,"
5%&'&:,% 8--0'.%.+3
;.<"9=()> 0.-+96:" G4?@IX J9:'1"?*A 09%"
(1,+' $0 68)1)63'1$='( -9 38' )11'03'( ('7'#,:"
+'%3 ,2 4 6'##0 )3 38' ?*A #'7'# G+1(20'(,/ 3#-#02I;
<8'1' $0 )% )-.%()%6' ,2 6$16.#)3$%* +Y )%( (Y
4 6'##0/ -.3 8)1(#9 )%9 *Y ,1 )Y 4 6'##0; <8' ('2'63
$0 !"681,+,0,+'"#$%&'( )%( 1'6'00$7'#9 $%8'1$3'(;
F$%6' $3 $0 -)0'( ,% +.3)3$,%0 $% 38' *'%' ,2 38'
ZM[P"#$*)%(/ ZM[P $0 %, #,%*'1 )-#' 3, +'($)3'
6#)00 0C$368$%* $% 4 6'##0; >'6.11'%3 1'0:$1)3,19
31)63 $%2'63$,%0 )1' 38' +)$% 6#$%$6)# 2')3.1'0 ,2
?*@ )%( ?*E ('2$6$'%6$'0; 4'0$('0 38' 68)1)63'1$03$6
4 6'## :)33'1%/ 381,+-,:'%$) )%( %'.31,:'%$) +)9
)#0, -' ,-0'17'(; ?*@ )%( )%3$-$,3$6 )(+$%$031)3$,%
$0 38' 31')3+'%3 ,2 68,$6';

6$)3'( C$38 0'1,%'*)3$7' ,#$*,)1381$3$0; D)3$'%30

C$38 !"#$%&'( )*)++)*#,-.#$%'+$) .0.)##9 1'"
0:,%( C'## 3, $%31)7'%,.0 ?*@ 1':#)6'+'%3;
1" 234+,--,+%./0%&')-&,
!"#"$%&'" ()* +",&$&"-$.; E% )-%,1+)##9 #,C 6,%"
6'%31)3$,% ,2 ?*E $% -,($#9 0'61'3$,%0 $0/ -9 2)1/
,%' ,2 38' +,03 6,++,% 2,1+0 ,2 8.+,1)# $++."
%,('2$6$'%69; <8' $%6$('%6' ,2 38' ('2'63 +)9 -'
0:,1)($6 ,1 2)+$#$)#; F'#'63$7' ?*E ('2$6$'%69 $0 6,+"
5" 5.--.' 6,7&,/%) 8--0'.*)9&:&)':3
Z,++,% 7)1$)-#' $++.%,('2$6$'%69 GZ\?MI $0 )
8'3'1,*'%',.0 *1,.: ,2 ($0')0'0 )## )00,6$)3'(
C$38 $%)('S.)3' $++.%,*#,-.#$% :1,(.63$,%; F$"
+$#)1 3, FKH/ Z\?M $0 ,23'% )00,6$)3'( C$38 JKE
E]/ 4L/ )%( M>N )%3$*'%0; F,+' ,2 38' +,03 6,+"
+,% 6).0'0 ,2 $++.%,*#,-.#$% .%('1:1,(.63$,%
)1' #$03'( -'#,C;
!
E11'03'( 4 6'## ('7'#,:+'%3 )3 38' :1'"4 6'##

# +,%#9 )00,6$)3'( C$38 )% )3,:$6 ($0:,0$3$,% G'#'" 03)*'/ 38.0 :1'7'%3$%* 38' 2,1+)3$,% ,2 :#)0+)
7)3'( ?*HI )%( JKE 39:'0 4L )%( M>N; E1,.%( 6'##0
OP Q ,2 38' :)3$'%30 1'+)$% )09+:3,+)3$6; ?*E ('"
!
M$03.1-)%6' ,2 4 6'## 1'*.#)3$,% -9 <"8'#:'1 6'##0
2$6$'%69 $0 +)$%#9 )00,6$)3'( C$38 1'6.11'%3 1'"
!
>'6,*%$3$,% ,2 +)3.1$%* 4 6'##0 -9 ).3,)%3$-,"
0:$1)3,19 31)63 $%2'63$,%0/ -.3 +)9 )#0, ,66.1 $% ($'0
).3,$++.%' ($0')0'0 #$&' 0903'+$6 #.:.0 '1938'"
!
4#,6&)*' ,2 $++.%$*#,-.#$% 0'61'3$,% (.' 3,
+)3,0.0 GFKHI )%( 0:1.'; ('2'63$7' *#96,09#)3$,%
!"#"$%&'" ()/ 012$#300 +",&$&"-$&"0 G4;5I; M'" Z\?M $0 .0.)##9 ('3'63'( )3 ) #)3' 03)*' C8'% 1'"
:'%($%* ,% 38'$1 0:'6$2$6 :1,:'13$'0/ ('2$6$'%6$'0 6.11'%3 -1,%68,:.#+,%)19 $%2'63$,%0 8)7' )#1')(9
,2 6'13)$% ?*@ 0.-6#)00'0 6)% #')( 3, 7)1$)-#' ('" #'( 3, -1,%68$'63)0$0;
*1''0 ,2 8.+,1)# $++.%,('2$6$'%69; ?*@R ('2$"
6$'%69 6)% #')( 3, 0'7'1' $%2'63$,%0 -9 :)38,*'%0
0.68 )0 !"#$%&'()*+ (,-)*#,."#/ $#,(,/%0%00*+/
)%( &,#*$%0%00*+; E S.)%3$3)3$7' )%)#90$0 ,2 ?*@
0.-6#)00'0 08,.#( -' :'12,1+'( $% :)3$'%30 C8,
('7'#,: 1'6.11'%3 1'0:$1)3,19 31)63 $%2'63$,%0 ,2
.%&%,C% 6).0';
!"#"$%&'" 3-%&26+. +",&$&"-$. 7&%8 -69:3#
0"91: &::1-6)#621#&- #"'"#0; ?% 0,+' $%($7$"
(.)#0/ 38' $++.%,*#,-.#$% 6,%6'%31)3$,%0 1'+)$%
%,1+)# ('0:$3' 38' ('7'#,:+'%3 ,2 1'6.11'%3 $%"

"
2'63$,%0 -9 6'13)$% :)38,*'%0; <8' $++.%' 0903'+
2)$#0 3, 1'6,*%$=' ) :)13$6.#)1 )%3$*'% )%( $0 38'1'"
2,1' ('2'%0'#'00 )*)$%03 $3; <8' :)3$'%30 6)% -'
31')3'( C$38 ) 7)66$%' 6,%3)$%$%* 38' )%3$*'% $%
S.'03$,%/ C8$68 $0 .0.)##9 )(+$%$03'1'( C$38 )% )("
;<< T.7)%3 G0'' ::; RNUVRNWI;
 Pyoderma Meningitis
=0-.7,% 8--0'.*)9&:&)':&)4

Albumin
"
Infections
Xq21 of upper
and lower ! 1 !2 " #-fraction
airways is missing
X-linked Sepsis
recessive

A. Bruton’s agammaglobulinemia Serum protein electrophoresis

Bacterium Monocyte Opsonization, S. pneumoniae, Produced from

phagocytosis, H. influenzae, 2nd year or life on;
Ab-mediated N. meningitidis Ab against bacterial
cellular polysaccharides,

5%&'&:,% 8--0'.%.+3
cytotoxicity teichoic acid
Fc# receptor Absence increased Absence increased
susceptibility to susceptibility
IgG1 + IgG3 bacterial infections IgG2 to infections

Not able to Half life (t 1 2 ):

activate
C1q of IgG1 = 23 days
Ag complement
t1
2 ~12 days
Complement Dangerous when Dangerous when IgG1

IgG4
cascade other subclasses
are absent

1. Selective IgG subclass defects/properties of IgG subclasses

Mutations
in the gene for
TCR
IgG3

Ag
MHC
is absent because of
short half-life of IgG3

IgM or IgD
#
CD40 ligand

Xq26 Class switch

CD40 CD40
ligand IgG or IgA
2. Hyper-IgM syndrome
B. Dysgammaglobulinemia

Pro-B pre-B Virgin-B Recurrent

pneumonia
Arrest in Circulating Auto-Ab
pre-B B cell
phase Association
with HLA-A1,
Impaired
B8, DR3, see
TH regulation
SLE-association
Defective Bronchiectasis

"
glycosylation of Ig Plasma
cell Gastrointestinal
symptoms:
spruelike celiac
disease,
diarrhea,
C. CVID: Common variable immunodeficiency – possible causes malabsorption
;<;

#
" .))/,(-$0+1+$,1+$<

!" #$%$&$ '()*+,$- .))/,(-$0+1+$,12

!"#"$" %&'()*"+ )'',*&+"-)%)"*%. /.*+$&'"
0!1234 )/ 5 6"7"$&8"*"&,/ 8$&,9 &- :;%"<< +"-"%7/=
16)<+$"* 5--"%7"+ (. 76" +"-"%7 /75$7 7& +"#"<&9
/.'97&'/ 57 >?@ '&*76/ &- 58" &*%" 76" 5*7)(&+.
9$&7"%7)&* -$&' 76" '&76"$ /75$7/ 7& +)')*)/6= :6"
'5)* /)8*/ &- !123 )* 5 (5(. 5$" -5)<,$" 7& 76$)#" 5*+
$"%,$$"*7 )*-"%7)&*/= A"/9)$57&$. 7$5%7 )*-"%7)&*/
0'5)*<. %5,/"+ (. !"#$%&'()*+) ',-+"++ 5*+ .,"/+0
/,4 5*+ 85/7$&)*7"/7)*5< )*-"%7)&*/ 0-&*,1+-$)4 5$"
76" '&/7 %&''&* '5*)-"/757)&*/= B%C"'5 )/ 5</&
7.9)%5<= :6" 76.',/D <.'96 *&+"/ 5*+ 7&*/)</ 5$"
,/,5<<. 5(/"*7D 5*+ 13>;9&/)7)#" %"<</ %5**&7 ("
+"7"%7"+ )* 76" (<&&+=
';+,+18; .))/,(;(62
'" !789+8 :$;$8,6+$178<+8
L75K)5 7"<5*8)"%75/)5D &$ 2&$+)03,- )("/-&%#D )/
%65$5%7"$)C"+ (. 5 %<)*)%5< 7$)5+ &- /.'97&'/D
*5'"<.D 9$&8$"//)#" )'',*&+"-)%)"*%.D %"$"("<<5$
575K)5D 5*+ &%,<&%,75*"&,/ 7"<5*8)"%75/)5= :6)/ /.*;
+$&'" )/ 5 6"7"$&8"*"&,/ 8$&,9 &- 6"$"+)75$. +)/;
&$+"$/ 7$5*/')77"+ 5/ 5,7&/&'5< $"%"//)#" +"-"%7/
5<< &- M6)%6 65#" %6$&'&/&'5< )*/75()<)7. )* %&';
'&*= N$"5E58" 5*+ 7$5*/<&%57)&* &- %6$&'&/&'"/D
"/9"%)5<<. %6$&'&/&'" WQD <"5+ 7& +"-"%7/ )* 76"
8"*" <&%) -&$ :1A 5*+ )'',*&8<&(,<)*/= !)*%"
3XL $"95)$ )/ 5</& 8$"57<. )'95)$"+D 76" 957)"*7/
5$" "K7$"'"<. /"*/)7)#" 7& )&*)C)*8 $5+)57)&*=
Y"*%"D $5+)&8$596)% "K5')*57)&*/ /6&,<+ *&7 ("

!123 /.*+$&'" 65/ #5$)&,/ %5,/"/D "=8=D
!
5* 5,7&/&'5< $"%"//)#" +"-"%7 &- 76" $"%&'();
*5/" 8"*" 7657 9$"#"*7/ 76" 9$&9"$ <)*E58" &-
76" FD 3D 5*+ G 8"*"/ -&$ :1A 5*+ )'',*&;
8<&(,<)*/H 5*+
!
9&)*7 ',757)&* &- 76" 8"*" -&$ 76" ! %65)* &-
76" 2I;J $"%"97&$D <"5+)*8 7& )*6)()7)&* &- $";
%"97&$ 5%7)#)7.=
!123 %5* 5</& (" )*+,%"+ (. #5$)&,/ 9,$)*" '"75;
(&<)/' +)/&$+"$/D "=8=D
9"$-&$'"+ )* 76"/" 957)"*7/ ,*<"// 76" ("*"-)7/
%<"5$<. &,7M")86 76" $)/E/= L95$7 -$&' 76" 7.9)%5<
%<)*)%5< /.'97&'/D 76" +)/&$+"$ )/ 5</& %65$5%7"$;
)C"+ (. "<"#57"+ 5<965;-"7&9$&7")* <"#"</ 5*+
8$"57<. $"+,%"+ <"#"</ &- 28L 5*+ 28B= :6)/ 9$&8$"/;
/)#" )'',*&+"-)%)"*%. <"5+/ 7& /"#"$" (&,7/ &-
/)*,/)7)/ 5*+ <,*8 )*-"%7)&* 0/&;%5<<"+ )+"&4$5%&"0
,-( )("/-&%#4= :6"$59. )/ /.'97&'57)%=
4" =+<>(77?!;-&+1@ #2,-&()$

# +"-"%7)#" %"<< +)#)/)&*D "/9"%)5<<. &- : %"<</D +," Z)E%&77?L<+$)%6 /.*+$&'" 0ZL!4 )/ 5 6"$"+)75$.
!

7& 76" )*6)()7)&* &- 76.')+.<57" /.*76"75/" (";
%5,/" &- 5* )*%$"5/" )* +"/&K.5+"*&/)*" )*
76" 5(/"*%" &- 5+"*&/)*" +"5')*5/" 0L3L4H 5*+
!
: %"<< +5'58" $"/,<7)*8 -$&' 76" -&$'57)&* &-
7&K)% )*&/)*" '"75(&<)7"/ +," 7& 76" +"-"%7)#"
+"8$5+57)&* &- )*&/)*" 7& 6.9&K5*76)*" )* 76"
5(/"*%" &- 9,$)*" *,%<"&/)+" 96&/96&$.<5/"=
L<<&8"*")% (&*" '5$$&M 7$5*/9<5*757)&* )/ *&M
%&*/)+"$"+ 7& (" 76" 7$"57'"*7 &- %6&)%"= N"%5,/"
&- 76" +"-"%7D *& $"O"%7)&* $"/9&*/" %5* (" )*+,%"+
(. "*+&8"*&,/ : %"<</=
+)/"5/" %65$5%7"$)C"+ (. 76$&'(&%.7&9"*)% 9,$;
9,$5D $"%,$$"*7 )*-"%7)&*/D 5*+ "%C"'5= :6" +)/"5/"
)/ 7$5*/')77"+ 5/ 5* [;<)*E"+ $"%"//)#" %6$&'&;
/&'" +"-"%7= Z)/E&77?L<+$)%6 /.*+$&'" )/ %5,/"+
(. 5<7"$"+ "K9$"//)&* &- 13Q>D 5 8<.%&9$&7")* 7657
-&$'/ 5* )'9&$75*7 95$7 &- 76" %.7&/E"<"7&*= 3";
-"%7)#" 5%7)* (,*+<" -&$'57)&* )* : %"<</ 5*+ 76$&';
(&%.7"/ %5* (" #)/,5<)C"+ (. "<"%7$&* ')%$&/%&9.=

3" 4+ 5$(&6$ #2,-&()$

3) P"&$8" /.*+$&'" )/ %5,/"+ (. '5<-&$'57)&* &-
76" >$+ 5*+ Q76 965$.*8"5< 9&,%6"/ +,$)*8 -"75<
+"#"<&9'"*7= L<< &$85*/ 7657 5$)/" -$&' 76"/"
/7$,%7,$"/ 5$" /"#"$"<. +./-,*%7)&*5<= R$)'5$.
6.9&95$576.$&)+)/' '5*)-"/7/ 5/ 6.9&%5<%"')%
7"75*.= 2* 5$&,*+ JS T &- %5/"/D 6.9&9<5/)5 &- 76"
76.',/ )/ 5%%&'95*)"+ (. $"%,$$"*7 )*-"%7)&*/

"
+," 7& : %"<< +"-)%)"*%)"/= U5%)5< +./'&$96)/'D '5<;
-&$'57)&* &- 76" 5&$7)% 5$%6D 6.9&76.$&)+)/'D 5*+
"/&9658"5< 57$"/)5 5$" 5</& &(/"$#"+ )* 957)"*7/
M)76 3) P"&$8" /.*+$&'"= :6"$59. )/ '5)*<. /.'9;
7&'57)% 5*+ %&*/)/7/ &- 76" 5+')*)/7$57)&* &- 15JV
ABC 5*+ #)75')* 3 /,99<"'"*7/=
 V+D+J+C VDJ+C!
'$;;/;8& .))/,(-$0+1+$,1+$<
"
# " !
Recombinase Point
mutationXq13
IgG, heavy
TCR, " chain RAG I, II-genes chain
X-linked IL-2-receptor
A. Forms of SCID recessive

Clinical
1. Eustachian tube Facial
picture
abnormalities Thymic
22q11 Pharyngeal tonsil hypoplasia
2. Hypopara-
Thymus thyroidism
Frequent
3. Parathormone infections

';+,+18; .))/,(;(62
Embryonic Lower
4. Parathyroid
developemental cCa2+ cp Aortic
disorder Upper glands i arch
of 3rd and 4th
5. malformation
Ultimobranchial
pharyngeal body (C cells)
pouches Hypo-
Lateral pharynx calcemic seizures
B. Di George syndrome

Autos. recessive, Ionizing

#
heterogenous 1. Oculo-1. radiation
group cutaneous #, ", !, X
1. telangi-
1. ectasia
Impossible
Chromosomal 2. Cerebellar Thymidine to repair
instability 2. ataxia dimer DNA
3. Dys- damage
morphism
Breakages and
translocations
in chromosome 14
(gene loci for Caution during
TCR and Ig)
Clinical triad radiodiagnostics!

C. Ataxia telangiectasia

Xp11.22
1.Frequent infections

2. Eczema
Thrombo-
2. constitution
cytes
3. Thrombo-
3. cytopenic
3. purpura: 1
3. epistaxis;

"
CD43 T cells 3. petechial
(Sialoglyco- 2
3. skin bleeding;
proteins) Bundle formation
3. melena
of actin filaments Impaired
in cytoskeleton function
Clinical triad
D. Wiskott – Aldrich syndrome
ABD

#
! #<<0$17*%(-(*$-(*3

!" #$%&$'()* +*,'(- ./&$0)1-2'13(3

!"#$"%&'( )(*%&+ ,-$".'/+0%/)&) 1!234 &) +5$-$+%(-&6(7
80 %5( &"%-$+(''.'$- 9&''&", /# 8$+%(-&$ 80 :&+-/8&+&;
7$' /<0,(" -$7&+$') &" %5( *-()("+( /# "/-:$' 8$+;
%(-&$' 8&"7&", $"7 *5$,/+0%/)&)= >5( 7(#(+% &)
+$.)(7 80 $ '$+9 /# +0%/+5-/:( !??@ &" %5( *5$,/;
)/:$' :(:8-$"( /# ,-$".'/+0%()= ABCDE &) ."$8'(
%/ %-$")*/-% %5( ('(+%-/") -(F.&-(7 #/- %5( #/-:$;
%&/" /# /<0,(" -$7&+$') %5-/.,5 %5( :(:8-$"(
$"7 %-$")#(- %5(: %/ GH :/'(+.'()= I0%/+5-/:(
8??@ 7(#&+&("+0 &) $" J;'&"9(7 -(+())&K( +5-/:/;
)/:( 7(#(+%= ABCDE /<&7$)( *'$0) $ 9(0 -/'( &"
%5&) -(7/< -($+%&/"= 3'.+/)(;L;*5/)*5$%( 7(507-/;
,("$)( :$9() ABCDE $K$&'$8'( &" %5( +0%/*'$):
5)($(-&) #<<0$1)1;2
5" =*081-2'* !76*/*$-* >/1'*($ ?*%*-'3
>5(-( $-( %M/ %0*() /# '(.9/+0%( $75(-("+( *-/%(&"
7(#(+%) 1RBDC4= !" %0*( SN $75(-("+(N +5(:/%$<&)N
$"7 *5$,/+0%/)&) $-( &:*$&-(7 7.( %/ -(7.+(7 (<;
*-())&/" /# ICS@N %5( !;+5$&" /# %5( $75(-("+(
).-#$+( *-/%(&" RTB;SN +/:*'(:("% -(+(*%/- UN
$"7 %5( IU7, -(+(*%/-= >0*( H &) +5$-$+%(-&6(7 80
&:*$&-(7 &"%(-$+%&/" 8(%M((" ,-$".'/+0%() $"7
("7/%5('&$' +('') M5&+5N &" %.-"N &"5&8&%) %5( ,-$";
.'/+0%() #-/: -/''&", /" %5( K())(' M$'') $"7 :&;
,-$%&", %/ %5( #/+& /# &"#(+%&/"= >5&) %0*( /# &"%(-$+;
%&/" &) "/-:$''0 :(7&$%(7 80 )('(+%&") $"7 %5(&-
-(+(*%/- :/'(+.'()= 2&$'/,'0+/*-/%(&" 2,*?V &)
%5( -(+(*%/- #/- R;)('(+%&" &" '(.9/+0%()N $"7

$#%(- -(:/K&", &% #-/: %5( 5(</)( :/"/*5/)*5$%(
*$%5M$0= B" ABCDE /<&7$)( 7(#(+% $"7 $ '$+9 /#
,'.+/)(;L;*5/)*5$%( 7(507-/,("$)( $')/ :$9(
,-$".'/+0%() &"+$*$8'( /# 9&''&", *5$,/+0%/)(7
8$+%(-&$= >5( +'&"&+$' :$"&#()%$%&/") /# %5( ,-$".'/;
+0%( 7(#(+% $-( '0:*5$7("&%&)N /-/"$)$' *0/7(-:$N
$"7 +/'/"&6$%&/" /# )(*%&+ 8$+%(-&$ &" %5( '.",)N &";
%()%&"()N 8/"(N $"7 '&K(-= >5( :/)% +/::/" *$%5/;
,(") $-( "#$%&'()*)**+,N "-..$#/$N 0(-!,/-(($N $"7
1,%-.2/((+, )%-$&")= I$%$'$)(;"(,$%&K( )%-$&") ).+5
)&$'0';R(M&);J;/'&,/)$++5$-&7( &) %5( -(+(*%/- #/-
W;)('(+%&" &" ("7/%5('&$' +('')= W$+5 5$) +$-8/;
507-$%( +5$&") M&%5 #.+/)( :/'(+.'() %5$% M(-(
"/% 7(-&K(7 #-/: :$""/)( 7.( %/ $" ("60:(
7(#(+%=
?" @2*)1,*/1A(7&3* ?*%(-(*$-2
Q0('/*(-/<&7$)( 1QDG4 +/"K(-%) EHGH $"7 +5'/-;
&7( &/") %/ GI';N M5&+5 &) )%/-(7 &" )*(+&#&+ ,-$".'()=
QDG 7(#&+&("+0 &) +$.)(7 80 $ )&,"&#&+$"% -(7.+%&/"

" $) "#.-%#)*)**+, $"7 3$-4)%&/(+, /56(+-57$- +$"

8( 9&''(7 &"%-$+(''.'$-'0 8(+$.)( %5(0 #/-: EHGHN
M5&+5 %5( ,-$".'/+0%() +$" .)( $) $ 8$+%(-&+&7(=
>5(-$*0 +/")&)%) /# )0:*%/:$%&+ %-($%:("%
M&%5 $"%&8&/%&+) $"7 ).-,&+$' -(:/K$' /# %5( )(*%&+
#/+& /# &"#(+%&/"=
&" %5( ".:8(- /# ,-$".'() &" ,-$".'/+0%() $"7
:/"/+0%()= B) $ -().'%N &"%-$+(''.'$- 8$+%(-&+&7$'
$+%&/" &) -(7.+(7N %5/.,5 "/% ("%&-('0 $8)("%=
A/"( %5( '())N 8$59/9$ $(!/*$5, +$""/% 8( 9&''(7
M&%5/.% :0('/*(-/<&7$)(=

4" 56*7(&89:(;&36( +2$7/1<*

>5&) 7&)($)( &) $" $.%/)/:$' -(+())&K( 7(#(+% %5$%
/++.-) &" $ 7&)*-/*/-%&/"$%( ".:8(- /# &"7&K&7.$')
/# O(M&)5 /-&,&"= C(#(+%&K( +5(:/%$<&) $"7 7(#(+;
%&K( &"%-$+(''.'$- 9&''&", /# 8$+%(-&$ +$" 8( /8)(-K(7=
B8"/-:$'N ,&$"% ,-$".'() +$" 8( /8)(-K(7 .*/"
:&+-/)+/*0= >5( $8)("+( /# 7(,-$".'$%&/" &) $%%-&8;
.%(7 %/ :&+-/%.8.'$- 70)#."+%&/"= !" $77&%&/" %/
%5( ,-$".'/+0%( $+%&K&%0N &:*$&-:("% /# "$%.-$'
9&''(- +('') $"7 $ -(7.+%&/" &" $"%&8/70;7(*("7("%
+(''.'$- +0%/%/<&+&%0 1BCII4 +$" $')/ 8( /8)(-K(7=
>5( :$&" +'&"&+$' :$"&#()%$%&/") /# I5(7&$9PE&,$;
)5& )0"7-/:( $-( *$-%&$' /+.'/+.%$"(/.) $'8&"&):
$))/+&$%(7 M&%5 *5/%/*5/8&$ $"7 K$-&/.) "(.-/;

!
'/,&+$' )0:*%/:)= D$%&("%) M&%5 %5&) 7(#(+% $-(
*$-%&+.'$-'0 ).)+(*%&8'( %/ &"#(+%&/") +$.)(7 80 +$%;
$'$)(;"(,$%&K( 8$+%(-&$= I5/'&"(-,&+ $,("%) $-(
%5(-$*(.%&+$''0 (##(+%&K( 8(+$.)( %5(0 *-/:/%(
:&+-/%.8.'$- -(*$&- 80 &"+-($)&", %5( &"%-$+(''.'$-
BCD '(K(') /# +3QD=
 Glucose-6- P -dehydrogenase
./&$0)1-2'(- ?*%(-(*$-(*3

Hexose monophosphate pathway

!
Glucose-6- P Ribulose-6- P + CO2
Xp21 NADP+ NADPH + H+
NADPH oxidase
e-
g1
22
Defect
Staphylo-
e- coccus,
Cytochrome b558 O2 O2 (radical) Klebsiella,
Serratia

5)($(-&) #<<0$1)1;2
Pronasal Septic abscesses in lung, intestine, bones, liver Abscesses in
pyoderma lymph nodes
A. Infantile septic granulocytosis

Streptococcus, Neurological

"
Pneumococcus, symptoms
H. influenzae

Intracellular Partial
Chemotaxis bactericidal function oculocutaneous
(degranulation) Clinical albinism
B. Chediak – Higashi syndrome outcome

CD18-expression Homo- a Mannose Fucose Endothelium

logies
with WF
Granulocyte
and FB
granulocyte
Trans-
surface
migration Adhesion
CD18 CD11a CD18 CD11b CD18 CD11c
Rolling
! " ! " ! "

Sgp50
L-selectin
LFA-1 CR-3 C3dg-R
Type 1 Type 2 E-selectin LewisX ligand
C. Leukocyte adhesion deficiency

H2O2 + Cl- OCl- + H2O

!
17q21 MPO

defect Bactericidal activity C. albicans

D. Myeloperoxidase deficiency
BCE

"
! F669&*@-.%/%-&/%-5

!"# $%&' () *+(*#+$, )-.&/0(.0.1 &(2*$#2#./ *+(3

/#0.4 "%4 #))#&/4 4020$%+ /( /"(4# () 022-.(1$(3
5-$0. 6#)0&0#.&,7 !"# *%/0#./4 "%8# %. 0.&+#%4#6
)+#9-#.&, () 4#8#+# 5%&/#+0%$ 0.)#&/0(.47 !"#4# 0.3
)#&/0(.4 %+# 1#.#+%$$, &(./+($$#6 5, (*4(.0:%/0(.
%.6 &(2*$#2#./ $,404 0. 0.60806-%$4 ;0/" % "#%$/",
022-.# 4,4/#27 < 4#&(.6 /,*# "%4 401.4 %.6
4,2*/(24 4020$%+ /( /"(4# () =>? %.6 8%+0(-4 8%43
&-$0/06#4 @4## /%5$#A7
!" #$ %&'%(%)*+ ,-.%/%-&/0
>(; 4#+-2 &(.&#./+%/0(.4 () BC 0."050/(+ +#4-$/ 0.
+#&-++#./ %.10(#6#2%/(-4 4;#$$0.1 () /"# 4'0. %.6
2-&(4%#7 D) $(&%$0:#6 0. /"# (+(*"%+,.1#%$ +#10(.E
#7%&%/37 F669&*7*;0
&0#.&0#47 !"# 0.&+#%4#6 +#&#*/080/, () /"#0+ #+,/"+(3
&,/#4 /( "(2($(1(-4 BO5 /+011#+4 /"# %$/#+.%/08#
*%/";%, () &(2*$#2#./ %&/08%/0(.7 >,404 (&&-+4
2(+# +%*06$, %.6 2(+# )+#9-#./$, %)/#+ /"# )(+2%3
/0(. () 2#25+%.# %//%&' &(2*$#I @P<BA7 J%/0#./4
;0/" JKL /"#+#)(+# 4-))#+ )+(2 +#&-++#./ %//%&'4 ()
0./+%8%4&-$%+ %.6 #I/+%8%4&-$%+ "#2($,404E /"# &$0.3
0&%$ 2%.0)#4/%/0(. () ;"0&" 04 "#2(1$(50.-+0%7
#" 2*5%)%>- ?--@(3/A B**C ,05.9&/)%*&
D."050/(+, )%&/(+4 L %.6 D #))#&/08#$, &(./+($ BO %&3
/08%/0(. 0. "#%$/", 0.60806-%$47 Q"#. % 6#)0&0#.&,
() /"#4# +#1-$%/(+, *+(/#0.4 #I04/4E /"# *(40/08#
)##65%&' $((* %+(-.6 /"# BO5R53BO &(.8#+/%4# #.3

%&-/# (54/+-&/0(. () /"# -**#+ %0+;%,4 2%, %$4( (&3
&-+7 !"#+# %+# /;( /,*#4 () BC 0."050/(+ 6#)0&0#.&,F
%-/(4(2%$ 6(20.%./ %.6 %&9-0+#67 D. 5(/" &%4#4E
/"# BC 0."050/(+ 04 6#1+%6#6 2(+# 9-0&'$, /"%. 0/
04 *+(6-&#67 G.&(./+($$#6 *+(/#%4# %&/080/, $#%64
/( /"# +#$#%4# () 0.)$%22%/0(. 2#60%/(+4 /"%/ 0.3
&+#%4# $(&%$ 8#44#$ *#+2#%50$0/,E /"#+#5, 2%'0.1
/"# /044-#4 4-4&#*/05$# /( #6#2% )(+2%/0(.7 !+#%/3
2#./ 04 ;0/" %.6+(1#. 6#+08%/08#47 H%.%:($E )(+
#I%2*$#E 0.&+#%4#4 BC 0."050/(+ *+(6-&/0(. -40.1
:,2# &(.4-2#4 %$$ %8%0$%5$# .%/08# BO -.*+(6-&3
/08#$,7 < &#+/%0. %-/(%./05(6, %$4( 50.64 /( /"#
BO5R5 &(2*$#I7 !"04 *+#8#./4 /"# 2($#&-$# )+(2
6044(&0%/0.1 0./( BO5 %.6 R5 )+%12#./4E % *+(&#44
2#60%/#6 5, )%&/(+ L7 <4 0. *+02%+, BO 6#)0&0#.&,E
5(/" () /"#4# +#1-$%/(+, 6,4)-.&/0(.4 2%.0)#4/
&$0.0&%$$, %4 60))-4# 4-5&-/%.#(-4 $0*(6,4/+(*",
%.6 2#4%.10(&%*0$$%+, 1$(2#+-$(.#*"+0/047 S#&-+3
+#./ *,(1#.0& 0.)#&/0(.4 %+# %$4( (54#+8#6 5#&%-4#
(*4(.0:%/0(. %.6 &#$$ $,404 %+# +#6-&#6 6-# /( /"#

"
/"# *+#4#+8#6 %.6 )-.&/0(.%$ 1#.# 0. /"# $08#+ ()
*%/0#./4 ;0/" /"# "#+#60/%+, )(+2 () /"# 604#%4#7
1" 23+*405637 8*/)9+&37
:-6*;7*(%&9+%3 <28:=
J%+(I,42%$ .(&/-+.%$ "#2(1$(50.-+0% @JKLA 04
&%-4#6 5, % 6#)#&/ () &(2*$#2#./3+#1-$%/0.1 4-+3
)%&# *+(/#0.47 !"# 2#&"%.042 0.8($8#4 4-+)%&#
2($#&-$#4 %.&"(+#6 /( /"# 2#25+%.# 5, 1$,&(4,3
$%/#6 *"(4*"%/06,$0.(40/($ @MJDA7 H#&%,3%&&#$#+%/3
0.1 )%&/(+ @H<NAE #+,/"+(&,/0& %&#/,$&"($0.#4/#+%4#E
%.6 >N<3O %+# *+02# #I%2*$#47 JKL 04 &"%+%&/#+3
0:#6 5, /"# *+($0)#+%/0(. () "#2%/(*(0#/0& 4/#2
&#$$ &$(.#4 ;0/" 2#25+%.#35(-.6 *+(/#0. 6#)03
%54#.&# () BO7
#*6C7-6-&) D-/-C)*+ ,-.%/%-&/0
K#-/+(*"0$32#60%/#6 %6"#40(.E &"#2(/%I04E %.6
*"%1(&,/(404 () )(+#01. 4-54/%.&#4 (*4(.0:#6 5,
0BO5 04 4#8#+#$, 02*%0+#6 0. /"04 +%+# "#+#60/%+, 6043
#%4#7 T0+/-%$$, .( .#-/+(*"0$4 0.)0$/+%/# /"# 40/#4 ()
0.)$%22%/0(.7 !"# *%/0#./4 6#8#$(* $0)#3/"+#%/#.3
0.1 4#*4047 !"# 4#8#+0/, () /"# 604#%4# 04 6#*#.6#./
(. /"# 6#1+## () 02*%0+#6 4-+)%&# #I*+#440(. ()
&(2*$#2#./ +#&#*/(+4 BSO %.6 BSU %.6 >N<3C7
V/"#+ &$0.0&%$ )#%/-+#4 () /"04 022-.(6#)0&0#.&,
4,.6+(2# %+# 6#4&+05#6 0. /"# /%5$#7

#*6C7-6-&) ,-.%/%-&/%-5

#*6C7-6-&) C+*)-%&5 ,-.%/%-&/0E355*/%3)-@ 63&%.-5)3)%*&5

!"#!$ %&'( )*+,-./0 /.1-02/+.3 4-5,5( ).-67+0+0089 3-)3/3:

!;( <=( <" >*+,-./0 /.1-02/+.3( ,9+7-?69+.-)@?/2/3

!
$GH
!A

!F;( !F$( &<G#"

B.1-02/+.3( -3)-0/899* C* !"#$$"%#& 3))5 4,+.+0+00/( 7-./.,+0+00/:D
309-?+E802*9*

H/.,/I/2/3( E-98*-E E-0/E682/+. +1 2@- 67C/9/089 0+?E( ?-06??-.2

3-)3/3
 C1 inhibitor
#*6C7-6-&) ,-.%/%-&/%-5 3&@ ,-.-/)5
!
C1 Plasminogen
XI

C4 C2 Pre-
kallikrein Plasmin
C1qrs
XII
C4b C2b

#7%&%/37 F669&*7*;0
Complement activation Coagulation Kallikrein Fibrinolysis

“Kinin-like” High molecular Bradykinin

C2b-fragment kininogen

"
Local permeability of blood vessels , edema

A. C1 inhibitor deficiency

Protein E.g. DAF

C-terminal z.B. LFA-3 C3 H P
z.B. N-CAM
P z.B. erythr.
Carbohydrate chain

G z.B. AChE
G M C3b

G G M M C4b C2b Bb
C
I
Ba
C3a
GPI-anchor

P
H2C CH CH2 C3b
Phosphatidylinositol

C
O O C3b B
C O C O
C3b B

B. Paroxysmal nocturnal
B. hemoglobinuria (PNH)
C3c C3dg

C. Positive feedback loop dysfunction

!
$GI

"
! >..&-)0(*2'2(-'2(6

! "#$%&'()*+ (,-,'., &//(,'0$1&2&$,2+ )+,3

0#'/$ 4564 "#$0'/&,6,4*+ 611$24$0 5'/')$7(6*
/6*$) .6) 1&#)4 0$)2#&8$0 &, 9:;9< =5$ )+,0#'/$
.6) 6))'2&64$0 .&45 *&1$345#$64$,&,> !"#$%&'()*+)
',-+"++ ",$(/',&6 6,0 ?6"')&@) )6#2'/6 A 4.'
2',0&4&',) 4564 560 8$$, #6#$ (,4&* 45$,< B&/&*6#
26)$) '1 62C(&#$0 &//(,'0$1&2&$,2+ )+,0#'/$
D!EFBG .$#$ *64$# '8)$#%$0 &, 5$/'"5&*&62) .5'
560 #$2$&%$0 2*'44&,> 1624'# HEEE 4#6,)1()&',) 6,0
&, '45$# #$2&"&$,4) '1 8*''0 '# 8*''0 "#'0(24)< E4
.6) 45$#$1'#$ 6))(/$0 4564 45$ 6>$,4 #$)"',)&8*$
1'# !EFB .6) 4#6,)/&44$0 8+ &,1$24&'()I )$7(6*I 6,0
5$/64'>$,&2 #'(4$)< ! 1#6,4&2 )$6#25 1'# 45$ 26()63
4&%$ 6>$,4 *$0 4' 45$ 0&)2'%$#+ '1 45$ ,$. %&#() 8+
782-2'/8 >..&-)8)4;
7" 9(:82'/$2)- 7;'8( 2- $+( 5)6$ 7(88
!14$# 45$ 4.' *&"&0 /$/8#6,$) 1()$I 45$ 2',4$,4) '1
45$ %&#&', 6#$ #$*$6)$0 &,4' 45$ 2+4'"*6)/< E//$3
0&64$*+ 614$#.6#0I 45$ #$%$#)$ 4#6,)2#&"46)$ )46#4) 4'
4#6,)2#&8$ 45$ OP! &, 0'(8*$3)4#6,0$0 FP!< =5$
!"# D*',> 4$#/&,6* #$"$64)G ', 8'45 $,0) '1 45$
#$4#'%&#()I 4'>$45$# .&45 45$ $,N+/$ &,4$>#6)$I
"$#/&4 45$ &,4$>#64&', '1 45$ >$,'/$ &,4' 45$
5')432$** >$,'/$I .5$#$ &4 $7&)4) 6) 6 "#'%&#()< W#'3
0(24&', '1 45$ %&#6* "#'4$&,I .5&25 &) )(""*&$0 8+
2$**@) "#'4$&, )+,45$)&) /$256,&)/I 26, ,'. 8$
&,&4&64$0 8+ #$>(*64'#+ )$C($,2$) '1 45$ J=O 6,0
8+ 45$ >$,$) -#.I *,*I 6,0 .0-<

6 .'#- >#'(" 5$60$0 8+ J(2 K',46>,&$# &, 9:;L<
=5$ %&#() .6) *64$# ,6/$0 45$ 5(/6, &//(,'3
0$1&2&$,2+ %&#() DMEHG<
!" #$%&'$&%( )* $+( ,(-).( /-0 12%2)-
MEH &) 6 /$/8$# '1 45$ *$,4&%&#() )(816/&*+ '1
#$4#'%&#()$)< !** #$4#'%&#()$) 2',46&, -#.#-)# *-,")/
'-+0*,)#I 6, $,N+/$ 4564 4#6,)2#&8$) )&,>*$3
)4#6,0$0 >$,'/&2 OP! &,4' FP!< =5$ MEH >$,'/$
2'/"#&)$) 6""#'7&/64$*+ 9Q -8< =5$ "#'4$&,3
<" 7(886 #&6'(:$2=8( $) 5>1 >-*('$2)-
MEH 64462-) VFUX = 2$**) 6,0 '45$# 2$**) '1 45$ &/3
/(,$ )+)4$/< =5&) &,2*(0$) 2$**) '1 45$ /','2+4&2
)+)4$/I )(25 6) /','2+4$)I 4&))($ /62#'"56>$)I
6,0 J6,>$#56,) 2$**< E4 &) )4&** (,2*$6# .5$45$#
MEH 26, &,1$24 "*(#&"'4$,4 )4$/ 2$**)< V$**) '1 45$
>6)4#'&,4$)4&,6* 4#624 6,0 2$,4#6* ,$#%'() )+)4$/
26, 8$ &,1$24$0< K&2#'>*&6 D/62#'"56>$)GI 6)4#'3
2+4$)I '*&>'0$,0#'2+4$)I 6,0 45$ $,0'45$*&6* 2$**)
'1 45$ 2$#$8#6* 8*''0 %$))$*) 6#$ 45$ VPB 2$**)

"
$,2'0&,> >$,$) 1,1D>#'("3)"$2&1&2 6,4&>$,GI 0&2 /')4 2'//',*+ &,1$24$0 8+ MEH< E4 &) (,2*$6#
D#$%$#)$ 4#6,)2#&"46)$ 6,0 '45$# $,N+/$)GI 6,0 .5$45$# ,$(#',) 26, 6*)' 8$ &,1$24$0<
#".D&,4$>#6* /$/8#6,$ "#'4$&,) 1'# 45$ *&"&0
/$/8#6,$ $,%$*'"$G 6#$ 45#$$ 600&4&',6* 1$64(#$)
4564 MEH )56#$) .&45 '45$# #$4#'%&#()$) D$<><I M=3
JHG< =5$ MEH >$,'/$ 6*)' 2',46&,) '45$# #$>(*64'#+
>$,$) 1'# 45$ 4#6,)2#&"4&', '# '#>6,&N64&', '1 45$
*64$ #$"*&264&', 2+2*$R .+3D%&#&', &,1$24&%&4+ 1624'#GI
-#. D#$>(*64'# '1 $7"#$))&', '1 %&#&', "#'4$&,)GI
6,0 "#3 D,$>64&%$ #$>(*64'#+ 1624'#G< =5$ >$,$)
'%$#*6"I 4564 &)I 45$+ 6#$ *'264$0 ', 45$ )6/$
)$>/$,4 '1 45$ OP! /'*$2(*$< F&11$#$,4&6* 4#6,)3
2#&"4&', 8+ 45$ "#'4$&, )+,45$)&) /$256,&)/ '1
45$ 5')4 2$** +&$*0) 45$ %6#&'() >$,$ "#'0(24)<
=5$ MEH %&#&', &) 68'(4 9QQ ,/ &, 0&6/$4$#< E4)
'(4$# *&"&0 $,%$*'"$ &) )4(00$0 .&45 ST )"&-$)
0$#&%$0 1#'/ >*+2'"#'4$&, >"9TQ< =5$ )"&-$) 6#$
6,25'#$0 &, 45$ /$/8#6,$ 8+ 4#6,)/$/8#6,$
"#'4$&, >"U9< =5$ *&"&0 /$/8#6,$ /6-$) MEH $)"$3
2&6**+ %(*,$#68*$ 4' 64462- 8+ *&"'"5&*&2 0$4$#>$,4)I
)(25 6) 6*2'5'*<

!
3" 32-02-4 $) $+( 5)6$ 7(88
=5$ 644625/$,4 '1 45$ %&#6* "6#4&2*$ 4' 45$ )(#162$
'1 45$ 5')4 2$** &,%'*%$) 4.' )4$")R 8&,0&,> '1 >"9TQ
4' 45$ )$2',0 0'/6&, '1 45$ VFU /'*$2(*$I 6,0
?@A )$2',06#+ 8&,0&,> 4' 6 25$/'-&,$ #$2$"4'# 614$#
6 2',1'#/64&',6* 256,>$<
Nucleocapsid
nuclear
Increases
infectiosity
Enables
budding
Viral surface proteins
mediate CD4 binding
5>1 #$%&'$&%( /-0 9(:82'/$2)-
!
proteins and membrane fusion
nef
gag vif vpu env
LTR pol vpr tat LTR
rev
Reverse
Long transcriptase Weak, strong Regulator of
terminal Protease transcription expression of
repeats Ribonuclease activator structural proteins

gp 120
gp 41
Structural proteins
RNA
Enzymes p7-nucleocapsid
Regulatory proteins Lipid membran

782-2'/8 >..&-)8)4;
Other proteins p24-capsid
p17-matrix

A. Structure of the genome and the virion

gp 41 HIV Hemato-
poietic
2. stem cell ?
Change in
gp 120 conformation

"
(V3-loop)

1. Binding Chemokine
1. to CD4 receptor Monocyte
1. molecule CXCR-4
or CCR-5

CD4+ Langerhans Macro-

CD4+ T cell cell phage
T cell
B. Binding to the host cell D. Cells susceptible to HIV

Reverse Viral DNA Production of viral

transcriptase RNA and proteins
transforms RNA
HIV into DNA Integration in
cell genome

Protease
Integrase

Binding
to CD4,
membrane
fusion
Release of
virion contents
into the cell

C. Replication cycle of HIV in the host cell

Production of integral
membrane proteins
(gp 41, gp 120)
RER
Budding of
virus
particles !
?@B

"
! +55%.$9()-/-(./-('

!" #$%&'( $) *+, -.)(/0-$.

!"# $%&#'() *+,- ./0 1'*#(&1,' &, &"# ,'2#& ,* 2#3
4#+# 2)-5&,-2 ,* 1--6',7#*1(1#'() 89/:;< 12 %
-#%' => )#%+2? !"# 1--6'# 2)2&#- -%'%@#2 &,
A##5 &"# ./0 1'*#(&1,' 6'7#+ (,'&+,$ 76+1'@ &"#
$%&#'() 5#+1,7? /' &"# 1'1&1%$ 5"%2# ,* 1'*#(&1,'B
&"# 41+62 12 %C$# &, 5+,$1*#+%&# D1&" 41+&6%$$) ', +#3
212&%'(#? !"# '6-C#+ ,* *+## 41+%$ 5%+&1($#2 1'3
(+#%2#2 7+%-%&1(%$$)? !"# 1'*#(&#7 !3"#$5#+ (#$$2
%'7 -%(+,5"%@#2 5+,76(# &",62%'72 ,* '#D 41+3
1,'2 C) C6771'@ C#*,+# &"#) 71#? E'$) %+,6'7
F> G ,* %$$ ./031'*#(&#7 1'714176%$2 7#4#$,5 2)-53
&,-2 8#?@?B *#4#+B ("1$$2B $)-5"%7#',5%&")< %& &"12
2&%@#?
#:-.-/;: +55%.$:$<7
-,+# &"%' &"+## -,'&"2 %'7 12 ("%+%(&#+1T#7 C)
&"# 1'4,$4#-#'& ,* %&)51(%$$) $,(%&#7 $)-5" ',7#2?
!"# (,$$%52# ,* &"# 1--6'# 2)2&#- $#%72 &, &"#
-%'1*#2&%&1,' ,* '6-#+,62 2)-5&,-2? !"# '6-3
C#+ ,* !3"#$5#+ (#$$2 1' 2#+6- *%$$2 C#$,D &"# (+1&1(%$
$1-1& ,* R>>W!V? X6+&"#+-,+#B &"# 2#+6- /@U (,'3
(#'&+%&1,' 12 #$#4%&#7B C6& -%1'$) (,'&%1'2 1'#**#(3
&14# N','2#'2# @$,C6$1'2O 76# &, &"# 2&1-6$%&1,' ,*
6'25#(1*1( 5,$)($,'%$ K (#$$2? E&"#+ ($1'1(%$ *#%&6+#2
1'($67# D#1@"& $,22B *#4#+B %'7 '1@"& 2D#%&2? !"#2#
%+# +#*#++#7 &, %2 &"# !"#$%&'()*'+ ,-./('0 89YI<
,* 2)-5&,-2?
9/:; 12 7#*1'#7 C) &"# ,((6++#'(# ,* ,55,+&6'123
&1( 1'*#(&1,'2B 26(" %2 12'3.-,45*65 ,)&6266 5'#6-,3

'1%B 7)2+6+) #2,5"%@1&12B %'7 ,+%$ "%1+) $#6A,5$%A1%

1" 2('3$.'( $) 04( +55%.( 67'0(5
!,@#&"#+ D1&" ($%22 / H.I -,$#(6$#2B &"# 1'*#(&#7
(#$$2 5+#2#'& 41+%$ #51&,5#2B &"#+#C) %(&14%&1'@ &"#
(#$$6$%+ ()&,&,J1( 1--6'# +#25,'2#? I$%22 // H.I3
+#2&+1'@#'& ! (#$$ %(&14%&1,' $#%72 &, &"# +#$#%2# ,*
1'&#+$#6A1'2B &"# %(&14%&1,' ,* K (#$$2B %'7 %'&1C,7)
5+,76(&1,'? !"# %'&1C,71#2 C1'7 *+## 41+%$ 5%+&1($#2
%'7 -%A# &"#- 1'71@#2&1C$# *,+ -%(+,5"%@#2? !"#
,4#+%$$ 41+62 5,56$%&1,' 7#(+#%2#2 2"%+5$)? L'7#+
8ZK0<? 9/:; 12 %$2, ("%+%(&#+1T#7 C) &"# ,((6++#'(#
,* (#+&%1' -%$1@'%'& '#,5$%2-2? [%5,21\2 2%+(,-%B
*,+ #J%-5$#B 12 (%62#7 C) &"# ("+,'1( ,4#+5+,3
76(&1,' ,* 1'*$%--%&,+) %'7 %'@1,@#'1( @+,D&"
*%(&,+2? I,31'*#(&1,' D1&" "6-%' "#+5#241+62 ]
8..03]< 12 %$2, % 7#(1214# *%(&,+? H%$1@'%'& $)-3
5",-%2 ,((6+ 1' => G ,* %$$ 1'714176%$2 1'*#(&#7
C) ./0? I^; -%'1*#2&%&1,'2 ,((6+ 1' &"# $%&# 2&%@#2
,* ./0 1'*#(&1,'? 9 712&1'(&1,' 12 -%7# C#&D##'

" &"12 2&+,'@ 2#$#(&14# 5+#226+#B '#D -6&%&1,'2 (,'3 5+1-%+) #'(#5"%$,5%&"1#2 (%62#7 C) '#6+,&+,51(
&1'6,62$) 7#4#$,5 76+1'@ &"# 5+,(#22 ,* ./0 +#5$13 ./0 %'7 2#(,'7%+) #'(#5"%$,5%&"1#2B 26(" %2
(%&1,'? H12&%A#2 1' +#&+,41+%$ +#4#+2# &+%'2(+15&1,'B (#+#C+%$ &,J,5$%2-,212B IH0 #'(#5"%$1&12B %'7
D"1(" ,((6+ ,'(# 1' %55+,J1-%&#$) #4#+) M>>> -#'1'@1&17#2 ,* 4%+1,62 ,+1@1'2?
'6($#,&17#2B 25##7 65 &"# 5+,(#22? !"#2# '#D -63
&%'&2 (%' 5+,$1*#+%&# 6'("#(A#7 6'&1$ &"# 1--6'#
2)2&#- "%2 %7%5&#7 &, &"# '#D #51&,5#? !"# (,'3
2&%'& 5+,76(&1,' ,* '#D 41+%$ -6&%'&2 -%A#2 &"#
./0 5,56$%&1,' 2, @#'#&1(%$$) 714#+2# &"%& &"# 1-3
-6'# 2)2&#- 6$&1-%&#$) C#(,-#2 N(,'*62#7O %'7
6'%C$# &, (,'&+,$ &"# 1'*#(&1,' #**#(&14#$)? /& C#3
(,-#2 1-5,221C$# &, -,6'& % (,,+71'%&#7 %&&%(A
%@%1'2& &"# 41+62? 9& % 5+,76(&1,' %'7 7#2&+6(&1,'
+%&# ,* %+,6'7 =>P 41+1,'2 5#+ 7%)B #%(" ./0 5%+&1($#
@#'#+%&1,' 25%'2 %55+,J1-%&#$) M?Q 7%)2? .#'(#B
%+,6'7 =R> 41+%$ @#'#+%&1,'2 %+# 5+,76(#7 D1&"1'
&"# (,6+2# ,* ,'# )#%+? !,D%+72 &"# #'7 ,* $%&#'()B
&"# 1--6'# 2)2&#- 12 (,'*+,'&#7 D1&" &"# 5+,76(3
&1,' ,* %+,6'7 => -1$$1,' ./0 4%+1%'&2 5#+ 7%)? !"#
#J%(& -#("%'12- +#25,'21C$# *,+ &"# 7#2&+6(&1,'
,* &"# 1--6'# 2)2&#- 12 2&1$$ $%+@#$) 6'A',D'?

!
==>
#" !+86
S#+212&#'& @#'#+%$1T#7 $)-5"%7#',5%&") 8SUV< 7#3
4#$,52 5+1,+ &, &"# ,'2#& ,* *6$$3C$,D' 9/:;? V)-3
5"%7#',5%&") 2)'7+,-# 8V9;< 626%$$) 5#+212&2 *,+
 Acute phase Symptom-free interval ARC
#$%&'( $) *+, +.)(/0-$.

AIDS
!
Helper T cells
Cytotoxic T cells

Anti-HIV antibodies
HIV particles

1 2 3 4 5 6 7 8 9 10 11 12
Months Time (years)
A.Time course of HIV Infection

#:-.-/;: +55%.$:$<7
Infection Immune response
– Sexual intercourse – Anti-HIV antibodies
– Blood products – Acute infection, – Immune cells
– Mother child often unapparent that recognize HIV
– Infected needles – Symptom-free – Cellular cytotoxicity
carrier
– Viral suppression
– Viral mutation – New immune response
– Viral replication – Humoral and cellular
adjustment to new

"
– Virus activated by epitopes
- other infections ?
– Migration into brain ? – Viral suppression

– Loss of immune cells – Insufficient-

- CD4+ T-cells <400/µL immune response
– New mutations
– Increased
viral replication – Viral remains active

ARC
B. Immune response

AIDS

Opportunistic infections Neurological complications HIV-associated tumors

Pneumocystis carinii Acute meningo- Vacuolar Kaposi’s sarcoma
Toxoplasmosis encephalitis myelopathy Malignant lymphomas: NHL
Mycobacteria
Herpes viruses: HSV, CMV, EBV

Chronic
AIDS-

!
Peripheral encephalo-
neuropathy pathy

Pneumocystis carinii infection Kaposi’s sarcoma

C. AIDS
===

"
! ,446'(7.*$/$.'/$.)

!" #$%&'()$) (* +,- ,'*./0$('

!"# $%&'()*%* )+ ,-. %(+#/0%)( %* 1*1&223 #*0&42%*"#$
43 %($%5#/0 $#0#/0%)( )+ *6#/%+%/ *#517 &(0%4)$%#*
0) ,-. 43 #(837#92%(:#$ %771()*)54#(0 &**&3
;<=->?@A !"# 0#*0 %* 6#5+)57#$ %( 0"5## *0#6*B
C ,-. &(0%4)$%#* 4%($ 0) ,-. &(0%'#( %( 0"# /)&0%('
)+ 0"# 0#*0 D#**#2A
E !"# 4)1($ &(0%4)$%#* &5# 2&4#2#$ 1*%(' &( #(9
837#9/)(F1'&0#$ &(0%"17&( %771()'2)412%(A
G !"# #(837# +)57* & /)2)5#$ 5#&/0%)( 65)$1/0 %(
0"# 65#*#(/# )+ ,-. &(0%4)$%#*A
? 6)*%0%D# <=->? 0#*0 *")12$ &2H&3* 4# /)(+%57#$ 43
&0 2#&*0 )(# )0"#5 0#*0I *1/" &* & J#*0#5( 42)0 )5 &
*6#/%+%/ %771()+21)5#*/#(/# 0#*0 ;*## 66A KELKM@A
89$'$/%9 ,446'(9(&:
/&( 4# 05&(*+#55#$ 0) "&572#** D%51*#*I *1/" &*
/)H6)NA !"%* 7&3 6#57%0 0"# 1*# )+ +1(/0%)(&223
H#&:#(#$ 410 *0%22 "%'"23 %771()'#(%/ D%51*#*
&* & 2%D# D&//%(#A ?()0"#5 &665)&/" %* 0) 1*# 615%9
+%#$ UV? &* 0"# D&//%(#A [#/&1*# 0"# %(F#/0#$ UV?
%* %(/)56)5&0#$ %( 0"# /#22 '#()7#I %0 /&( %7%0&0#
0"# #D#(0* )+ & D%5&2 %(+#/0%)( H%0")10 0"# D%512#(/#A
9-.&'#&5:,-) ;'@B ?/0%D&0#$ RUW\ ! /#22* 65)$1/#
%(0#52#1:%(9C] ;2376")/30# /"#7)0&/0%/ +&/0)5I
=R^@I H"%/" %("%4%0* 0"# 5#62%/&0%)( )+ 0"# D%51*A
?0 0"# *&7# 0%7#I %0 &2*) %($1/#* 0"# /5)**92%(:&'#
)+ RU_ 7)2#/12#* )( 0"# *15+&/# )+ RU_\ ! /#22*A !"#
D%5&2 65)$1/0%)( )+ %(+#/0#$ RU_\ /#22* %* 5#$1/#$
43 )(#90#(0"A !"# /"#7):%(#* S?V!<>I Y-Q9C!I

.%5&2 /12015# %* & 5&0"#5 #N6#(*%D# 0#/"(%O1#
&($I 0"1*I %* ()0 1*#$ +)5 5)10%(# ,-. $%&'()*%*A
P#(# &762%+%/&0%)( 0#/"(%O1#*I *1/" &* !"#$%&'()&
*+(,- '&(*.,"- ;QRS@ &($ '&/&')& .'(-)*',!.()& 012
;S!9QRS@I &5# /155#(023 4#%(' 0#*0#$ &* ,-. */5##(9
%(' 0#*0*A !"# QRS %* 1*#$ 0) $#0#/0 ,-.T* 65)D%5&2
UV?I &($ S!9QRS %* 1*#$ 0) $#0#/0 0"# D%5&2 SV?
;*## 6A WK!@A
1" 23.%04.'0 503%0.&$.)
&($ Y-Q9C" "&D# *%7%2&5 #++#/0* )( 0"# ! /#22*
$1# 0) 0"# 42)/:&$# )+ /"#7):%(# 5#/#60)5* 5#9
O1%5#$ +)5 ,-. $)/:%('A S#/)74%(&(0 %(0#5+#5)(9
! ;5-^V9!@ &($ %(0#52#1:%(9CE %("%4%0 & (174#5 )+
*0#6* %( 0"# 5#62%/&0%)( /3/2#A !"#3 &5# /155#(023
4#%(' 1*#$ %( /)(F1(/0%)( H%0" 5#D#5*# 05&(*/5%69
0&*# %("%4%0)5* +)5 05#&07#(0 )+ &*3760)7&0%/
,-.9%(+#/0#$ *14F#/0* %( #N6#5%7#(0&2 /)74%(&0%)(
$51' 0"#5&6%#*A

" 3-.,/,'(# 4'56) ;"@B V1/2#)*%$# &(&2)'1#* ;7)$%+%#$

(1/2#)*%$#*@ %("%4%0 5#D#5*# 05&(*/5%60&*# &($ 2#&$
0) /"&%( 0#57%(&0%)( H"#( %(/)56)5&0#$ %(0) 0"#
D%5&2 UV?A ?8%$)0"37%$%(# ;?X!@ H&* 0"# +%5*0 5#9
D#5*# 05&(*/5%60&*# %("%4%0)5 $#D#2)6#$ +)5 ,-. %(9
+#/0%)(I 410 0"# D%51* 4#/)7#* 5#*%*0&(0 0) ?X! D#53
O1%/:23 ;#@A !"# %(/)56)5&0%)( )+ +&2*# (1/2#)*%$#*
&2*) 42)/:* /#2212&5 6)237#5&*#I H"%/" 2#&$* 0)
*%$# #++#/0* *%7%2&5 0) 0")*# )4*#5D#$ H%0" /30)9
*0&0%/ $51'*A
?()0"#5 '5)16 )+ /)76)1($* 4%($* 0) 0"# /&0&9
230%/ /#(0#5 )+ 5#D#5*# 05&(*/5%60&*#I 0"#5#43 %(&/0%9
D&0%(' 0"# #(837# ;$@A Y)5# 5#/#(023 $#D#2)6#$
/)76)1($* )+ 0"%* '5)16 5#7&%( #++#/0%D# &+0#5
7120%62# !"# '#(# 710&0%)(*A !"# #++%/&/3 )+ 0"#*#
$51'*I H"%/" %* 7#&*15#$ &* 0"# 5#$1/0%)( %( D%5&2
2)&$I /&( 4# #("&(/#$ 43 &$7%(%*0#5%(' 0"#7 %(
/)74%(&0%)( H%0" )0"#5 D%51*0&0%/*A !"#3 &5# #*6#9
/%&223 #++#/0%D# H"#( /)74%(#$ H%0" 0"# (#H '5)16
)+ !'".&()& ,-+,7,."') ;%@A Q5)0#&*# %("%4%0)5* &5#
*051/015&223 *%7%2&5 0) 0"# 65#/15*)5 65)0#%( *#9

!
O1#(/# 5#/)'(%8#$ 43 0"# D%5&2 65)0#&*#A
8(**,-&) ;&@B !"# 1*# )+ 0"# &00#(1&0#$ 2%D# D%51*
%* 0)) 5%*:3 4#/&1*# 0"# %771(%03 )4*#5D#$ %( 0"#
&(%7&2 7)$#2 ;7)(:#3*@ /&(()0 4# #N0#($#$ 0)
"17&(*A !"# $#D#2)67#(0 )+ "345%$ D%51*#* "&*
;;< )6#(#$ (#H 6)**%4%2%0%#*A !"# ,-. '#(# +)5 '6CEZ
 Patient Anti-human-Ig
#$%&'()$) %'7 23.%04.'0 (* +,- ,'*./0$('

Chromagic
!
serum + enzyme substrate

Well coated with HIV Substrate is enzymatically

processed Photometric
antigen determination
A. Diagnosis of HIV infection by ELISA

RNA a) Blocking of H3C

H O Nevirapin
catalytic center N

N N N

89$'$/%9 ,446'(9(&:
Produced DNA b) Incorporation HO Azidothymidine
of wrong N3 O H (AZT)
Reverse O
Translation nucleoside, N
transcriptase N O
strand breakage
CH3

c) Blocking of catalytic center because of

similarity with cleavage site H
H O

Viral proteins
1. Antiviral drugs
Protease
Saquinavir

Binding to MHC I molecules

N
O
N

O
NH2
N
H OH O
N

MHC I–peptide
complex
N
H
H

"
RER
Cellular
Immune response
Endogenous
processing Humoral
Translation
Plasmid

2. Pure DNA as vaccine Free proteins

Antigen, HIV-provirus Signal transduction

mitogen
IL-16 ?

Infected CD4+ T cell Virus production

TCR

Activated
CD8+ T cell

3. Interleukins
B. Treatment strategies
MIP-1!/",
RANTES
Chemokine
receptor

CD4
Non-
infected
!
;;=

"
! 9)*+-&(1: 41')6')' 62. 8&(+0)216'

!" !#$ %&'()* +, #-++. /&0123

!"# $%& '(')#* +,'-./#0#+ 1( 2304 536+')#,6#0
,6 7897 ,' )"# *.') ,*:.0)36) '(')#* ;.0 14..+
4#3+' ). )"# +#/#4.:*#6) .; 0 "!#'1+!I J",-"
,' #B:0#''#+ .6 0#+ 14..+ -#44' 36+ -.6',')'
.; <4?-.'#I <343-).'#I 2N3-#)(4<4?-.'3*,6#I
<343-).'#I 36+ ;?-.'#= $6 3-),/# $ <#6# @,6 ,6N
)(:,6<= >) ,' 13'#+ .6 )"# .--?00#6-# .; !"#$%"&
+,/,+?34' J,)" 14..+ )(:# $A -.+#' ;.0 3 ':#-,;,-
"!#'()*'+, @,'.3<<4?),6,6'A 3<3,6') $ 36+ %
2N3-#)(4<343-).'3*,6(4)036';#03'#= !",' 4#3+'
14..+ <0.?: 36),<#6' #B:0#''#+ .6 0#+ 14..+
). #4.6<3),.6 .; )"# V 36),<#6 1( 36 2N3-#)(4N
-#44'= $6),1.+,#' +#/#4.: .64( 3<3,6') 36),<#6'
<343-).'3*,6# *.4#-?4#I )"#0#1( ;.0*,6< )"#
6.) #B:0#''#+ 1( ".') C%D'= !(:# $ ,6+,/,+?34'
$ 36),<#6= >; )"# % <#6# ,' 3-),/#I 3 <343-).'(4N
@30.?6+ EF G .; )"# :.:?43),.6 ,6 D#6)034
)036';#03'# *.4#-?4# ,' '(6)"#',W#+ ,6')#3+=
H?0.:#I E7 G .; $*#0,-36 J",)#'I 36+ FK G .;
>6 .)"#0 J.0+'I 3 <343-).'# *.4#-?4# 3))3-"#'
$*#0,-36' .; 143-L .0 M#B,-36 .0,<,6A "3/#
). )"# V 36),<#6 ,6 ,6+,/,+?34' J,)" 14..+
36),1.+,#' +,0#-)#+ 3<3,6') )"# % 14..+ <0.?:
)(:# %= >6 ,6+,/,+?34' J,)" 3-),/# $ 36+ % <#6#'I
36),<#6= !"#'# 36),1.+,#' 30# -3:314# .; 3<<4?N
1.)" $ 36+ % 36),<#6 30# #B:0#''#+ .6 0#+
),63),6< 36+ 4(',6< C%D' 1#30,6< % 36),<#6' 36+
14..+ -#44'= &)"#0 ,6+,/,+?34' "3/# 36 3-),/#
30# -344#+ "!#'-. "!#'()*'+,= >; '?-" #0()".-()#'
8-121:6- ;**<2+-+3&

& <#6#= !",' <#6# ,' 3 ',4#6) 344#4# )"3) 4#3/#'

30# )036';?'#+ ). 36 $O ,6+,/,+?34I )"#( 30#
V 36),<#6 ?6*.+,;,#+ 36+ -.00#':.6+' ).
,**#+,3)#4( 4('#+= !(:# % ,6+,/,+?34' @-3= 7E G
14..+ )(:# &=
,6 H?0.:#I F9 G .; $*#0,-36 143-L'I 7P G .;
!"# $% 36+ & <#6#' 30# ,6"#0,)#+ 3--.0+,6<
M#B,-36'I 36+ FQG .; $',36'AI .6 )"# .)"#0
). M#6+#4X' :0,6-,:4#'= V#6-#I )(:# $ ,6+,/,N
"36+I "3/# 63),/# "!#'-/ "!#'()*'+,= >6 !(:#
+?34' *3( "3/# <#6.)(:# $$ .0 $&I 36+ )(:#
$% ,6+,/,+?34' @3::0.B,*3)#4( R G .; )"# :.:?N
% ,6+,/,+?34' *3( "3/# <#6.)(:# %% .0 %&=
43),.6AI 1.)" $ 36+ % 36),<#6' 30# #B:0#''#+ .6
!(:# $% ,6+,/,+?34' "3/# <#6.)(:# $%I 36+ ,6N
0#+ 14..+ -#44'I 36+ 6#,)"#0 36),N$ 6.0 36),N%
+,/,+?34' J,)" )(:# & 14..+ "3/# <#6.)(:# &&=
36),1.+,#' 30# :0#'#6) ,6 )"# '#0?*= >6 !(:#
!"# 63)?034 36),N$ 36+ 36),N% 36),1.+,#' 30#
& ,6+,/,+?34' @-3= PS G ,6 H?0.:#I EQG .; $*#0N
*3,64( ><MN-43'' ,**?6.<4.1?4,6'= >6+,/,N

"
,-36 J",)#'I E8 G .; $*#0,-36 143-L'I 36+ QR G
+?34' J,)" 14..+ )(:# &I ".J#/#0I 34'. "3/#
.; $*#0,-36 M#B,-36'AI 6#,)"#0 .; )"# 36),<#6'
><Y 36),1.+,#' 3<3,6') $ 36+ % 36),<#6=
,' #B:0#''#+ .6 0#+ 14..+ -#44'I 36+ 1.)" 36),N$
Z,6-# 36),N$ 36+ 36),N% ,'.3<<4?),6,6' .--?0
36+ 36),N% 36),1.+,#' 30# :0#'#6) ,6 '#0?*=
63)?0344(I '#/#0# "#*.4(',' -36 .--?0 3;)#0 3
$ 36),<#6' 30# '?1+,/,+#+ ,6). '?1)(:#' $7
',6<4# )036';?',.6 .; $%&N,6-.*:3),14# 0#+
@S9GA 36+ $F @F9 GA= $6),N$7 36),1.+,#' '#4+.*
14..+ -#44'= $;)#0 ;,0')N),*# #B:.'?0#I 6#J ,*N
.--?0 ,6 $FN:.',),/# ,6+,/,+?34'= !"# $ 36+
*?6.<4.1?4,6' 30# ;.0*#+ ,6 3++,),.6 ). )"#
% 36),<#6' 30# *3,64( #B:0#''#+ .6 0#+ 14..+
:0##B,'),6< 63)?034 36),1.+,#'=
-#44'I 1?) 30# 34'. J#3L4( #B:0#''#+ .6 :43)#4#)'
36+ #6+.)"#4,34 -#44'=

#" 4)5)-+0*)2( +, ! 62. # !2(17+.1)'

T#J1.06' +#/#4.: 36),N$ 36+ 36),N% 36),1.+,#'
.6 -.6)3-) J,)" ?1,U?,).?' 36),<#6'= %3-)#0,3
36+ :.44#6I ,6 :30),-?430I "3/# 430<# 3*.?6)'
.; $ 36+ % 36),<#6'= >; )"#'# 36),<#6' 30# #BN
:0#''#+ .6 )"# ".') C%D'I -4.6#' .; -#44' )"3)
:0.+?-# 36),1.+,#' 3<3,6') )"#* J,44 1# #4,*,N
63)#+=

8" 4)5)-+0*)2( +, !#$ !2(13)2'

!"# $% 36+ & <#6#' 30# 4.-3)#+ .6 )"# 4.6< 30*

!
.; -"0.*.'.*# 8= !"#( -.+# ;.0 /30,.?' <4(-.N
'(4)036';#03'#' )"3) )036';#0 /30,.?' '?<30 *.N
4#-?4#' .6). 3 :0#-?0'.0 '?1')36-#= 5 N;?-.'# ,'
)036';#00#+ .6). 3 :0#-?0'.0 -"3,6 @:303<4.1.N
',+#A 1( 3 <#6# :0.+?-) @)"# '.N-344#+ 0 1+!+A
==> )"3) ,' 3-),/# ,6 88=8 G .; )"# :.:?43),.6= !",'
Blood group A: ~ 42% Blood group B: ~ 14% Blood group AB: ~ 6%
!#$ #-++. ?@+<0 %&'()*

Blood group O: ~ 38%

!
Antibodies Antibodies No Antibodies
against B against A antibodies against
against A A and B
or B

A antigen B antigen A antigen No A

or B
B antigen antigens

A. The ABO blood group system

Deletion of
Bacteria, Rich in A, B clones producing
antigens antibodies against
pollen own erythrocyte

8-121:6- ;**<2+-+3&
IgM-antibodies antigens
Newborn
against A, B, AB
B. Development of A and B antibodies

Ceramide Glu Gal GlcNAc Gal

Precursor substance (paragloboside)
Erythrocyte GPD-
L-fucosyltransferase

"
fucose
(H-gene active in 99.9% of population)

Chromosome 9 Fuc

Ceramide Glu Gal GlcNAc Gal

H-antigen
B
A
0
O gene Active A gene Active B gene Both A and B
(silent allele) (galactosaminyl- (galactosyl- genes active
transferase) transferase)

Unmodified N-Acetyl- Galactose A antigen + B antigen

H antigen galactosamine
A antigen

B antigen

Blood group O Blood group A

C. Development of the ABO antigens
Blood group B Blood group AB !
==A

"
! 8%+.-)*/9 :/&%2&%& 207 4)*.;%0/2&

!"#$ %&'( )* +,--$#$(% ./""+ 0#"12 343%$53 '#$

2#$3$(% "( #$+ ./""+ 6$//37 8&$ 6/,(,6'//4 5"3%
,52"#%'(% 343%$53 '#$ %&$ 9:; 343%$5< %&$
+,$3 %&'% 6#"33 %&$ 2/'6$(%'7 8&$ -$%13 5'4 +,$
,( 1%$#" '3 ' 6"(3$V1$(6$ "- %&$ #$31/%,(0
3$J$#$ &$5"/4%,6 '($5,' ?$#4%&#"./'3%"3,3
#&$313 343%$5< %&$ =$// 343%$5< '(+ %&$ >1--4 -$%'/,3A7 X$5"0/".,( 6/$'J'0$ 2#"+16%3 5'4
343%$57 .$ +$2"3,%$+ ,( %&$ .#',(< 2'#%,61/'#/4 ,( %&$
.#',(3%$5 ?Q$#(,6%$#13A7 8" 2#$J$(% '(%,B>
!" #$%&'& ()&*%+ ,551(,R'%,"(< @&B($0'%,J$ H"5$( 3&"1/+ #$B
6$,J$ '(%,B> ,551("0/".1/,(3 H,%&,( Z) &"1#3
8&$ #&$313 ?@&A 343%$5 ,3 0$($%,6'//4 '(+ 2&$B
'-%$# +$/,J$#4< '5(,"6$(%$3,3< 32"(%'($"13
("%42,6'//4 6"52/$C7 8&$ #&$313 '(%,0$(3 '#$
'."#%,"(< "# ,(%$##12%,"( "- 2#$0('(647 8&$
+$3,0('%$+ >+D6E$ '(+ '#$ $(6"+$+ .4 %&$
'+5,(,3%#'%,"( "- %&$3$ '(%,."+,$3 6'( ,55$+,B
6"##$32"(+,(0 0$($37 8&$ F+G 6"52"($(% ,3 '
'%$/4 $/,5,('%$ '(4 -$%'/ #$+ ./""+ 6$//3 %&'%
3,/$(% '//$/$ %&'% +"$3 ("% /$'+ %" '(%,0$( $CB
5'4 &'J$ .$$( %#'(3-$##$+ '(+ 2#$J$(% 3%,51B
2#$33,"(7 966"#+,(0 %" ' 3,52/,-,$+ 5"+$/<
/'%,"( "- %&$ 5'%$#('/ ,551($ 343%$5 '(+
%&$4 '#$ 6"(%#"//$+ .4 %H" ($,0&."#,(0 0$($
'(%,."+4 -"#5'%,"(7
/"6, "( 6&#"5"3"5$ I7 E,%&$# %&$ 3,/$(% !
4-/0/92- <++'0.-.3)

0$($ "# %&$ " 0$($ %&'% 6"+$3 -"# %&$ > '(%,0$(
5'4 .$ '6%,J$ "( /"613 I7 K"1# '//$/$3 '#$ /"6'%$+
"( %&$ 3$6"(+< '+L'6$(% /"613M #$< #%< &$< '(+ &%7
8&$ 0$($3 "- %&$ %H" /"6, '#$ 6"+"5,('(%7 N(
"%&$# H"#+3< %&$ 0$($ 2#"+16% "- %&$ -,#3% /"613
,3 $C2#$33$+ %"0$%&$# H,%& %&'% "- %&$ 3$6"(+
/"6137 8&$ -"//"H,(0 6"5.,('%,"(3 5'4 "661#M
"#$< "#%< "&$< "&%< !#$< !#%< !&$< !&%7 O,(6$
H$ '// ,(&$#,% "($ 5'%$#('/ '(+ "($ 2'%$#('/
'//$/$< %&$ 0$("%42$ 2"%$(%,'/ ,3 J$#4 +,J$#3$7
4" 5*$%6 #%7 4%-- !0*/3%0&
8&$ =$// ./""+ 0#"12 343%$5 ,3 ,52"#%'(% +1$ %"
%&$ 2"H$#-1/ ,551("0$(,6,%4 "- = '(%,0$(
?#"10&/4 6"##$32"(+3 %" %&$ #&$313 > '(%,0$(A7
= '(%,0$( "661#3 ,( "(/4 [ T "- %&$ 2"21/'%,"(7
8&$ %#'(35,33,"( "- =B2"3,%,J$ #$+ ./""+ 6$//3
+1#,(0 2#$0('(64 "# ./""+ %#'(3-13,"( /$'+3
%" %&$ -"#5'%,"( "- '(%,B= '(%,."+,$3< H&,6&
513% .$ 6"(3,+$#$+ ,( 31.3$V1$(% %#'(3-13,"(37

"
9// 0$($ 2#"+16%3 ,( H&,6& ' > 0$($ 2#"+16% :'6%$#,'/ '(%,0$(3 6'( '/3" ,(+16$ %&$ -"#5'B
,3 $C2#$33$+ '#$ 3',+ %" .$ #&$313B2"3,%,J$ %,"( "- '(%,B= '(%,."+,$37
?@&PA< '(+ '// 0$("%42$3 /'6Q,(0 > '(%,0$( ?"# O,(6$ "600+ /2,-7%2. ?K4' '(+ K4.A '#$ "(/4
,( H&,6& %&$ 3,/$(% ! '//$/$ ,3 '6%,J$A '#$ +$-,($+ H$'Q/4 ,551("0$(,6< '(%,BK4 '(%,."+,$3 '#$
'3 #&$313B($0'%,J$ ?@&BA7 8&$ 5"3% 6"55"( #'#$7 :"%& '(%,0$(3 '#$ '.3$(% ,( \U T "- '//
0$("%42$3 '#$ /,3%$+ ,( ?!A7 > '(%,0$( ,3 .4 9-#,6'(B95$#,6'(37 8&,3 ,3 '%%#,.1%$+ %" ('%1#'/
-'# %&$ 5"3% ,551("0$(,6 '(%,0$(7 3$/$6%,"( 3,(6$ %&$ K4 0/46"2#"%$,( 3$#J$3 '3 %&$
#$6$2%"# -"# %&$ 5'/'#,' 2'%&"0$( 8*/.()!-6(
," !--./++'0/12*/.0 232/0&* #$ !0*/3%0& 9-9/:7 X$(6$< %&$ '.3$(6$ "- K4 '(%,0$(3 #$31/%3
,( #$3,3%'(6$ %" 5'/'#,'7 Y$H -,(+,(03 ,(+,6'%$
9//",551(,R'%,"( %" #&$313 '(%,0$(3 "661#3
%&'% %&$ >1--4 '(%,0$( ,3 ' 6&$5"Q,($ #$6$2%"#
-"//"H,(0 $C2"31#$ %" ,(6"52'%,./$ #$+ ./""+
?>1--4 9(%,0$( @$6$2%"# -"# D&$5"Q,($3<
6$//37 8&,3 "661#3< -"# $C'52/$< H&$( @&B($0'B
>9@DA %&'% ,3 '/3" 2#$3$(% "( $(+"%&$/,'/ 6$//3
%,J$ 2'%,$(%3 #$6$,J$ ' %#'(3-13,"( "- @&B2"3,B
%,J$ @:D37 @&B2"3,%,J$ ./""+ J"/15$3 '3 35'// '(+ 2"3%6'2,//'#4 J$(1/$37 N% ,3 ' #$6$2%"# -"#
5'(4 +,--$#$(% D]D '(+ DD 6&$5"Q,($3 ?3$$
'3 I 5/ /$'+ %" %&$ -"#5'%,"( "- N0! 6/'33
8'.7 [A7
'(%,B> '(%,."+,$3 ,( IS T "- 6'3$3< '(+ U* T "-
'// @&B($0'%,J$ ,(+,J,+1'/3 +$J$/"2 '(%,B> '(%,B
."+,$3 '-%$# #$6$,J,(0 )S* 5/ "- @&B2"3,%,J$ $#B
4%&#"64%$37 @$$C2"31#$ %" $J$( 35'// V1'(%,%,$3
"- @&B2"3,%,J$ $#4%&#"64%$3 6'( ,(+16$ %&$
2#"52% -"#5'%,"( "- N0W '(%,."+,$3 %" > '(%,B
0$(7 '%()*+,-& !-.%/.% )0 ,1% 2%34)52 ?X>YA ,3
'( ,52"#%'(% 6/,(,6'/ $C'52/$ ?"A7 N( '( @&B($B

!
==>
0'%,J$ 5"%&$# H,%& '( @&B2"3,%,J$ -$%13< -"# $CB
'52/$< %&$ 5"%&$# -"#53 '(%,B> N0! '(%,."+,$3
+1#,(0 %&$ 2'33'0$ "- -$%'/ @&P #$+ ./""+ 6$//3
?131'//4 +1#,(0 +$/,J$#4A7 N- ' 3$6"(+ 2#$0('(64
"661#3< 6"(%'6% H,%& $J$( 35'// V1'(%,%,$3 "- -$B
%'/ @:D3 '6%,J'%$3 %&$ 2#"+16%,"( "- N0W '(%,."B
 Chromo-
#$%&'& 207 5*$%6 ,-..7 ?6.'; ()&*%+&

Most common Fre- Pheno- Immuno-

!
some 1
genotypes quency type genicity
Locus 1 Locus 2 +++
DCe/DCe 18% D
2 possible 4 possible
alleles: alleles: DCe/dce 35%
c
D or Ce, cE, DCe/DcE 13%
d (inactive) CE, ce Rh+
DcE/dce 12% E
cE
CE Ce
DcE/DcE 2% C
ce D
Dce/dce 2%
e
dce/dce 15% Rh- (+)

A. Rhesus system

4-/0/92- <++'0.-.3)
1st Contact Reexposure to 1. Pregnancy 2. Pregnancy
< 0,5 ml Rh+ Fetus Rh+ Fetus Rh+
D antigen, erythrocytes
immunogenic Entry of a
++++ Mother Rh- few Rh+
erythrocytes
Entry of Rh+ sufficient
Rh- erythrocytes during Lysis of
labor fetal

"
erythro- IgG production
IgM-anti- Immediate Mother produces
cytes of anti-D Ab
1 ml Rh+ D production IgG IgM Ab against
erythrocytes in 15% production D antigen
2. Hemolytic disease of the newborn

IgM-Anti-D Immediately Lysis of Rh+

production after delivery erythrocytes:
250 ml Rh+
in 80% Fetus Rh+ anti-D immuno- no immune
erythrocytes
Mother Rh- globulins stimulation
1. Anti-D immune response 3. Prophylaxis by Rh immunization
B. Alloimmunization against Rh antigens

Kell system = Erythrocyte

Duffy system = Fya and Fyb membrane
K and k

Phenotype Frequency Phenotype Frequency (USA)

K- k+ 91% Whites Blacks

Fy-
Fya+b- 17% 9% glyco-
K+ k+ 8.8% protein

K+ k- 0.2% Fya+b+ 49% 1%

K immunogenic after
– pregnancy
– infection
– transfusion
C. Other erythrocyte antigens
Fya-b+

Fya-b-
34%

<1%
22%

68%
Plasmodium
vivax
!
==@

"
! .$+,/02)% :)*$'*$* '(< 802,;$()'*

!"#$%&'( )'** +"#$,-($'. )+" $"(/)' *0.$. -1

#2' '&0#2&-)0#'.3 &'4+&(*'.. -1 52'#2'& #2'0
+&' $"(/)'( 620.$-*-4$)+**0 +1#'& #2' #&+".%
1/.$-" -1 $")-76+#$,*' &'( ,*--( )'**. 89:;.<
-& (/' #- $77/"' (0.&'4/*+#$-" 8+/#-$77/"'
2'7-*0.$.<=
!" #$%&'()*+* ,- .$+,/0*)*
>'7-*0.$. $. )2+&+)#'&$?'( +. $"#&+@+.)/*+& -&
'A#&+@+.)/*+&= B2' +(2'&'")' -1 C4D +"#$,-($'.
#- 9:;. )+" *'+( #- )-76*'7'"# ,$"($"4 $"
#2' ,*--(.#&'+7 +"( 6-&' 1-&7+#$-" +1#'& +)#$%
@+#$-" -1 #2' *0#$) .'E/'")' 8!<= B2$. #06' -1
$"#&+@+.)/*+& 2'7-*0.$. *'+(. #- #2' &'*'+.' -1
*+&4' E/+"#$#$'. -1 2'7-4*-,$"3 52$)2 $. ,-/"(
8/)()%'/ =++5(,/,30
.'&/7 8#<= B2' 6+#$'"#G. .'&/7 $. $")/,+#'(
5$#2 ($11'&'"# #'.# '&0#2&-)0#'. #2+# 2+@' +
H"-5" +"#$4'" 6&-1$*'= C1 #2' .'&/7 )-"#+$".
+"#$,-($'. #- -"' -1 #2' #'.# +"#$4'".3 #2' +"#$%
,-($'. ,$"( #- #2' 9:;.3 52$)2 5$** +44*/#$"+#'
-" +(($#$-" -1 ;--7,. .'&/7= B2' ;--7,. #'.#
$. /.'( #- ('#')# +"#$,-($'. #- '&0#2&-)0#' +"#$%
4'". ,'1-&' ,*--( #&+".1/.$-". +"( $1 2'7-*0.$.
$. ./.6')#'( (/&$"4 6&'4"+")0=
8" :$2$%2),( ,- 8,+;/$2$ '(< =(%,+;/$2$
>18?1,5(< !(2)4,<)$*
C4D +"#$,-($'. +44*/#$"+#' 9:;. $" $.-#-"$) .+*%
$"' .-*/#$-"R 2'")'3 #2'0 +&' )+**'( 2$#,&"."
0).('$+("/= C4Q +"#$,-($'.3 -" #2' -#2'& 2+"(3

,0 + !"#$%&$'()*'()+()% ,-$."() 82+6#-4*-,$"< +&' 7-"-@+*'"# 7-*')/*'. #2+# +&' /"+,*' #-

$" .'&/7= F2'" #2' 6&-#'$"G. ,$"($"4 )+6+)$#0
$. 'A2+/.#'(3 1&'' 2'7-4*-,$" $. 'A)&'#'( ,0
#2' H$("'0 82'7-4*-,$"/&$+<= I$")' 2'7-4*-%
,$" 7-*')/*'. 6&')$6$#+#' $" +" +)$($) '"@$&-"%
7'"#3 (+7+4' #- #2' &'"+* #/,/*'. -))/&.= B2'
6&-)'.. $. +44&+@+#'( ,0 #2' 6&')$6$#+#$-" -1
$77/"' )-76*'A'. -1 +"#$,-($'. +"( +"#$4'".
1&-7 #2' 7'7,&+"' -1 #2' (+7+4'( 9:;.=
B2' $77/"' )-76*'A'. +"( 1&'' 2'7-4*-,$"
.6+" #2' ($.#+")' ,'#5''" #5- 9:;.= !*#2-/42
C4Q 7+0 ,' ,-/"( #- 9:;.3 +44*/#$"+#$-" -1 #2'
)'**. (-'. "-# -))/&= C4Q +"#$,-($'. +&' #2'&'%
1-&' &'1'&&'( #- +. ()2$#,&"." 0).('$+("/= B2'
6&'.'")' -1 $")-76*'#' +"#$,-($'. +"( )-76*'%
7'"# )*'+@+4' 6&-(/)#. -" #2' ./&1+)' -1 9:;.
$. ('#')#'( ,0 +(($#$-" -1 ;--7,. .'&/7=
:" .$+,/0*)* '(< !(2)4,<0 !--)()20

"
+(($#$-"+**0 +)#$@+#' #2' )-+4/*+#$-" )+.)+('=
S0.$. -1 +4$"4 9:;. 8+1#'& + *$1'.6+" -1 +&-/"(
B2$. &'./*#. $" +(//"#()0."+ ().-010/23&0- 2$0*
TUV (+0.< $. -"' -1 #2' #+.H. -1 #2' 9K .0.#'7=
%3&0.($) 8JC;< +..-)$+#'( 5$#2 7$)&-#2&-7,-.$.
B2' .'@'&$#0 -1 2'7-*0.$. /./+**0 )-&&'*+#'.
$" #2' H$("'0.3 */"4.3 ,&+$"3 +"( *$@'&=
5$#2 #2' "/7,'& -1 +"#$,-(0 7-*')/*'. ,-/"(
KA#&+@+.)/*+& 2'7-*0.$. -))/&. 52'" #2'&'
#- '+)2 9:;= C" &+&' )+.'.3 .'@'&' 2'7-*0.$.
$. "- ($&')# )-76*'7'"# ,$"($"4 ,0 #2' +"#$%
7+0 ,' $"(/)'( ,0 .7+** )-")'"#&+#$-". -1
,-($'.3 #2+# $.3 52'" #2' *0#$) )-76*'7'"#
2$42%+11$"$#0 +"#$,-($'.= B2' *$1'.6+" -1 + &'(
.'E/'")' 8;LM;N< $. "-# +)#$@+#'( $" #2' )$&%
,*--( )'** )+" ,' &'(/)'( #- #2&'' (+0. ,0 +.
)/*+#$-"= :0 5+0 -1 O) &')'6#-&. +"( &')'6#-&.
1'5 +. TV +"#$%92 +"#$,-($'.= C" #2$. )+.'3 #2'
1-& )-76*'7'"# )*'+@+4' 6&-(/)#. 8;P,<3 #2'
;--7,. #'.# 7+0 ,' "'4+#$@' -& -"*0 5'+H*0
'&0#2&-)0#'. /"('&4- 62+4-)0#-.$. $" #2' &'#$%
6-.$#$@' .$")' #2' *-5'& *$7$# -1 ('#')#$-" -1
)/*-'"(-#2'*$+* 89K< .0.#'7 +"( $"#&+)'**/*+&
7-.# ;--7,. &'+4'"#. $. PVVMLVV +"#$,-($'.
($4'.#$-" 8"<= B2' )-/&.' -1 'A#&+@+.)/*+& 2'%
6'& 9:;= ;-76*'7'"# )-76-"'"#.3 ./)2 +.
7-*0.$. $. *'.. (&+7+#$) #2+" #2+# -1 $"#&+%
;P,3 )+" .$4"$1$)+"#*0 $")&'+.' #2' &+#' -1 2'7-%
@+.)/*+& 2'7-*0.$.=
*0.$.=
1" !(2)3/,45/)( 6$*2 78,,+4* 6$*29
4$$#'/ /"-3# $. + 6-*0.6')$1$) .'&/7 /.'( #-
('#')# 9:; +"#$,-($'. #- 2/7+" C4Q3 C4D3
+"( )-76*'7'"# 8!<= :')+/.' +"#$%C4! +"#$,-%
($'. +&' /./+**0 +,.'"# $" ;--7,. &'+4'"#.3 C4!
+/#-+"#$,-($'. +&' -1#'" "-# ('#')#'(=
B2' +(-"2. 4$$#'/ ."/. $. /.'( #- ('#')# '&0%

!
@@A
#2&-)0#'%,-/"( -& )-76*'7'"#%,-/"( +"#$,-%
($'.= C1 #2'.' +&' 6&'.'"#3 ;--7,. .'&/7 )+/.'.
)&-..%*$"H+4' -1 #2' +"#$,-($'. +"( +44*/#$"+%
#$-" -1 #2' )'**. 8"<=
B2' ()+(-"2. 4$$#'/ ."/. $. /.'( #- ('#')# #2'
6&'.'")' -1 +"#$%'&0#2&-)0#' +"#$,-($'. $" #2'
 #$%&'()*+* ,- .$+,/0*)* '(< !(2)4,<0 :$2$%2),(

Complement
!
– Free receptor
RES
hemo- Comple-
- globin ment
– immune
Fc-receptor
- complex
-formation
– DIC
– nephro-
- pathy
Complement – hemo-
binding Ab - globinuria
(IgM) Phagocytosis
1. Intravascular hemolysis 2. Extravascular hemolysis
A. Mechanisms of hemolysis

8/)()%'/ =++5(,/,30
RBCs Test erythrocytes
sensitized with known
with Ab or antigen profile
Immunization
complement
with human serum
+ Patient
+ serum
+ Coombs
+ serum

+ Coombs

"
or + serum

Polyspecific Coombs Agglu-

serum: anti-IgG, anti- tination
IgM, anti -complement
1. Production of
Coombs serum 2. Direct Coombs test 3. Indirect Coombs test
B. Detection of erythrocyte antibodies: Antiglobulin test (Coombs test)

IgM-Ab: Severe
agglutination Coombs- Coombs-
in suspension = test +/- test +++
complete Ab

No agglutination =
Hemolysis

incomplete Ab (IgG)
or complement only

+ Coombs
serum lgG only
IgG+C3
rare

!
high-affinity
antibodies
None
0 101 102 103 104 105
Agglutination Agglutination
by anti-C3 by anti-IgG Antibody molecules/erythrocyte

C. Complete vs. incomplete antibodies D. Hemolysis and antibody affinity

@@B

"
! 0)/'12%,3 ;,+)$+)+ $*8 92%'=)*,$+
!" #$%&'()*)+,+ '- !.%',//.*)
0)/'12%,3 !*)/,$+
!"# $%&'&( $) *+,$&--+(# "#-$./,&0 *(#-&*
123425 &6 +(7($8( 1&9&$:*,"&0 "#-$./6&65 &(
*%$+(9 ;< = $) 0*6#6> !"# $,"#% ;<= $) 0*6#6
*%# 0*+6#9 ?/ @*%&$+6 #,&$.$'&#6A 6+0" *6 &(B
)#0,&$(6 ,"*, &(9+0# ,"# )$%-*,&$( $) *+,$B
*(,&?$9&#6 9+# ,$ ,"# 0%$66B%#*0,&$( $) ?*0,#%&*.
$% @&%*. *(,&'#(6 8&," %#9 0#.. *(,&'#(6> C$((#0B
,&@# ,&66+# 9&6#*6#6A #6:#0&*../ 6/6,#-&0 .+:+6
#%/,"#-*,$6+6 16## ::> DEFGDE;5A *%# 0"*%*0,#%B
&H#9 ?/ &(0%#*6#9 !B"#.:#% *0,&@&,/ &( *99&,&$(
,$ ,"# &(0%#*6#9 *+,$*(,&?$9/ :%$9+0,&$(>
!B *(9 IB0#.. ./-:"$:%$.&)#%*,&@# 9&6#*6#6 *(9
,"/-$-*6 0*( &(,#%)#%# 8&," %#'+.*,$%/ !B0#..
91,*,3$1 >//.*'1'(2
)+(0,&$(A ,"#%#?/ .#*9&(' ,$ ,"# $@#%:%$9+0,&$(
$) *+,$*(,&?$9&#6> 4#-*,$.$'&0*. 9&6$%9#%6A
6+0" *6 4$9'7&(J6 9&6#*6#A ($(B4$9'7&(J6 ./-B
:"$-*A *(9 0"%$(&0 ./-:"$0/,&0 .#+7#-&*A
-*/ 9#@#.$: 9+# ,$ ,"# -*.&'(*(, ,%*(6)$%-*B
,&$( $) *+,$%#*0,&@# I 0#..6 ,"*, :%$9+0# *+,$B
*(,&?$9&#6 $% -*/ 9&6%+:, &("&?&,$%/ -#0"*(B
&6-6 ,"*, ($%-*../ :%#@#(, *+,$*(,&?$9/
)$%-*,&$(> 2($,"#% &-:$%,*(, ,/:# $) *+,$B
&--+(# "#-$./6&6 &6 0*+6#9 ?/ 0#%,*&( 9%+'6
"
16## :> DFK5>
4" 5$6/ !*%,7'8,)+
4#-$./,&0 *(#-&*6 *%# 0.*66&)&#9 *00$%9&(' ,$
,"# ,"#%-&0 *0,&@&,/ $) ,"# *+,$*(,&?$9&#6 &(B
@$.@#9> !"#$ %&'()"$(*+ ?&(9 -$%# #))&0&#(,./
,$ LIC6 *, K !CA 8"#%#*6 ,%-. %&'()"$(*+
?&(9 -$%# #))&0&#(,./ *, ME !C> 2::%$N&-*,#./
E< = $) :*,&#(,6 8&," 2342 "*@# 8*%- *(,&?$B
9&#6A D;GF<= "*@# 0$.9 *(,&?$9&#6A *(9 ,"# %#6,
"*@# * -&N,+%# $) ,"# ,8$> !"# 8*%- *(,&?$9&#6
*%# +6+*../ 0.*66 3'O &--+($'.$?+.&(6> C$-B
:.#-#(, )&N*,&$( ?/ ,"#6# *(,&?$9&#6 &6 6+?B
$:,&-*. ?#0*+6# ,"# CD 0$-:.#-#(, -$.#0+.#
-+6, +(9#%'$ 0$()$%-*,&$(*. 0"*('#6 &( $%9#%
,$ ?#0$-# *0,&@*,#9> !"&6 "*::#(6 $(./ 8"#(
CD ?&(96 ,$ ,8$ 0.$6#./ *9P*0#(, &--+($'.$B
?+.&( -$.#0+.#6> !"&6 &6 *.8*/6 ,"# 0*6# 8&,"
:$./@*.#(, 3'Q *(,&?$9&#6 ,"*, (*,+%*../ $00+%
*6 :#(,*-#%6A ?+, $00+%6 8&," 3'O *(,&?$9&#6
$(./ 8"#( ,"# *(,&'#( 9#(6&,/ $( ,"# 0#..
-#-?%*(# $) ,"# LIC6 &6 @#%/ "&'"> R/6&6 $)
!
3'OB?#*%&(' LIC6 ?/ -*0%$:"*'#6 &6 -*&(./ #NB
,%*@*60+.*%> !"# "#-$./,&0 :%$0#66 &6 %#.*,&@#./
&(#))&0&#(, ?#0*+6# 0&%0+.*,&(' &--+($'.$?+B
.&(6 ?.$07 ,"# S0 %#0#:,$%6> !"# $(./ 6&,# 8"#%#
,"# :%$0#66 &6 #))&0&#(, &6 &( ,"# 6:.##(A 8"#%#
?@A ,"# 0&%0+.*,&$( $) LIC6 &6 #N,%#-#./ 6.$8> !"&6
%#9+0#6 ,"# 0$(0#(,%*,&$( $) 6#%+- &--+($B
'.$?+.&(6 8&," %#6:#0, ,$ ,"# (+-?#% $) #%/B
,"%$0/,#6> !"# %*,# $) "#-$./6&6 &(0%#*6#6
8"#( CM? &6 ?$+(9 ,$ ,"# LIC -#-?%*(#>
9" 91,*,3$1 :,(*+ '- 0)/'12+,+
2+,$&--+(# "#-$./6&6 -*(&)#6,6 *6 * 9#0%#*6B
&(' "#-$'.$?&( 0$(0#(,%*,&$( &( 0$(P+(0,&$(
8&," -*%7#9 *(&6$0/,$6&6> T&," 8*%- *(,&B
?$9&#6A #%/,"%$0/,# ./6&6 ,*7#6 :.*0# -*&(./ &(
,"# LU 6/6,#-V ,"# 6#%+- 0$(0#(,%*,&$( $)
,"# "#-$'.$?&(B?&(9&(' :%$,#&( "*:,$'.$?&(
9#0%#*6#6 $(./ &) ,"#%# &6 6#@#%# "#-$./6&6> 4#B
:*,$6:.#($-#'*./ $00+%6 9+# ,$ ,"# &(0%#*6#9
%*,# $) "#-$./6&6 &( ,"# 6:.##( *(9 .&@#%> 3(,%*B
0#..+.*% #(H/-#6A 6+0" *6 .*0,*,# 9#"/9%$'#(B
*6# 1RW45A *%# %#.#*6#9> U%/,"%$:$&#6&6 &6 6,&-+B
.*,#9 &( ,"# ?$(# -*%%$8A *(9 %#,&0+.$0/,#6 *%#
&(0%#*6#9> !"# )%##9 "#-$'.$?&( &6 %#9+0#9 ,$
?&.&%+?&(A 8"&0" ?&(96 ,$ '.+0+%$(*,# &( ,"#
.&@#% *(9 &6 #N0%#,#9 &( ,"# ?&.#> 4/:#%?&.&%+?&B
(#-&*A 8"&0" .#*96 ,$ /#..$8&6" 9&60$.$%*,&$(
$) ,"# 60.#%* *(9 67&( 1P*+(9&0#5A &6 )%#X+#(,./
6##(> Y%$?&.&($'#(A *($,"#% 9#'%*9*,&$( :%$B
9+0,A 0*+6#6 9*%7 9&60$.$%*,&$( $) ,"# +%&(#>
;" <$*$()/)*% '- 5$6/ !*%,7'82
!.%',//.*) 0)/'12+,+
3( -$6, 0*6#6A ,"#6# :*,&#(,6 *%# &(&,&*../ ,%#*,#9
8&," 0$%,&0$6,#%$&96> !"#6# 9%+'6 6+::%#66
*(,&?$9/ :%$9+0,&$(A ?+, -*/ *.6$ %#9+0# ,"#
#))&0*0/ *(9 (+-?#% $) S0 *(9 CM %#0#:,$%6
$( ,"# -*0%$:"*'#6> 4&'"B9$6# &--+($'.$B
?+.&(6 *.6$ ?.$07 S0 %#0#:,$%6> C$%,&0$6,#%$&96
*(9 &--+($'.$?+.&(6 +6+*../ 9$ ($, *0"&#@#
.$('B,#%- 0+%#6> Z:.#(#0,$-/ $% 6:.#(&0 %*9&$B
,"#%*:/ &6 $),#( :#%)$%-#9 ?#0*+6# ,"# 6#X+#6B
,%*,&$( $) *''.+,&(&(B0$*,#9 LIC6 -*&(./ $00+%6
&( ,"# 6:.##(> R*%'# X+*(,&,&#6 $) 3'O *%# *.6$
:%$9+0#9 &( ,"# 6:.##(> 3--+($6+::%#66*(,6A
6+0" *6 0/0.$:"$6:"*-&9#A *H*,"&$:%&(#A $%
0/0.$6:$%&(#A 0*( *.6$ ?# +6#9 *6 * .*6, %#6$%,>
L#0#(,./A '$$9 %#6+.,6 "*@# ?##( $?,*&(#9
8&," *( *(,&BCWF< -$($0.$(*. *(,&?$9/
1L&,+N*(!5> !"&6 *(,&?$9/ #.&-&(*,#6 I ./-B
:"$0/,#6A 8"&0" *%# ,"# 6$+%0# $) *+,$*(,&B
?$9&#6>
 !.%',//.*) 0)/'12+,+ ;.) %' 5$6/ !*%,7'8,)+

APC Infections Drugs CH3

!
Idiopathic
– Myco- C CH2 C COOH
- plasms
– Viruses NH2
!-methyldopa-type

Clonal
transformation
– Hodgkin’s disease
CLL, NHL B cell T-helper Regulatory T cell
Plasmocytoma

Alteration of T-cell regulation:

Collagen – lymphoproliferative disease

91,*,3$1 >//.*'1'(2
vascular diseases (AILD)
– SLE – thymoma

A. Pathogenesis of autoimmune hemolytic anemia

Fc-mediated
phagocytosis

"
+20°C +37°C Spleen
Macrophage
Warm antibodies = IgG, rarely IgM, IgA
B. Warm antibodies

Immuno-
suppressive
Spleen therapy:
irradiation
Anemia Cyclo-
phosphamide
jaundice
Azathioprine
Hepato-
splenomegaly Cyclosporine

Anti-CD20
antibody
Hyperplasia
of Prednisone:
bone marrow, Splen- 20% success
erythropoiesis ectomy
1. Reduced
Saturation of Ab production
LDH

!
Fc-receptors by
Haptoglobin high-dose i.v. 2. Reduced2.
immunglobulins phagocytosis
Urobilinogen

D. Treatment of warm antibody-induced

C. Clinical features autoimmune hemolysis
?@?

"
! /.-$%+()3 8)0.50.0 5'& #+($9.')50

!" #$%& !'()*$&+ !,($)--,'. /.-$%+0)0

!"#$ %&'()"$(*+ %,* -+-%##. /01 %&$ "&#. "22%3
+("&%##. /045 622",$(&0#.7 '8*. 2%& 2%-+* %00#-3
'(&%'("& "9 *,.'8,"2.'*+ %&$ %,* '8*,*9",* 2%##*$
%00#-'(&(&+5 :8*. %,* ;"+' 2";;"&#. ")+*,<*$
9"##"=(&0 (&9*2'("&+7 *+>*2(%##. ). !"#$%&'()'*
?>+'*(&@A%,, <(,-+7 ", 2.'";*0%#"<(,-+7 %&$
,%,*#. %9'*, )%2'*,(%# $(+*%+*+5 :8*+* (&9*2'("&+
-+-%##. #*%$ '" '8* 9",;%'("& "9 >"#.2#"&%# 2"#$3
,*%2'(<* %&'()"$(*+ '8%' )(&$ '" *,.'8,"2.'*+
;"+' *99(2(*&'#. %' #"= '*;>*,%'-,*+5 /& ;"+'
2%+*+7 2"#$ %&'()"$(*+ %,* $(,*2'*$ %0%(&+' /
%&'(0*&7 =8(28 (+ ;%(&#. *B>,*++*$ "& ;%'-,*
CA!+7 )-' %#+" "& +";* >%'8"0*&+5 D";* ;%#(03
&%&' #.;>8%'(2 $(+*%+*+ ;%. #*%$ '" +*2,*'("&
#%)')35% :--,'$%$7+
1" 2.345')0- $6 /.-$%+0)0
!"#$ %&'()"$(*+ )(&$ '" *,.'8,"2.'*+ ;"+' *99(3
2(*&'#. %' SG !! %&$ )(&$ >"",#. ", 8%,$#. %'
PK !!5 :8* $*0,** "9 )(&$(&0 %' ,""; '*;>*,%3
'-,* <%,(*+5 D(&2* 2"#$ %00#-'(&(&+ %,* -+-%##.
/01 %&'()"$(*+7 2";>#*;*&' %2'(<%'("& 2%&
;*$(%'* $(,*2' (&',%<%+2-#%, 8*;"#.+(+ =('8 %
$,%;%'(2 2#(&(2%# >(2'-,* (&2#-$(&0 8*;"0#")(3
&-,(%7 ,*&%# 9%(#-,*7 %&$ $(++*;(&%'*$ (&',%<%+3
2-#%, 2"%0-#%'("& E+** %#+" >5 FFMI5 T",'-&%'*#.7
'8(+ 8%>>*&+ ,%,*#.5 N*;"#.+(+ $*<*#">+ 0,%$-3
%##. (& ;"+' 2%+*+5 :8* !P) ;"#*2-#* )"-&$ '"
'8* CA! +-,9%2* ;*$(%'*+ )(&$(&0 '" 2";>#*3
;*&' ,*2*>'",+ "& U->99*, 2*##+ (& '8* #(<*,5
D(&2* >8%0"2.'*+ $" &"' 8%<* T2 ,*2*>'",+ 9",

"9 ;"&"2#"&%# %00#-'(&(&+ E+** >5 FGHI5 1"&"3
2#"&%# %00#-'(&(&+ ;%. )* $(,*2'*$ %0%(&+'
)"'8 / %&$ ( %&'(0*& E(;;%'-,* 9*'%# *,.'8,"3
2.'*+I5 1"&"2#"&%# 2"#$ %00#-'(&(&+ %#+" (&$-2*
!"#$%&! &'&$()*"&! !$+' ",-)..+/*&%&% '&01
,)0, E>*%J (&2($*&2* )*'=**& KL %&$ ML .*%,+
"9 %0*I5
:8* +*<*,('. "9 2"#$ %00#-'(&(&3(&$-2*$ 8*3
;"#.+(+ (+ $*>*&$*&' "& '8* '8*,;(2 %;>#('-$*
"9 '8* %&'()"$.7 =8(28 (+ $*9(&*$ %+ '8* %;"-&'
/017 T23;*$(%'*$ >8%0"2.'"+(+ $"*+ &"' '%J*
>#%2* E(& 2"&',%+' '" =%,; %&'()"$. 8*;"#.+(+I5
N*&2*7 '8* >,"+>*2'+ "9 +-22*++9-# ;%&%0*3
;*&' "9 2"#$ %&'()"$. 8*;"#.+(+ ). +>#*&*2'3
";.7 8(083$"+* (;;-&"0#")-#(&+7 ", +'*,"($+
%,* &"' 0""$5
#" 25'57.-.'(
V"= #*<*#+ "9 2"#$ %00#-'(&(&+ %,* "9'*& $*3
'*2'*$ (& #%)",%'",. '*+'+5 N"=*<*,7 '8(+ 9(&$(&0

"
"9 %&'()"$. )(&$(&0 '" '8* CA! %' % 0(<*& '*;3
0*&*,%##. (+ &"' 2#(&(2%##. ,*#*<%&' +(&2* 2"#$ %03
>*,%'-,*5 6+ '8* '*;>*,%'-,* $*2,*%+*+7 %&'(3
0#-'(&(&+ -+-%##. 8%<* % #"= '8*,;(2 %;>#('-$*5
)"$. )(&$(&0 (&2,*%+*+7 )-' '8* #.'(2 %2'(<('.
6#+"7 ;%&. >%'(*&'+ =('8 2"#$ 8*;%00#-'(&(&
"9 2";>#*;*&' $*2,*%+*+5 N*;"#.+(+ '8*,*9",*
$(+*%+* 8%<* "&#. +#(08'7 0,%$-%##. >,"0,*++(<*
"22-,+ "&#. (& %& "<*,#%> O"&*7 =8(28 -+-%##.
8*;"#.+(+ '8%' $"*+ &"' ,*W-(,* ',*%';*&'5 /&
,%&0*+ 9,"; FL !! '" PL !! E2I5 /9 '8* '8*,;(2 %;3
+";* 2%+*+7 8"=*<*,7 +*<*,* 8*;"#.'(2 2,(+*+
>#('-$* "9 '8* %&'()"$. (+ <*,. #%,0* E"<*, PL !!I7
;%. "22-, ->"& *B>"+-,* '" '8* 2"#$5 A#""$
8*;"#.+(+ "22-,+ %' '*;>*,%'-,*+ '8%' %,* *%3
',%&+9-+("&+ +8"-#$ &"' )* %$;(&(+'*,*$ -&#*++
+(#. %28(*<*$ (& '8* +J(&5 !"#$ %00#-'(&(&+ %,*
<('%# 9", +-,<(<%#5 :8* )#""$ +8"-#$ )* =%,;*$
"9'*& $(+2"<*,*$ (&2($*&'%##. $-* '" '8* %00#-3
'" PK !! $-,(&0 '8* ',%&+9-+("&5 :8*,* (+ &" +>*3
'(&%'("& "9 CA!+ (& ,"-'(&* CA! 2"-&'+ E3I5 ?#*23
2(9(2 ',*%';*&'5 :8* ;"+' (;>",'%&' >,*<*&'(<*
',"&(2 )#""$ 2*## 2"-&'*,+ $*'*2' '8* 2#-;>*$
;*%+-,* (+ '" =*%, =%,; 2#"'8(&05 /9 '8* +.;>3
2*##+ %+ #%,0* (&$(<($-%# 2*##+5 :8(+ ,*+-#'+ (& %
'";+ %,* *B',*;*#. +*<*,*7 ,*#"2%'("& '" % =%,3
9%#+*#. 8(08 ;*%& 2",>-+2-#%, <"#-;* E1!QI
;*, 2#(;%'* (+ '8* "&#. +"#-'("&5 ?B2(+("& ",
%&$ % 9%#+*#. #"= ,*$ 2*## 2"-&' (& >%'(*&'+
,%$("'8*,%>. "9 '8* +>#**& (+ -+-%##. (&*99*2'(<*5
=('8 % &",;%# 8*;"0#")(& 2"&2*&',%'("&5
!.'"+'%'(2+ ", (;;-&"+->>,*++%&'+ %,* >"'*&3
D(&2* '8* '*;>*,%'-,* (& '8* 2%>(##%,(*+ "9
'(%##. -+*9-# "&#. =8*& '8*,* (+ %& -&$*,#.(&0
'8* +J(& 2%& $,"> )*#"= PL !!7 '8* 2"#$ %00#-3
#.;>8">,"#(9*,%'(<* $(+*%+*5 C*2*&' >-)#(2%3
'(&(&+ 2%-+* '8* *,.'8,"2.'*+ '" 2#-;> '"0*'8*,5
'("&+ +-00*+' '8%' ',*%';*&' =('8 % ;"&"2#"&%#
:8(+ (&',%<%+2-#%, %00#-'(&%'("& >,"2*++ #*%$+
%&'()"$. $(,*2'*$ %0%(&+' !XHL EC('-B%&!I ;%.
'" 2%>(##%,. ")+',-2'("&7 =8(28 ;%&(9*+'+ %+ %23
,*+-#' (& 2"&',"# "9 8*;"#.+(+5
,"2.%&"+(+ E)#-(+8 $(+2"#",%'("& "9 '8* 9(&0*,+7
*%,+7 %&$ '(> "9 '8* &"+*I ", #(<*$" ,*'(2-#%,(+

!
;<<
E,*$$(+8R)#-(+8 ,*'(2-#%, >%''*,& "9 '8* +J(&I5
:,">8(2 #*+("&+ E-#2*,+7 &*2,"+(+I ;%. "22-,
(& +*<*,* 9",;+5
 Infections Polyclonal
!,($)--,'. /.-$%+0)0 8,. ($ #$%& !'()*$&).0

– Idiopathic Monoclonal
!
– Mycoplasma agglutinins (chron. cold agglutinins
pneumonia agglutinin
– Infectious disease)
mononucleosis –Lymphomas,
– Cytomegaly myeloma
– Listeriosis – Solid tumors

Anti-i (fetal
erythrocytes)
Predominantly anti-I Anti-I (adult
(adult erythrocytes) erythrocytes)

#%)')35% :--,'$%$7+
1. Specificity of cold antibodies

100%
- Falsely - Anemia
high
MCV - Acrocyanosis
- Falsely
50%
- low - Livedo
Ab binding Complement - erythrocyte - reticularis

"
activity - count
- Trophic
0% Hemolysis - disorders
0 10º 20º 30º 40ºC
2. Thermic amplitude 3. Changes in blood chemistry 4. Clinical symptoms

A. Autoimmune hemolysis by cold antibodies

100% CD20 antibody

Erythrocyte binding

Intravascular
hemolysis or

0% +4°C +20°C +30°C

Cold antibodies
= IgM, rarely IgG

Kupffer cell

B. Mechanisms of hemolysis
C3-receptor-
mediated
phagocytosis

C. Therapy
!
;<=

"
! 1,0.23-/+ #/4,74,4 7)* :3-.;,)/74

!" #$%&'()*%+,* !%-./00%), 1,0.234/4

!"#$% &'( )'#%* +*&,-(%.% /( ' 0#&/*" ,1 .&2
&#0* &*)+'0.%&%3
E*/".-*7 0,0+*&,-(8.) "*')8.,0% ,))#" .0
'/,#8 L N ,1 '-- 8"'0%1#%.,0%3 C+.% 8(5* ,1
5,%828"'0%1#%.,0 "*')8.,0 .% '0 '--*"$.) "*')8.,0
.06#)*6 /( '--*"$*0% ," 4$S .&&#0,$-,/#-.0%
! 40 5*0.).--.02.06#)*6 +*&,-(%.%7 8+* 6"#$
.0 8+* %*"#& ,1 8+* 6,0,"3 C+* '--*"$*0% -*'6
')8% '% ' "#$%&'3 40 8+.% )'%*7 8+* '08./,6.*%
8, 8+* "*-*'%* ,1 4T2L '06 +.%8'&.0*3 C+* #%*
'"* %5*).1.)'--( 6."*)8*6 '$'.0%8 8+* '08./.,2
,1 B'%+*6 /-,,6 ," 5"*&*6.)'8.,0 B.8+ '08.+.%2
8.)3 98".)8-( %5*':.0$7 8+.% 6,*% 0,8 ;#'-.1(
8'&.0*% %+,#-6 "*6#)* 8+.% 5",/-*&3
8+*& '% 8"#* '#8,'08./,6.*%3 <*&,-(%.% ,)2
K--,.&&#0.U'8.,0 '$'.0%8 1,"*.$0 <TK '08.2
)#"% .1 8+* 6"#$ 1."&-( '88')+*% 8, 8+* )*--
$*0% O),08'&.0'8*6 -*#:,)(8*% .0 8+* /-,,6
&*&/"'0* ,1 =>?%3 @*0.).--.0 )'0 *A*0
5",6#)8Q7 ," '$'.0%8 "*62)*-- S7 !7 ? '08.$*0%7
1,"& ),A'-*08 /,06% B.8+ 5",8*.0% ,0 8+*
&'( ,))#" '18*" /-,,6 8"'0%1#%.,0 .0 &#-8.5-(
=>? &*&/"'0*3 <.$+ '08./,6( 8.8*"% '"*
8"'0%1#%*6 ," &#-8.5'",#% 5'8.*08%3 C+* 5",2
&,%8 ),&&,0-( ,/%*"A*6 .0 5'8.*08% "*)*.A2
)*%%*% ,1 '--,.&&#0.U'8.,0 '"* 5+(%.,-,$.)'-
.0$ +.$+26,%* 5*0.).--.03 C+* '08./,6.*% .0
.&&#0* "*')8.,0% 8+'8 )'0 /* &.0.&.U*6 /(
;#*%8.,0 '"* #%#'--( 4$D B'"& '08./,6.*%7
:2/)/+72 (00%).2.&3

-*#:,)(8* 1.-8*".0$ '06 )'"*1#- 6,0," %)"**0.0$3

'06 +*&,-(%.% ,))#"% 6#* 8, E)2&*6.'8*6
!"#$%&'(")*)&+,)% ODV<Q "*')8.,0 O%** 53 LMWQ
5+'$,)(8,%.%3 @'8.*08% 8"*'8*6 B.8+ )*1'-,%2
.% ' "'"* ),&5-.)'8.,0 ,1 /-,,6 8"'0%1#%.,03 DV<
5,".0% 1"*;#*08-( 6*A*-,5 5,%.8.A* ?,,&/%
"*')8.,0% '"* )'#%*6 /( A.'/-* -(&5+,)(8*% .0
8*%8%7 /#8 +*&,-(%.% ,))#"% "'"*-(3
8+* 8"'0%1#%.,0 5",6#)8 8+'8 '88'): 0,"&'-
( F8+*" 6"#$%7 %#)+ '% ;#.0.6.0* ," %8./,5+*07
8.%%#* .0 '0 .&&#0,),&5",&.%*6 8"'0%1#%.,0
1."%8 1,"& .&&#0* ),&5-*G*% B.8+ 4$D ,"
"*).5.*083 C+.% 5",/-*& )'0 /* 5"*A*08*6 /(
4$H '08./,6.*% 6."*)8*6 '$'.0%8 8+* 6"#$3
#%.0$ -*#:,)(8* 1.-8*"% ," /( .""'6.'8.0$ 8+*
C+*%* .&&#0* ),&5-*G*% 8+*0 /.06 8, 8+*
/-,,6 5",6#)8 5".," 8, #%*3
%#"1')* ,1 8+* "*6 /-,,6 )*--%3 C+.% ')8.A'8*%
C+* #%* ,1 ),08'&.0'8*6 /-,,6 5",6#)8% .%
8+* ),&5-*&*08 )'%)'6*7 8+*"*/( -*'6.0$ 8,
"'"*-( 8+* )'#%* ,1 .01*)8.,0 8"'0%&.%%.,03

"
-(%.% ,1 #0.0A,-A*6 =>?%3 C+.% .% %,&*8.&*%
C+* &,%8 1"*;#*08-( 8"'0%&.88*6 5'8+,$*0%
"*1*""*6 8, '% 8+* I)''*+&'% ,-.%#'/&0J &*2
'"* +*5'8.8.%7 )(8,&*$'-,A."#%7 '06 <4V3 H'-'"2
)+'0.%& ,1 +*&,-(%.%3 C,6'(7 &'0( B,":*"%
.'7 ?+'$'%P 6.%*'%*7 '06 1.-'".'- 6.%*'%*% )'0 /*
/*-.*A* 8+'8 '8 -*'%8 %,&* ,1 8+* '08./,6.*%
8"'0%&.88*6 .0 *06*&.) "*$.,0%3 >')8*".'7 %#)+
'"* 6."*)8*6 '$'.0%8 "*62)*-- '08.$*0% '06
'% -)(*.,/,0#)7 12 3,457 '06 6(")505#7 '"* "'"*-(
8+'8 8+* 6"#$% )'#%.0$ 8+.% 8(5* ,1 +*&,-(%.%
8"'0%&.88*6 .0 /-,,6 6,0'8.,0%3
')8 '% +'58*0%3 40 ,8+*" B,"6%7 8+*( &#%8 /*
@'8.*08% B.8+ 4$K 6*1.).*0)( OLXYZZ .06.A.2
/,#06 8, )'"".*" 5",8*.0% .0 ,"6*" 8, $*0*"2
6#'-%Q &'( '-%, 6*A*-,5 '0'5+(-')8.) "*')8.,0%
'8* '0 .&&#0* "*%5,0%*3
'18*" /-,,6 8"'0%1#%.,0%3 C+* "*'%,0 .% 8+'8 8+*
1 ?*"8'.0 6"#$%7 %#)+ '% !23&%"-4/*$#7 .06#)*
8"'0%1#%.,0 5",6#)8% ,18*0 ),08'.0 %&'-- ;#'02
8+* %5*).1.) .0+./.8.,0 ,1 "*$#-'8,"( C )*--%7
8.8.*% ,1 %*"#& .&&#0,$-,/#-.0%3 C+*%* 5'2
8+*"*/( )'#%.0$ 8+* #0),08",--*6 5",6#)8.,0
8.*08% %+,#-6 8+*"*1,"* "*)*.A* ,0-( )'"*1#--(
,1 '#8,'08./,6.*%3 C+.% .% ' 8"#* 1,"& ,1 '#8,2
B'%+*6 /-,,6 5",6#)8%3
.&&#0* +*&,-(8.) '0*&.'3 C+* '08./,6.*%
"*')8 &,%8-( B.8+ "+*%#% '08.$*0 ),&5,2
0*08%3 K55",G.&'8*-( LM N ,1 5'8.*08% ,0
!2&*8+(-6,5' 6*A*-,5 '08./,6.*% O5,%.8.A*
?,,&/%P 8*%8Q7 /#8 ,0-( '",#06 L N B.--
6*A*-,5 +*&,-(%.%3

5" 6$7)48%4/.) 9,7+-/.)4

K6A*"%* *A*08% &'( 6*A*-,5 '18*" ' /-,,6

!
8"'0%1#%.,03 9*A*"* +*&,-(8.) "*')8.,0% '"*
#%#'--( '88"./#8'/-* 8, 8+* &.%8':*0 8"'0%1#%.,0
,1 .0),&5'8./-* /-,,63 KL7 R*--7 '06 !#11( '08.2
$*0% '"* &,%8 ),&&,0-( .0A,-A*63 K-8+,#$+
%8",0$-( .&&#0,$*0.)7 "+*%#% '08.$*0% '"*
<=> "'"*-( 8+* )'#%* ,1 8"'0%1#%.,0 "*')8.,0% /*2
)'#%* "+*%#% .0),&5'8./.-.8( .% *'%.*" 8, 6*8*)83
E.g., penicillin
#$%&'/)*%+,* 1,0.234/4 7)* 6$7)48%4/.) 9,7+-/.)4

Binding to erythrocyte membrane

!
O CH2 R O CH2 R

R
1. Hapten type

HO CH R HO CH R
E. g.,
quinidine, HO CH R
stibophen, etc.

2. Innocent bystander type

CH3 Regulatory T cell T-helper B cell Auto-Ab production

:2/)/+72 (00%).2.&3
C CH2 C COOH
NH2

3. !-Methyldopa type
A. Drug-induced autoimmune hemolysis

39 °C

"
IgE
Febrile reaction C, D, E-
antigens HLA
Anti-A1
Anti-Kell
Anti-Duffy

Hemolytic reaction

Infections

B. Transfusion reactions
Graft-versus-host reaction
Anti-HLA
Anti-C, D, E
Allo-immunization !
<=?

"
! <)'%/;$&1 6&0)-0)0 -(5 2;$%,)(&-0

!" !#$%&''#() *)#$+%,)(&-

!"#$%&'"()* +*, -" .*#/"0 -, *($)-&0)"/1 .,2
$&3)("/1 &% $4" 0)%".$ .,$&$&5). "66".$/ &6 7 ."88/
*(0 !9 ."88/: ;#$&*($)-&0)"/ *<*)(/$ !;= *(0
!;> <%*(#8&.,$" *($)<"(/ *%" 6%"?#"($8, &-2
/"%@"0 )( *#$&)++#(" )0)&'*$4). ("#$%&'"()*/
A;B!C: 74"/" *($)<"(/ *8/& '8*, * %&8" )( +*$"%2
(&6"$*8 )++#()D*$)&( A("E-&%( ("#$%&'"()*C:
;#$&*($)-&0)"/ +*, *8/& -" 6&%+"0 )( $4"
.&#%/" &6 /,/$"+). 8#'#/ "%,$4"+*$&/#/ AFGHC
*(0 I"8$,J/ /,(0%&+"1 * /'".)*8 $,'" &6 %4"#+*2
$&)0 *%$4%)$)/: !"#$% $#"&'("# ()*+,-.)/% 0!1!2
(%'3%*4" &6 72."88 $,'" )/ *//&.)*$"0 E)$4 $4"
.8&(*8 0"@"8&'+"($ &6 7 ."88/ E)$4 .,$&$&5).
*.$)@)$, *<*)(/$ ("#$%&'4)8). <%*(#8&.,$"/: K*2
2/&(&1-/ 7''#(%/%=;
2" 3#+) 4)5 2)// !,/-0&-
K#%" %"0 ."88 *'8*/)* )/ * 0)/"*/" $4*$ "5.8#2
/)@"8, *66".$/ "%,$4%&'&)"/)/ E)$4&#$ 0)/$#%-)(<
8"#3&.,$" &% '8*$"8"$ 6&%+*$)&(: 74" 0)/"*/" )/
6%"?#"($8, *//&.)*$"0 E)$4 $4,+&+*/ *(0 '*%2
@&@)%#/ Q=U )(6".$)&(/: 72%"<#8*$&%, ."88/ $4*$
/"8".$)@"8, )(4)-)$ "%,$4%&'&)"/)/ *%" '%"/#+2
*-8, *.$)@*$"0: ;($)-&0)"/ *<*)(/$ "%,$4%&.,$).
'%".#%/&%/ 4*@" *8/& -""( &-/"%@"0:
6" 7''#() 89+%':%1;$%,)(&-
B++#(" $4%&+-&.,$&'"()* )/ *//&.)*$"0 E)$4
$4" 6&%+*$)&( &6 *($)2'8*$"8"$ *($)-&0)"/
A#/#*88, B<VC: 74)/ 0)/"*/" .*( &..#% )( .&((".2

$)@" $)//#" 0)/"*/" A"/'".)*88, FGHC1 *6$"% $4" #/"

$)"($/ E)$4 $4)/ 0)/"*/" 4*@" * 4)<4 )(.)0"(."
&6 ."%$*)( +"0).*$)&(/1 &% 6&88&E)(< @)%*8 )(6".2
&6 *#$&)++#(" 0)/&%0"%/1 )(.8#0)(< $4%&+-&2
$)&(/: ; '%)&% @)%*8 )(6".$)&( )/ $4" /#/'".$"0
.,$&'"()*1 '#%" %"0 ."88 *'8*/)* AKLM;C1 $4,%&)2
.*#/" )( +*(, .*/"/ &6 #(3(&E( "$)&8&<, A)0)&2
0)$)/1 FGH1 *(0 /,/$"+). /.8"%&0"%+*: ; $4)%0 &6
'*$4). $4%&+-&.,$&'"(). '#%'#%*1 B7KC: 74"
$4" '*$)"($/ 4*@" %4"#+*$&)0 *%$4%)$)/:
*($)-&0)"/ /4&%$"( $4" 8)6"/'*( &6 $4%&+-&2
7#+&%/ &6 $4" $4,+#/ A$4,+&+*/C +*, 8"*0
.,$"/: R"/')$" '%&8)6"%*$)&( &6 +"<*3*%,&.,$"/
$& $4" 0"@"8&'+"($ &6 +'#% 5,4/% .%(( "+("64"1 *
E)$4)( $4" -&(" +*%%&E1 $4" (#+-"% &6 '8*$"2
.&(0)$)&( )( E4).4 8*%<" ?#*($)$)"/ &6 72/#'2
8"$/ )( $4" -8&&0 0".%"*/"/: K*$)"($/ E)$4 /"@"%"
'%"//&% ."88/ A%"<#8*$&% ."88/C *%" <"("%*$"0:
0)/"*/" 4*@" * $"(0"(., $& 0"@"8&' 4"+&%2
74"/" ."88/ "5.8#/)@"8, )(4)-)$ $4" 0"@"8&'+"($
%4*<"/: 74" -8""0)(< #/#*88, &..#%/ */ '"$".4)*8

"
&6 <%*(#8&.,$"/: B( NBO2)(6".$"0 )(0)@)0#*8/1
("#$%&'"()* #/#*88, %"/#8$/ 6%&+ $4" )(4)-)$)&(
&6 ("#$%&'4)8 '%&0#.$)&( )( -&(" +*%%&E 0#"
$& 0)%".$ )(P#%, -, NBO1 &''&%$#()/$). )(6".$)&(/
&6 $4" -&(" +*%%&E1 &% $4" $&5). /)0" "66".$/ &6
$4"%*',: L*%"8,1 *($)2("#$%&'4)8 *($)-&0)"/ '8*,
* %&8":
." !,/-0$&1 !()'&-
B( *'8*/$). *("+)*1 $4" "($)%" '%&."// &6 4"+*2
$&'&)"/)/ )/ 6*)8)(<: Q8&&0 $"/$/ %"@"*8 '*(.,$&2
'"()*1 $4*$ )/1 $4" .&2&..#%%"(." &6 *("+)*1 8"#2
3&.,$&'"()*1 *(0 $4%&+-&.,$&'"()*: M8)().*8
/)<(/ *%" '*8"("// *(0 6*$)<#"1 )(.%"*/"0 /#/2
."'$)-)8)$, $& )(6".$)&(/1 *(0 -8""0)(< $"(0"(.,:
74" 0)/"*/" .*( -" .*#/"0 -, )(6".$)&(/1 $&5).
0*+*<"1 &% *#$&)++#()$,: ;#$&)++#(" '*$4&2
<"("/)/ /4&#80 -" /#/'".$"0 E4"( )(.%"*/"0
(#+-"%/ &6 8,+'4*$). ."88/ *%" 0"$".$"0 E)$4)(
$4" -&(" +*%%&E: 74"/" ."88/ *%" 72%"<#8*$&%,
."88/ $4*$ )(4)-)$ '8#%)'&$"($ /$"+ ."88/ ")$4"%
0)%".$8, &% @)* /$%&+*8 ."88/: !2)($"%6"%&(1 $#+&%
4"+&%%4*<": G)6"2$4%"*$"()(< ."%"-%*8 4"+&%2
%4*<"/ *%" )(6%"?#"($ "@"($/1 "@"( )( '*$)"($/
E)$4 '8*$"8"$ .&#($/ -"8&E SW WWWX+8: 74"
)++#(" %"*.$)&( $*%<"$/ <8,.&'%&$")( A<'C
'8*$"8"$ *($)<"(/ <'BBB*1 <'BB- A<'BBB*X<'BB- .&+2
'8"5C1 *(0 <'B-: 74" *($)-&0)"/ *%" 0"$".$"0 */
'8*$"8"$2*//&.)*$"0 )++#(&<8&-#8)(/ AK;B<VC:
;($)<"(Y*($)-&0, .&+'8"5"/ $4*$ *$$*.4 $&
'8*$"8"$/ @)* I. %"."'$&%/ 6&%+ )( $4" '%"/"(."
&6 4"'*%)(: K8*$"8"$/ $4*$ *%" Z)((&."($ -,2
/$*(0"%/[ .*( $4"( -" 8,/"0 &% '4*<&.,$&/"0
-, +*.%&'4*<"/: B7K )( .4)804&&0 )/ #/#*88,
*( *.#$" 6&%+ *//&.)*$"0 E)$4 * 4)<4 %*$" &6
/'&($*("&#/ %"+)//)&(: B( *0#8$/1 $4" .&#%/"
&6 0)/"*/" $"(0/ $& -" .4%&(). *(0 %"6%*.$&%,
$& $%"*$+"($: 74" "/$*-8)/4"0 $%"*$+"($ *8$"%2
(*$)@"/ )(.8#0" .&%$).&/$"%&)0/1 )++#(&/#'2
'%"//*($/1 4)<420&/" )($%*@"(&#/ )++#(&2
<8&-#8)(/1 *(0 /'8"(".$&+,: L"."($8,1 <&&0
%"/#8$/ 4*@" -""( *.4)"@"0 E)$4 *( *($)2
MR>W +&(&.8&(*8 *($)-&0, AL)$#5*(!C:

!
(".%&/)/ 6*.$&%2"1 *(0 )($"%8"#3)(2> /""+ $& -"
)(@&8@"0: MRST! ."88/ *%" 3)88"0 @)* I*/2)(0#."0
*'&'$&/)/: 74"/" '*$)"($/ .*( -" /#.."//6#88,
+*(*<"0 -, )++#(&/#''%"//)&( A/$"%&)0/1
.,.8&/'&%)("1 -&(" +*%%&E $%*(/'8*($*$)&(C:
>?@
 Idiopathic CD 8+
!#$%&''#() *)#$+%,)(&-0 -(5 A$9)+ 2;$%,)(&-0

Regulatory cell
!
autoimmune T cell
neutropenia

Newborn Stromal Pluripotent

neutropenia cell stem cell

SLE
Felty’s syndrome Cyto-
kines
LGL
lymphocytosis

Thymoma
(pure white cell
aplasia)

2/&(&1-/ 7''#(%/%=;
HIV Myelo- Megakaryo- Erythro- Lympho-
poiesis cytopoiesis poiesis poiesis
A. Autoimmune neutropenia B. Aplastic anemia

Thymoma Parvoviruses

Thymus
Regulatory cell

Megakaryo- Myelopoiesis
"
C. Pure red cell aplasia cytopoiesis Erythropoiesis

Idiopathic
thrombocypenic
purpura (ITP)
Antibody production

Viral infections
Heparin
gpIIIa
Drugs. Caution FcRII gpIIb 2. Petechial bleeding
with heparin !! !"

SLE Phagocytosis

Transfusion
(posttransfusion
purpura)

D. Immune thrombocytopenia
FcR

Macrophage
1. Pathogenesis 3. Increased megakaryocytes
!
>?B

"
! #$%&'(<(1*9&< >*+$&+$+

!"#$% &%#'%()*+ *,% -%./&*+$)" 0)+%*+%+ )-

12)"2 /,%"#,+., "%&&+ .3 $2% 4.-% (*,,.1 4%5
".(% #-*4&% $. 0)33%,%-$)*$% *-0 2*6% 2)72
/,.&)3%,*$)6% *"$)6)$89 :2% #-".-$,.&&%0 7,.1$2
.3 -%./&*+$)" "%&&+ +#//,%++%+ $2% -.,(*& 2%5
(*$./.)%+)+9 ;3 &%3$ #-$,%*$%0< *"#$% &%#'%()*
&%*0+ $. 0%*$2 1)$2)- * 3%1 1%%'+9
!" #$%&'()(*$+*+ &,- '.$ /0*1*,
(2 3$45$%*&
=*-8 &%#'%()*+ 0%6%&./ 3,.( /&#,)/.$%-$ +$%(
"%&&+9 :2)+ $8/% .3 #-0)33%,%-$)*$%0 &%#'%()* )+
0)33)"#&$ $. "&*++)38 (.,/2.&.7)"*&&89 >$2%, $8/%+
*,)+% 3,.( (8%&.4&*+$+ *-0 %?2)4)$ $2% ".,,%5
+/.-0)-7 (.,/2.&.789 =8%&.(.-."8$)" &%#'%5
=<*,*9&< ?%%4,(<(18
7#)+2%09 =.+$ &%#'%()*+ *,)+% 3,.( -%./&*+$)"
/,.&)3%,*$).- *$ $2% %*,&8 +$*7%+ .3 A5"%&& (*5
$#,*$).- B/,.5A *-0 /,%5A &%#'%()*C9 ;- "2)&5
0,%-< $2% %?/,%++).- .3 LMNE B".((.- !DD
*-$)7%-C 0%3)-%+ * +#47,.#/ .3 &%#'%()*+
1)$2 * 7..0 /,.7-.+)+9 V.1%6%,< LMNE )+ .3
&)$$&% /,%0)"$)6% 6*&#% )- *0#&$+9 ;- (*$#,%5"%&&
A5"%&& &%#'%()*+< )((#-.7&.4#&)-+ *,% %?5
/,%++%0 .- $2% "%&& (%(4,*-% B+&7C< 12)&% )-
/,.5A *-0 /,%5A !DD $2% )((#-.7&.4#&)-5*++.5
")*$%0 !5"2*)- )+ %?/,%++%09 =*$#,% A5$8/% &%#5
'%()*+ 2*6% * /.., /,.7-.+)+ *-0 (#+$ 4% $,%*5
$%0 *77,%++)6%&89 D%#'%()*+ .3 :5"%&& &)-%*7%
%?/,%++ LMO %)$2%, )- $2% "8$./&*+( ., .-
$2% "%&& +#,3*"%9 :2% %?/,%++).- .3 LMN* *-0

LMQ )0%-$)3)%+ 6*,).#+ +#4$8/%+ .3 &%#'%()*

()*+ 0%6%&./ 3,.( ".((.- /,%"#,+.,+ .3 $2%
B/,.5:< /,%5:< ".,$)"*& $28(."8$% $8/%< *-0
7,*-#&."8$)" *-0 (.-."8$)" &)-%*7%9 !"".,0)-7
(*$#,% :5!DDC 4#$ )+ .3 &)$$&% "&)-)"*& ,%&%6*-"%9
$. $2% @,%-"25!(%,)"*-5A,)$)+2 B@!AC "&*++)3)"*5
$).- +8+$%(< *"#$% (8%&.)0 &%#'%()*+ B!=DC
>" =8'(1$,$'*9 :$&'40$+ (2 !94'$ ;8$<(*-
*,% 0)6)0%0 )-$. %)72$ +#47,.#/+ B=E $. =FC
&,- 38%).&'*9 3$45$%*&+
#+)-7 (.,/2.&.7)"*& ",)$%,)* *-0 "8$."2%()"*&
+$*)-)-7 $%"2-)G#%+ B%979< $2% 0%$%"$).- .3 +/%5 =#$*$).-+< "2,.(.+.(% 0%&%$).-+ B0%&C< *-0
")3)" %-H8(%+< +#"2 *+ (8%&./%,.?)0*+%< =I>C9 "2,.(.+.(% $,*-+&."*$).-+ B$C $2*$ "*#+% $2%
08+3#-"$).- ., )-2)4)$).- .3 * 7%-% /,.0#"$ )(5
6" 7.$,('8)*9 :$&'40$+ (2 !94'$ ;8$<(*- /.,$*-$ 3., "%&& 0)33%,%-$)*$).- ., 0)6)+).- *,%

"
3$45$%*&+ $2% (.+$ ".((.- "*#+%+ .3 &%#'%()*9 :2%+%
4).&.7)"*& 3%*$#,%+ *,% .3 7,%*$ /,.7-.+$)" )(5
D8(/2.)0 *-0 (8%&.)0 &%#'%()*+ *,% (*-*7%0
/.,$*-"%< 4#$ $2%8 +%&0.( ".,,%&*$% 1)$2 +/%")5
0)33%,%-$&89 ;((#-.&.7)"*& $8/)-7 )+ (.+$ )(5
3)" (.,/2.&.7)"*& ",)$%,)*9 =O /,.(8%&."8$)"
/.,$*-$ )- "*+%+ 12%,% )$ )+ -.$ /.++)4&% $.
&%#'%()*< 12)"2 0%6%&./+ 0#% $. NRWNF "2,.5
0%$%,()-% $2% &)-%*7% #+)-7 (.,/2.&.7)"*&
(.+.(% $,*-+&."*$).-< )+ (.,/2.&.7)"*&&8 "2*,5
",)$%,)*9 J;((*$#,%K &%#'%()*+< +#"2 *+ =E
*"$%,)H%0 48 &*,7% G#*-$)$)%+ .3 *H#,./2)&)"
&%#'%()*< *,% "2*,*"$%,)H%0 48 $2% %?/,%++).-
7,*-#&%+9 D%#'%()*+ 1)$2 "2,.(.+.(% NS )-5
.3 .-&8 * 3%1 *-$)7%-+ B%979< LMNNF *-0 LMOPC
6%,+).- ., 0%&%$).- *,% *++.")*$%0 1)$2 %.+)-.5
., $2% 1%*' %?/,%++).- .3 %*,&8 (8%&.)0 *-$)5
/2)&)* B=PX.C9 :,*-+&."*$).-+ )-6.&6)-7 "2,.5
7%-+ BLMNO *-0 LMOOC9 ;$ )+ #+#*&&8 %*+8 $. 0)+5
(.+.(%+ Y *-0 QN *,% .3$%- .4+%,6%0 )- =Q
$)-7#)+2 !=D $8/%+ =N< =Q< *-0 =O 48 &)72$
(8%&.)0 &%#'%()*9 :2%+% $2,%% $8/%+ .3 &%#'%5
()",.+"./89 :2%,% )+ -. ".,,%&*$).- 1)$2 $2%
()* 2*6% * 4%$$%, /,.7-.+)+ $2*- (.+$ .$2%,
%?/,%++).- .3 +/%")3)" *-$)7%-+9 ;- (8%&.(.-.5
$8/%+< %+/%")*&&8 $2.+% 1)$2 ".(/&%? 7%-%$)"
"8$)" &%#'%()* B!=D5=PC *-0 (.-."8$)" &%#5
*-.(*&)%+9 :,*-+&."*$).-+ ., .$2%, *4-.,(*&5
'%()* B!=D5=RC< $2% /*$)%-$+ $%+$ /.+)$)6%
)$)%+ .3 4*-0 GQO .3 "2,.(.+.(% NN *,% 3,%5
3., LMNP *-0 LMSP9 =S &%#'%()*+ %?/,%++
G#%-$&8 3.#-0 )- (8%&.(.-."8$)" &%#'%()*+
7&8"./2.,)-5!< *- *-$)7%- .3 $2% %,8$2,."8$)"
*-0 /*,$)"#&*,&8 )- +%".-0*,8 &%#'%()*+ $2*$
&)-%*7%9 =F &%#'%()*+ *,% /.+)$)6% 3., LMSN<
0%6%&./ *3$%, %?/.+#,% $. "%,$*)- 0,#7+9 ;-
*- )-$%7,)- 3.#-0 .- /&*$%&%$+ *-0 (%7*'*,8.5
$2% 3#$#,%< /,.7-.+$)"*&&8 +)7-)3)"*-$ "&*++)3)"*5
"8$%+9
$).-+ .3 &%#'%()* 1)&& 4% 4*+%0 .- 7%-%$)" 3%*5
=" 7.$,('8)*9 :$&'40$+ (2 !94'$ $#,%+9 :2% (.+$ ".((.- *-.(*&)%+ *,% &)+$%0
)- B!C9
38%).&'*9 3$45$%*&+

!
@AB
T-0)33%,%-$)*$%0 &%#'%()*+ $2*$ 0. -.$ %?/,%++
&)-%*7%5+/%")3)" *-$)7%-+ *,% ,*,%9 ;- $2)+ "*+%<
$2% %-H8(% $%,()-*& 0%.?8-#"&%.$)08&$,*-+3%,5
*+% B:0$C )+ #+#*&&8 0%$%"$*4&%9 U%6%,*& +#4$8/%+
.3 &8(/2.4&*+$)" &%#'%()* "*- 4% 0)+$)-5
 Chronic Myeloid Leukemia (CML)
!94'$ 3$45$%*&+
!
Acute Myeloid Leukemia (AML) Acute Lymphatic Leukemia (ALL))
M0 = Undifferentiated AML undifferentiated ALL
M1 = AML without maturation T-ALL
M2 = AML with maturation Pluripotent B-ALL
M3 = Promyelocytic leukemia stem cell
M4 = Myelomonocytic leukemia
M5 = Monoblastic/monocytic leukemia
M6 = Erythroleukemia
M7 = Megakaryocytic leukemia CFU-
GEMM

BFU-E CFU-B CFU-Eo CFU-GM B T

=<*,*9&< ?%%4,(<(18
A. Hematopoiesis and origin of leukemia

MPO HLA-DR CD34 CD117 CD13 CD14 CD15 CD33 CD61 CD64
M0 +/- +/- +/- + +/- - - +/- - -
M1 + +/- +/- +/- +/- - - +/- - -
M2 + + +/- +/- + - +/- +/- - -
M3 + - - - -/+ + + + - +/-
M4
M5
M7
M6
+
-
-
+
+
+/-
-/+
-/+

= positive for glycophorin -A

+/-
-/+

B. Immunophenotypic features of acute myeloid leukemias

+
+
+/-
+/-
+/-
-
+/-
+
-
+
+
+/- +
-
-
+
+

"
TdT CD1a CD2 cyCD3 mCD3 CD10 CD19 CD79! cyIg slg
Pro-T-ALL + - - + +/- - - - -
Pre-T-ALL + - + + +/- - - - -
Cortical-ALL + + + +/- +/- +/- - - - -
Mature T-ALL +/- - + - + - - - - -
Pro-B-ALL + - - - - + + - -
Pre-B-ALL + - - - +/- + + + -
Mature B-ALL - - - - +/- + + - +

C. Immunophenotypic features of acute lymphatic leukemias

Myeloid leukemias Lymphatic leukemias
t (8;21) M2 t (9;22) Ph'+-ALL
inv (16), del (16q) M4Eo t (4;11) newborn -ALL or biphenotypic ALL
t (15;17) M3 t (8;14), (2;8), (8;22) B-ALL

!
t (11;17) M3-like t (11;14), (1;14) T-ALL
del (11) (q22-23) M5, M4 t (1;19) pre-B-ALL
t (9;11), t (11;19) M5, M4 t (5;14) B-ALL
monosomy/del 7 & 5 M1, M2, M5 del 9, t (9;n..) hyperleuk., extramedull. manifestations

D. Cytogenetic features of acute myeloid and lymphocytic leukemias

@AC

"
" :#+.3'0'7%2.0 A%1#.1#1

!"#$"%#& '( )*+,-'+. /0.11%(%2.3%'41

!"#$%&"&' #()*+,)"- "./ *.,#$0/."'$1/ 2$-3
/"-/- '+"' ".$-/ 0.,) '+/ #()*+ &,2/- ,. /4'."3
5,.2$&% ', '+/ &,.)"# *+(-$,#,%( ,0 '+/ %/.)3
$&"# 5/&'/.: "&2 2$00/./&5/- ;/'9//& ?35/## "&2
G35/## #()*+,)"- 9/./ 2/0$&/27 G( 2$00/./&3
'$"'$&% ;/'9//& #,93%."2/ "&2 +$%+3%."2/ )"3
&,2"# #()*+"'$5 '$--6/7 8& "55,.2"&5/ 9$'+ '+/
#$%&"&' #()*+,)"-: '+/ H$/# -(-'/) "#-, "'3
1".$/'( ,0 -'"%/- $&1,#1/2 $& '+/ )"'6."'$,& "&2
'/)*'/2 ', 2/-5.$;/ '+/ 5#$&$5"# ./#/1"&5/ ,0
2$00/./&'$"'$,& ,0 #()*+"'$5 5/##-: " &6);/. ,0
'+/ #()*+,)"-7
2$00/./&' '(*/- ,0 #()*+,)"- /4$-'7
?+/ H$/# 5#"--$0$5"'$,& 2$2 &,' %"$& "55/*3
<,2%=$&>- 2$-/"-/ 9"- 1$/9/2 "- " -/*"."'/
'"&5/ ,& '+/ I)/.$5"& 5,&'$&/&'7 ?+/ J/1$-/2
/&'$'( ;/5"6-/ ,0 $'- 2$-'$&5'$1/ ),.*+,#,%$5"#
C6.,*/"&3I)/.$5"& K()*+,)" E#"--$0$5"'$,&
"&2 5#$&$5"# 0/"'6./-7 ?+/ 5/## ,0 ,.$%$& ,0 <,2%3
LJCIKM 9"- '+/./0,./ /-'";#$-+/2 ;( "& $&'/.&"3
=$&>- #()*+,)" 9"- " )"''/. ,0 2$-56--$,& 0,.
'$,&"# *"&/# $& NOOP7 ?+/ JCIK 5#"--$0$5"'$,& 2$2
)"&( (/".-@ '+/ -'.$5' 2$-'$&5'$,& ;/'9//&
&,' "''/)*' ', ;/ " A;$,#,%$5"##( 5,../5'B #()3
<,2%=$&>- #()*+,)" "&2 ,'+/. #()*+,)"-
*+,)" 5#"--$0$5"'$,&: ;6' )/./#( *.,1$2/2 " #$-'
5,##/5'$1/#( 2/0$&/2 "- A&,&3<,2%=$&>- #()*+,3
,0 9/##32/0$&/2 /&'$'$/- ;"-/2 ,& '+/ #"'/-'
)"-B )"( ;/ 2.,**/2 $& '+/ 06'6./7
/0%4%2.0 @++B4'0'7*

),.*+,#,%$5"#: $))6&,#,%$5"#: ),#/56#". ;$,3

?+/ !"#$ %$&''"("%&)"*+ 9"- /-'";#$-+/2 ,& '+/
#,%$5"#: "&2 %/&/'$5 '/5+&$D6/-7 Q,)/ #()*+,3
C6.,*/"& 5,&'$&/&' $& '+/ *"-' 0/9 2/5"2/-7 8'
)" 5"'/%,.$/- 9/./ *.,1$-$,&"##( 2/0$&/27
"''/)*'/2 ', ./#"'/ '+/ 1".$,6- #()*+,)" /&3
?+/ JCIK 5#"--$0$5"'$,& ,0 )"#$%&"&' #()3
'$'$/- ', $))6&,#,%$5"##( 2/0$&/2 5/##- ,0 ,.$%$&7
*+,)"- $- *./-/&'/2 $& LIM7 ?+/ #()*+,)" /&3
?+$- 9"- ;"-/2 &,' ,&#( ,& ),.*+,#,%$5"# 5.$3
'$'$/- ,0 '+/ H$/# 5#"--$0$5"'$,& "./ "#-, #$-'/2 0,.
'/.$": ;6' "#-, "&2 ),-' $)*,.'"&'#( ,& '+/ $)3
5,)*".$-,&7 <,2%=$&>- 2$-/"-/ 9$## ;/ 2$-3
)6&,*+/&,'(*$5 0/"'6./- ,0 #()*+,)" 5/##- "-
56--/2 ,& *7 NRS: "&2 ,'+/. #()*+,)"- L&,&3
2/'/.)$&/2 ;( $))6&,+$-',5+/)$5"# -'"$&$&%
<,2%=$&>- #()*+,)"-M 9$## ;/ 2$-56--/2 ,& **7
'/5+&$D6/-7 E/&'.,5('$5 "&2 5/&'.,;#"-'$5 #()3
NRPTNPN7
*+,)"-: 0,. /4")*#/: 9/./ 5+"."5'/.$F/2 "53

# 5%#0 /0.11%(%2.3%'4 '( 6.0%74.43 8'49:';7<%4=1 )*+,-'+.1

>9/#00 )*+,-'+.1 ?9/#00 )*+,-'+.1

)'&97$.;# 6.0%74.43 )*+,-'+.1

!
!"#$%&'"()'* +,-!!. +,/!!. %0)1" '233 32452#)0 !
?,-!!. ?,$1&3"#$%&'"()' 32452#)0 9/!!;
! !"#$%&'"()'6$307#0'"(&)8 3"#$%&#0 ! !01B2 B10:4301 3"#$%&'"(2 3"#$%&'"(&7)7
9)##4:&'"(&#0; !
F"'&7)7 =4:B&)827. G2
H@01" 7":81&#2
!
/307#0'"(&)8 3"#$%&#0. $307#0'"(&#0 !
!"#$%&2$)(%23)&)8 3"#$%&#0
! -2:(1&<307()'6'2:(1&'"()' 3"#$%&#0 ! /32&#&1$%)' 7#033,'233 3"#$%&#0
9=&33)'4301. =&33)'4301 > 8)==472. 8)==472;
?,@&:2 3"#$%&#0
!
A:B)&)##4:&<307()' 3"#$%&#0 9AC!D. !BE;

@43#$+#;%.3#97$.;# 6.0%74.43 )*+,-'+.1

! -2:(1&'"()' 3"#$%&#0

:%7-97$.;# +.0%74.43 0*+,-'+.1

"
CDE
!

!
-2:(1&<307()' 3"#$%&#0
C##4:&<307()' 3"#$%&#0
+415)((I7 3"#$%&#0
!01B2,'233 0:0$307()' -DJK> +,'233 3"#$%&#0
!

!
/32&#&1$%)' #28)4# (& 301B2,'233 ?,'233
3"#$%&#0
?,)##4:&<307()' 3"#$%&#0
?,3"#$%&<307()' 3"#$%&#0
!01B2,'233 0:0$307()' -DJK> ?,'233 3"#$%&#0
 B-Cell Lymphomas
!"#$"%#& '( )*+,-'+. /0.11%(%2.3%'41
"
I. Precursor B-cell neoplasia
Precursor-B-lymphoblastic lymphomas/leukemias B-lymphoblastic lymphoma
II. Peripheral B-cell neoplasia
1. CLL, PLL, small-cell lymphocytic lymphomas B-lymphocytic lymphoma
2. Lymphoplasmacytoid lymphoma (immunocyt.) Lymphoplasmacytic immunocytoma

3. Mantle cell lymphoma Centrocytic lymphoma

Centrocytoid subtype of centroblastic lymphoma

4. Follicular center lymphoma, follicular, grade I – III Centroblastic-centrocytic lymphoma

diffuse (predominantly small cell) (preliminary) Follicular, diffuse
5. Marginal zone-B-cell lymphoma, Monocytoid lymphoma, including marginal
extranodal (MALT-type, +/- monocytoid B cells), zone lymphoma
nodal (+/- monocytoid B cells)

/0%4%2.0 @++B4'0'7*
6. Marginal zone lymphoma of the spleen (preliminary)
7. Hairy cell leukemia Hairy cell leukemia
8. Plasmocytoma/myeloma Plasmocytic lymphoma
9. Diffuse large cell B-cell lymphoma (subtype: Centroblastic lymphoma, B-immunoblastic
primary mediastinal large cell B-cell lymphoma) Lymphoma, large cell anaplastic Ki1+ lymphoma
10. Burkitt’s lymphoma Burkitt’s-lymphoma
11. High-malignancy B-cell lymphoma, Burkitt-like Centroblastic, immunoblastic lymphoma

#
T-Cell and Natural Killer-Cell Lymphomas
I. Precursor T-cell neoplasias
Precursor T-lymphoblastic lymphoma /leukemia T-lymphoblastic lymphoma
II. Peripheral T-cell and NK-cell neoplasias

1. T-CLL /T-PLL (prolymphocytic leukemia) T-lymphocytic lymphoma, CLL-type, PLL-type

2. Large cell granular lymphocyte leukemia
a) T-cell type; b) NK-cell type
3. Mycosis fungoides/Sézary syndrome
4. Peripheral T-cell lymphomas,
subcutanous panniculitic lymphoma (preliminary),
hepatosplenic !-"-lymphoma (preliminary)
5. Angioimmunoblastic T-cell lymphoma
6. Angiocentric lymphoma
7. Intestinal T-cell lymphoma (+/- enteropathy)
8. Adult T-cell lymphoma/leukemia, HTLV1+
9. Anaplastic large cell lymphoma (T and null)
T-lymphocytic lymphoma, CLL-type
Mycosis fungoides, Sézary syndrome
T-zone lymphoma, lymphoepitelioid lymphoma,
Pleomorphic small/large cell lymphoma,
T-immunoblastic lymphoma
Angioimmunoblastic lymphoma (AILD, LgX)
Pleomorphic HTLV1+ lymphoma
Anaplastic large cell T-cell lymphoma (Ki1+)

Hodgkin’s Lymphoma
I. Lymphocyte-predominante type
II. Nodular-sclerosis type Nodular sclerosis type

"
III. Mixed cellularity type Mixed cellularity type
IV. Lymphocyte depletion type Lymphocyte-depletion type
V. Lymphocyte-rich classic type Lymphocyte-predominante type

1. REAL classification 2. Kiel classification

A. Lymphoma entities: REAL classification vs. Kiel classification
CDC

#
! 1)7$%'/'(+,$/ 9+2)$2)2
!" #$%&'()*)%+, -'.)/
!"#$ %&' ($)*+ ),-$* .- /)+ ,.*+- 0$+1*.2$03 -4$
5)-4"6$7$+.+ ", 8"069.7:+ 0.+$)+$ +-.;; 4)+ 7"-
2$$7 ,<;;( $=5;).7$0> ?4$ 14)*)1-$*.+-.1 !$$0@
"-$*72$*6 AB!C 1$;;+ "* #"069.7:+ $.+$)+$ A8DC
1$;;+ A2.7<1;$)* "* 5";(7<1;$)* 1$;;+ /.-4 ;)*6$
7<1;$";. )70 ) 2*")03 2*.64- 1(-"5;)+#C 1"#E
5*.+$ "7;( %@F G ", -4$ -"-); 1$;; 5"5<;)-."7 ",
)7 ),,$1-$0 ;(#54 7"0$> ?4$ *$+- .+ ) H)*.$6)-$0
.7,.;-*)-$ 1"7+.+-.76 ", ;(#54"1(-$+3 4.+-."1(-$+3
$"+.7"54.;+3 5;)+#) 1$;;+3 )70 ,.2*"2;)+-+> I;"E
7); -*)7+;"1)-."7 ", 6$7$+ ,"* 4$)H( .##<7"E
6;"2<;.7 14).7+ /)+ ,"<70 .7 ) 7<#2$* ", B!
1$;;+> ?4.+ ,.70.76 .70.1)-$+ -4)- -4$ 1$;;+ )*$
", J ;(#54"1(-$ "*.6.7> ?4$ K5+-$.7@J)** H.*);
3/+*+,$/ @77A*'/'(6
6$7"#$ 1)7 2$ 0$-$1-$0 .7 -4$ B! 1$;;+ .7
L' G ", 1)+$+3 )70 +-*"76 $=5*$++."7 ", JE1$;;
)7-.6$7+ 1)7 );+" 2$ "2+$*H$0> M- .+ -4$*$,"*$
<70.+5<-$0 -4)- -4$ ;(#54"1(-$E5*$0"#.7)7-
-(5$ AJ>%C 1"**$+5"70+ -" ) JE1$;; ;(#54"#)>
N"7$-4$;$++3 +"#$ *)*$ 8DOB! 1$;;+ $=4.2.-
,$)-<*$+ ", )1-.H)-$0 ? 1$;;+3 /4$*$)+ "-4$* $=E
5*$++ )7-.6$7+ -(5.1); ", 0$70*.-.1 1$;;+3 $>6>3
IDPQ )70 5LL> B! 1$;;+ );+" 5"++$++ );; #";$E
1<;$+ *$R<.*$0 ,"* )7-.6$7 5*$+$7-)-."7S 1;)++
"
M )70 MM T8I #";$1<;$+3 1"E+-.#<;)-"*( )7-.E
6$7+ IDP' )70 IDP&3 )70 )04$+."7 #";$1<;$+
IDLU )70 IDLP> IDQ' .7-$*)1-+ /.-4 IDQ'V3 )7
)7-.6$7 $=5*$++$0 2( ? ;(#54"1(-$+3 #"7"E
1(-$+3 )70 #)1*"54)6$+> ?4.+3 .7 -<*73 .70<1$+
-4$ +$1*$-."7 ", 1(-"9.7$+ 2( B! 1$;;+> MVEL3
)70 5)*-.1<;)*;( $"-)=.73 )*$ *$+5"7+.2;$ ,"*
$"+.7"54.;.1 .7,.;-*)-."7> MVE%3 MVE&3 )70 MVEW )1-
)+ )<-"1*.7$ )70 5)*)1*.7$ 6*"/-4 ,)1-"*+> X2E
7"*#); <5*$6<;)-."7 ", -4$ -*)7+1*.5-."7 ,)1-"*
NY!J .+ ) -(5.1); 4);;#)*9 ", -4$ 0.+$)+$ )70
1"7-*.2<-$+ -" -4$ <5*$6<;)-."7 ", 1(-"9.7$ 5*"E
0<1-."7> Y.2*"+.+3 ) -(5.1); ,$)-<*$ ", 8"069.7:+
0.+$)+$3 .+ 1)<+$0 2( MVE% )70 ?ZYE">
0" 1+2%'/'(+,$/ 3/$22+4+,$%+'*
N"0<;)* +1;$*"+.+ .+ -4$ #"+- 1"##"7 +<2-(5$
", 8"069.7:+ 0.+$)+$ )70 .+ 14)*)1-$*.[$0 2(
1";;)6$7 2)70+ /.-4 H)*."<+ 0$6*$$+ ", +1;$*"E
+.+> N"0<;)* +1;$*"+.+ 8D 4)+ ) 6""0 5*"67"+.+>
M7 ;(#54"1(-$E5*$0"#.7)7- +<2-(5$+ A!"#"$
%#"&'()*"+C3 "7;( ) ,$/ B! 1$;;+ )*$ 5*$+$7->
!
?4.+ +<2-(5$ .+ 1;$)*;( ", JE1$;; "*.6.73 .- +4"/+
) +;"/ 6*"/-4 -$70$71( )70 4)+ )7 $=1$;;$7-
5*"67"+.+> V(#54"1(-$ 0$5;$-."7 .+ -4$ ;$)+-
<71"##"7 +<2-(5$> ?4.+ ,"*# ", 8"069.7:+
0.+$)+$ .+ #"*54";"6.1);;( +.#.;)* -" ) 0.,,$*$7-
BCD $7-.-(3 -4$ ;)*6$E1$;; )7)5;)+-.1 ;(#54"#) A+$$
5> %QLC> X7( H)*.)7- 7"- #)-14.76 "7$ ", -4$+$
-4*$$ -(5$+ .+ 0$,.7$0 )+ #.=$0 1$;;<;)*.-(
8"069.7:+ 0.+$)+$>
3" 5678%'72
\).7;$++ $7;)*6$#$7- ", -4$ ;(#54 7"0$+ .+
1"##"7 .7 8"069.7:+ 0.+$)+$> ?4$ 5*$+$7-.76
+(#5-"#+ )*$ *$1<**$7- ,$H$*3 7.64- +/$)-+3
)70 /$.64- ;"++ A]J +(#5-"#+^C .7 %'@L'G
", 5)-.$7-+3 0$5$70.76 "7 -4$ +-)6$ ", -4$
0.+$)+$> M7 )0H)71$0 +-)6$+3 -4$ #)7.,$+-)-."7+
", 8"069.7:+ 0.+$)+$ 2$1"#$ #"*$ )70 #"*$
5*"7"<71$0 .7 $=-*);(#54)-.1 "*6)7+3 +<14 )+
-4$ ;.H$*3 2"7$ #)**"/3 2"7$3 ;<76+3 )70 +9.7>
9" :$;'<$%'<6 =+*.+*(2
?4$ -(5.1); +.67+ ", .7,;)##)-."7 .7 8"069.7:+
0.+$)+$ .71;<0$ ) 4.64 $*(-4*"1(-$ +$0.#$7-)E
-."7 *)-$ AK!BC3 )7$#.)3 .*"7 0$,.1.$71(3 )70
$;$H)-$0 #FE6;"2<;.73 ,$**.-.73 )70 1"55$* ;$H$;+>
N$<-*"54.;.) "* #"7"1(-"+.+ .+ 1"##"7> K"E
+.7"54.;.) .+ *)*$ 2<- 1)7 2$ $=-*$#$> V(#54"E
1(-"5$7.) "11<*+ .7 #"*$ -4)7 Q' G ", 5)-.$7-+>
X +";<2;$ ,"*# ", IDQ' )7-.6$7 A+IDQ'C .+ "1E
1)+."7);;( 5*$+$7- .7 +$*<#> K;$H)-$0 +IDQ'
;$H$;+ 1"**$;)-$ /.-4 -4$ +-)6$ ", 0.+$)+$> ?4.+
,.70.76 .+ ) 7$6)-.H$ 5*"67"+-.1 ,)1-"*_ +" .+
-4$ 1"71$7-*)-."7 ", +";<2;$ MVEF *$1$5-"*
A+IDFLC .7 +$*<#>
>" ?&)<$86
T"+- 5)-.$7-+ /.-4 8"069.7:+ 0.+$)+$ 1)7 7"/
2$ 1<*$0> ?4$ 5*"67"+.+ 0$5$70+ "7 -4$ 0$6*$$
", +5*$)0 )70 -4$ 5*$+$71$ ", *.+9 ,)1-"*+ A$>6>3
;)*6$ #$0.)+-.7); -<#"*3 $=-*)7"0); .7H";H$E
#$7-3 #)++.H$ +5;$7.1 .7H";H$#$7-3 $;$H)-$0
K!BC> `4$7 +-)*-$0 .7 $)*;( +-)6$+3 *)0."-4$*E
)5( ;$)0+ -" *$#.++."7 .7 1)> P' G ", 5)-.$7-+
/.-4"<- *.+9 ,)1-"*+> J"-4 -4$ ),,$1-$0 )70
-4$ )0a)1$7- ;(#54 7"0$ *$6."7+ )*$ ",-$7 .**)E
0.)-$0 .7 -4$ +"E1);;$0 ]<55$* #)7-;$ ,.$;0^ )70
].7H$*-$0 b ,.$;0^ 5*"-"1";+ A%C> \";(14$#"-4$*E
)5( .+ 5$*,"*#$0 .7 )0H)71$0 0.+$)+$ "* .7
4.64E*.+9 5)-.$7-+> 8.64E0"+$ 14$#"-4$*)5(
/.-4 )<-";"6"<+ +-$# 1$;; -*)7+5;)7-)-."7
#)( 2$ .70.1)-$0 ., *$;)5+$ "11<*+> K=5$*.#$7E
-); -*$)-#$7- +-*)-$6.$+ )*$ 7"/ 2$.76 -$+-$0>
c7$ ", -4$+$ .+ 2)+$0 "7 ,-+!./-0-/ "&1-,)2-.+
-4)- 2*.76 1(-"-"=.1 ? 1$;;+ -" IDQ'd 8"069.7:+
1$;;+ A-)*6$-.76C A&C>
 T cell ?
CD30L
1'.(E+*F2 9+2)$2)
!
CD30
CD15
EBV
CD25
? CD71
HLA-DR
(CD20) Cytokine
B cell Activated (CD2) secretion
VH -
B cell (CD3)
genes
(CD4)
Monocyte/ Reed-
dendritic ? Sternberg
cell cell
A. Pathogenetic model

3/+*+,$/ @77A*'/'(6
Lymphocyte pre- Nodular sclerosis Mixed cellularity type Lymphocyte-depletion
dominant type ca.12% type ca. 46% ca. 31% type ca. 10%
B. Histological classification

B-symptoms:

–Fever > 38°C

–Weight loss- > 10%
–Night sweats
Liver

Bone marrow/
bone
–Anemia
–Leukocytosis
–Thrombocytosis
–Eosinophilia
"
Lung,
pleura,
pericardium Signs of
inflammation
–Pruritus
– Itching Skin Erythrocyte
–“Alcohol pain” sedimentation
–Bone pain
Extranodal
C. Symptoms manifestations D. Laboratory findings

– Adriamycin – Cyclophosphamide CD3 CD30

– Bleomycin – Oncovin (Vincristine)
– Vinblastine – Procarbacine
– Dacarbazine – Prednisone
Upper
mantle field T cell
BEACOPP E = etoposide

Inverted Y High-dose Autologous

!
chemo- stem cell
Bispecific Hodgkin’s
therapy transplantation
antibody cell

1. Radiotherapy 2. Polychemotherapy 3. Experimental

approaches
E. Therapy
BCC

"
! =%.34)2)>5&32 ?5(%3(%(
!" #$%&'$()$ *+,-./0)123(45&
,-./0).36,%'7%.53 8*+,9,:
!"#$%&'()*+,- ("#$%&#)* $.,#).,(" ).,*/ 0.&#
+%/ ("#$% 1&2/* )12 ()+/. -&(&1,3/ +%/ '&1/
#)..&45 4%/./)* ("#$%&'()*+,- (/67/#,)* $.,8
#).,(" ).,*/ 0.&# +%/ '&1/ #)..&4 )12 ()+/.
,10,(+.)+/ +%/ ("#$% 1&2/*9 :,1-/ ,+ ,* &0+/1 2,08
0,-6(+ +& 2,*+,1;6,*% '/+4//1 +%/ +4&5 (/67/#,)
,* 2,);1&*/2 4%/1 ("#$% -/((* -&#$.,*/ #&./
+%)1 <= > &0 +%/ -/(( $&$6()+,&1 4,+%,1 +%/ '&1/
#)..&49 ?8-/(( ("#$%&'()*+,- ("#$%&#)* -&#8
$.,*/ ).&612 @A > &0 )(( ("#$%&#) -)*/* ,1 -%,(8
2./19 B1 )26(+*5 &1 +%/ &+%/. %)125 +%/" -&#8
$.,*/ &1(" ).&612 < > &0 )(( 1&18C&2;7,1D*
("#$%&#)* EFC!G )12 ).&612 H= > &0 )(( )-6+/
;25@5&32 A..'@)2)>-
("#$%)+,- (/67/#,)*9 I&61; #/1 )./ #&*+
-&##&1(" )00/-+/29 ?%/" $./*/1+ 4,+% .)$,2("
;.&4,1; #/2,)*+,1)( #)**/* E).,*,1; 0.&# +%/
+%"#6*G )12J&. $/.,$%/.)( ("#$%)2/1&$)+%"9
B0 (/0+ 61+./)+/25 +%/ ("#$%&#) -/(( -&1+/1+*
)./ ./(/)*/2 0.&# +%/ ("#$% 1&2/* )12 +%/ 2,*8
/)*/ .)$,2(" $.&;./**/* +& 2/)+%9 !"#$%&'()*+*
).,*/ 0.&# +%"#&-"+/*K +%/" %)L/ .&612 16-(/,
4,+% *#)(( M6)1+,+,/* &0 -"+&$()*#9 ?%/ +6#&.
-/((* /N$./** OPQ )12 OPR ,1 +%/ -"+&$()*# &.
"
&1 +%/ -/(( *6.0)-/9 ?%/ /N$./**,&1 &0 &+%/.
?8-/(( #).7/.*5 *6-% )* OP< )12 OP=5 ,* L).,)'(/9
?%/ /13"#/ +/.#,1)( 2/&N"16-(/&+,2"( +.)1*8
0/.)*/ E?2+G ,* +"$,-)((" /N$./**/2 ,1 +%/ 168
-(/6*9 S;;./**,L/ -%/#&+%/.)$" -)1 -6./ +%,*
&+%/.4,*/ 0)+)( 2,*/)*/9
9" #%$5/0%$32 *+;%22 <%)/23(.(
! ?8-/(( -%.&1,- ("#$%&-"+,- (/67/#,) E?8O!!G
,* ) .)./ 0&.# &0 1&18C&2;7,1D* ("#$%&#)9
B1 #&*+ -)*/ &0 ?8O!!5 +%/ -/((* %)L/ ,../;6().
16-(/, 4,+% $.&#,1/1+ 16-(/&(, )12 ) ./()8
+,L/(" '.&)2 -"+&$()*#9 ?%/" )./ +%/./0&./
-()**,0,/2 )* $.&("#$%&-"+/*9 ?%/ 2,*/)*/
,* ,12,*+,1;6,*%)'(/ 0.&# ?8-/(( $.&("#$%&8
-"+,- (/67/#,) E?8T!!G9 ?%/ ("#$%&-"+/*
6*6)((" ,10,(+.)+/ +%/ '&1/ #)..&45 *$(//15 (,8
L/.5 )12 ("#$% 1&2/*5 '6+ #)" )(*& ,10,(+.)+/
*7,1 )12 #6-&*)/9 !"#$%&-"+/ -&61+* &0
&L/. HAA AAAJ##R )./ &0+/1 &'*/.L/29 ?%/
(/67/#,- -/((* /N$./** +%/ ?8-/(( #).7/.*
OP<5 OPR5 OP=5 OPQ )125 ,1 #&*+ -)*/*5
!
OP@ EU= >GK +%/ -&1-&#,+)1+ /N$./**,&1 &0
OP@ )12 OPV ,* &--)*,&1)((" &'*/.L/29 B18
L/.*,&1 &0 -%.&#&*&#/ H@ EMHHWMR<G ,*
0&612 ,1 Q= > &0 -)*/*K +.,*&#" V %)* )(*&
'//1 ./$&.+/29 ?%/ $.&;1&*,* ,* 610)L&.)'(/5
BCD ,1 0)-+5 #6-% 4&.*/ +%)1 +%)+ &0 -%.&1,-
X8-/(( ("#$%&-"+,- (/67/#,)9
" !).;/ ;.)16(). ("#$%&-"+/ E!Y!G (/67/#,)
).,*/* 0.&# -,.-6()+,1; OPVZ ? -/((* &. F[
-/((*9 \&2/.)+/ (/67&-"+&*,* E("#$%&-"+/
-&61+* &0 6$ +& <A AAAJ##RG ,* ) +"$,-)( 0,128
,1; +%)+ ,* &0+/1 )**&-,)+/2 4,+% 1/6+.&$/1,)9
S1/#,) )12 #,(2 *$(/1&#/;)(" 6*6)((" &-8
-6. ,1 +%/ ?8-/(( *6'+"$/9 ?%/ -&6.*/ &0 2,*8
/)*/ ,* #,(25 4,+% -"+&$/1,) '/,1; +%/ #&*+
-&##&1 -)6*/ &0 *"#$+&#*9 ?%/ +6#&. -/((*
%)L/ )1 /--/1+.,-5 .&612,*% +& &L)( 16-(/6*
4,+%,1 ) $)(/ '(6,*% -"+&$()*# -&1+),1,1;
)36.&$%,(,- ;.)16(/*9 ?%/ $%/1&+"$/ &0 +%/
?8-/(( *6'+"$/ EOPRZ5 OPVZ5 OPHUZ5 ?O]!"ZG
-&../*$&12* +& -"+&+&N,- ? -/((*9 ?%)+ &0 +%/
F[ *6'+"$/5 &1 +%/ &+%/. %)125 ,* OPR85
?O]!"85 OP=UZJ85 OPHUZ5 )12 OPVZJ89
# !"#$%&% '()*$&+,%5 ) -6+)1/&6* ("#$%&#)5
)12 -/^./0" %")+0$1,5 ,+* ;/1/.)(,3/2 -&618
+/.$).+5 ).,*/ 0.&# $/.,$%/.)( /$,2/.#&+.&8
$,- OP@Z ? -/((*9 ?%/ $)+,/1+* $./*/1+ 4,+%
$.6.,+,- /-3/#)5 4%,-% ()+/. +.)1*0&.#*
,1+& -6+)1/&6* $()M6/* &. 1&26(/*9 T)+,/1+*
4,+% :/^3)." *"12.&#/ 2/L/(&$ 2,006*/ /."8
+%.&2/.#) E2$11, 0$(*,G5 4%,-% ,* *&#/8
+,#/* 61'/).)'(" $.6.,+,-9 C,;% 16#'/.*
&0 ("#$%&#) -/((* -,.-6()+/ ,1 +%/ '(&&2 ,1
:/^3)." *"12.&#/5 '6+ &1(" ,*&()+/2 -/((* &-8
-6. ,1 #"-&*,* 061;&,2/*9 S1)$()*+,- ().;/8
-/(( ("#$%&#) ES!O!G #)" 2/L/(&$ )* +%/
2,*/)*/ $.&;./**/*9 C,*+&(&;,-)( *+62,/* ./8
L/)( +%/ $./*/1-/ &0 *#)(( ("#$%&-"+/*
4,+% -/./'.,0&.# 16-(/, ,1 ,10,(+.)+/* 0.&#
+%/ *7,1 )12 $).)-&.+/N &0 ("#$% 1&2/*9
?%/ +6#&. -/((* /N$./** OP<5 OPR5 OP=
)125 ,1 #&*+ -)*/*5 OP@9
$ 3,0&42,0/5 67#,55 5"142$1/% -)1 ).,*/ 0.&#
$/.,$%/.)( ?-/((* )+ L).,&6* *+);/* &0 #)+6.)8
+,&19 ?%/*/ 1/&$()*#* -&#$.,*/ -)9 HA > &0 )((
FC!9 ?%,* ,* ) %/+/.&;/1/&6* '6+ *+,(( $.&L,8
*,&1)((" 2/0,1/2 ;.&6$ &0 ("#$%&#)*9 ?%/
+6#&. -/((* &0+/1 %)L/ ,../;6(). 16-(/, )12
)./ ;./)+(" L).,)'(/ ,1 *,3/9 ?8-/(( #).7/.*
)./ L).,)'(" $.&1&61-/29 \&*+ &0 +%/ +6#&.
-/((* )./ OP@Z9 :&#/ %)L/ ) %,;% -&1+/1+ &0
/$,+%/(,&,2 -/((* E!/11/.+D* ("#$%&#) &.
("#$%&/$,+%/(,&,2 ("#$%&#)G9 C/$)+&*$(/8
1,- #J$ ("#$%&#) ,* -%).)-+/.,3/2 '" /N+/18
*,L/ ,10,(+.)+,&1 &0 +%/ (,L/. )12 *$(//19 _18
(,7/ #&*+ &+%/. ("#$%&#)*5 +%/ ("#$%&#)
-/((* /N$./** #J$ ?8-/(( ./-/$+&.*9
% `+%/. $/.,$%/.)( ("#$%&#)* )./ (,*+/2 */$)8
.)+/(" '/-)6*/ +%/" ./$./*/1+ -(,1,-)((" 4/((
2/0,1/2 /1+,+,/*9 8)*&$&11()$95/%:&# 67#,55
5"142$1/ #)1,0/*+* 4,+% *"#$+&#* &0 ;/18
/.)(,3/2 ("#$%)2/1&$)+%" ,1 -&1a61-+,&1
 4,+% 0/L/.5 4/,;%+ (&**5 *7,1 ./21/**5 )12
$&("-(&1)( %"$/.;)##);(&'6(,1/#,)9 ?%,*
*+;%22 ,-./0).3(

$.&;1&*,*9 ?%/ +6#&. -/((* )./ ().;/5 -"+&8

2,*/)*/ ,* )(*& ./0/../2 +& )* /)*&$&11()$7
95/%:&# 5"142/+,)$4/:2" ;&:2 +"%40$:,&),1&/
ESB!PG9 ?%/ ("#$% 1&2/ ).-%,+/-+6./ ,* 2/8
*+.&"/25 +%/ *,16* ,* 2,()+/25 )12 +%/ ,10,(8
+.)+/* $/1/+.)+/ +%.&6;% +%/ -)$*6(/ ,1+&
+%/ $/.,1&2)( 0)++" +,**6/9 S;;./;)+/* &0 0&(8
(,-6(). 2/12.,+,- -/((* EbPOG *6..&612 $.&(,0/.8
)+,1;5 '.)1-%,1; L/16(/*9 ?%/ +6#&. -/((* /N8
%,',+ +.)1*(&-)+,&1 &0 +%/ ?8-/(( ./-/$+&.9 ?%/"
/N$./** ?8-/(( #).7/.* )12 )./ 6*6)((" OP@Z9
C,;%8;.)2/ #)(,;1)1+ ?8-/(( &. X8-/(( ("#8
$%&#)* #)" &--)*,&1)((" 2/L/(&$9
& 8)*&$#,):0&# 5"142$1/% $./*6#)'(" ).,*/
$()*#8.,-% '()*+* +%)+ &0+/1 %)L/ %&.*/8
!
*%&/8*%)$/2 &. #6(+,$(/ 16-(/,5 /)-% 4,+%
#6(+,$(/ 16-(/&(,9 ?%/ #6(+,16-(/)+/ 0&.#*
*&#/+,#/* ./*/#'(/ ]//2h:+/.1'/.; -/((*9
?%/ #)a&.,+" &0 +%/*/ +6#&.* %)L/ ?8-/((8)*8
*&-,)+/2 #).7/.* EOPRZJ85 OP<=ZJ8GK ./)..)1;/8
#/1+ &0 +%/ ?8-/(( ./-/$+&. ,* &'*/.L/2 ,1
&L/. =A >9 S(&1; 4,+% OPRA5 +%/ +6#&. -/((*
)(*& /N$./** /$,+%/(,)( #/#'.)1/ )1+,;/1
Eg\SG9 T.,#)." *"*+/#,- S!O! ,* &0+/1 )**&8
-,)+/2 4,+% <W= +.)1*(&-)+,&1 ,1 4%,-% +%/
16-(/&$%&*#,1 ;/1/ FT\5 ) -/(( -"-(/8./;68
()+,1; 16-(/&(). $.&+/,15 06*/* 4,+% ) 7,1)*/
'/(&1;,1; +& +%/ 0)#,(" &0 ,1*6(,1 ./-/$+&.*

;25@5&32 A..'@)2)>-
0.&# F[ -/((* &. ? -/((*K +%/" )00/-+ +%/ E)1)$()*+,- ("#$%&#) 7,1)*/5 S![G +& ;,L/
1&*/5 $)()+/5 )12 *7,19 ?%/*/ ("#$%&#)* &.,;,1 +& +%/ FT\8S![ 06*,&1 $.&+/,19 S(+/.)8
#)" '/ ,12&(/1+ &. );;./**,L/9 B10,(+.)+/* -&18 +,&1* &0 +%/ 7,1)*/ ,* )**6#/2 +& $()" ) .&(/ ,1
+),1,1; *#)(( ("#$%&-"+/* )12 )+"$,-)( ("#8 +%/ ("#$%&#) ;/1/*,*9
$%&,2 -/((* )./ 6*6)((" 0&6129 ?%/ L)*-6(). (68
#/1 '/-&#/* */)(/2 &005 +%6* (/)2,1; +&
,*-%/#,- 1/-.&*,*9 ?%/ +6#&. -/((* /N$./**
OP< )125 ,1 #)1" -)*/*5 OPQ )12 OP=9
?%/" )./ *&#/+,#/* OPR8 )12 OP=UZ9
' <):,%:&)/5 67#,55 5"142$1/% #&*+ -&##&1("
&--6. ,1 $)+,/1+* 4,+% ) %,*+&." &0 ;(6+/18*/18
*,+,L/ /1+/.&$)+%"9 ?%/ /1+,+" 4)* 0&.#/.("
-)((/2 c#)(,;1)1+ ,1+/*+,1)( %,*+,&-"+&*,*9d
?%/ $)+,/1+* %)L/ #6(+,0&-)( #)(,;1)1+ 6(8
-/.* ,1 +%/ a/a616# +%)+ +/12 +& $/.0&.)+/9
?%/ ("#$%&#)* -&1+),1 ) #,N+6./ &0 -/((*
"
&0 2,00/./1+ *,3/*9 ?%/ )'1&.#)( -/((* )./
OPRZ )12 OPQZ )12 *&#/+,#/* OPVZ9 ?%/"
#)" )(*& /N$./** OPHAR5 ) #6-&*)( ?8-/((8)*8
*&-,)+/2 )1+,;/19
( 8+(5: 67#,55 5"142$1/=5,(>,1&/ ,* -)6*/2 '"
C?!eH5 +%/ %6#)1 ? -/(( ("#$%&+.&$,- L,.6*9
?%,* /1+,+" #),1(" &--6.* ,1 f)$)1 )12 +%/
O).,''/)15 '6+ )(*& &--6.* *$&.)2,-)((" ,1
g6.&$/9 ?%/ -&6.*/ &0 2,*/)*/ ,* 6*6)((" )-6+/5
4,+% */L/./ (/67&-"+&*,*5 %/$)+&*$(/1&#/8
;)("5 %"$/.-)(-/#,)5 )12 &*+/&("*,*9 ?%/
#/)1 *6.L,L)( +,#/ ,* (/** +%)1 &1/ "/).9 O/((*
4,+% #6(+,(&'6().5 -(&L/.(,7/ 16-(/, )./ $./8
*/1+ ,1 +%/ $/.,$%/.)( '(&&29 ?%/ +6#&. -/((*
/N$./** OPR5 OP<5 OP@5 )12 OP<=5 )12 )./
OPQ81/;)+,L/9 S -%.&1,- 0&.# -%).)-+/.,3/2

!
'" (/** */L/./ (/67&-"+&*,* )12 ) ()-7 &0 %/8
$)+&*$(/1&#/;)(" )12 &*+/&("*,* %)* ) *&#/8
4%)+ '/++/. $.&;1&*,*9
) 8)/45/%:&# 5/0*,7#,55 5"142$1/% ?8@A@B ).,*/
0.&# OPRAZ /N+.)0&((,-6(). '()*+*9 ?%/ 2,*/)*/
#)" '/ $.,#).,(" *"*+/#,- &. -6+)1/&6*5 &.
#)" &--6. )* ) */-&12)." 1/&$()*#9 ?%/ $.,8 BCE

"
#)." -6+)1/&6* *6'+"$/ %)* ) #6-% '/++/.
! =%.34)2)>5&32 ?5(%3(%(

Thymus
2% 1. T-CLL (<1%)

CD7+
–Mediastinum
CD3+
–Bone marrow CD7+
TdT+ CD2+/-
–Blood CD2+
CD5+/-
–Lymph nodes CD3+
CD1a+/-
CD5+
Bone marrow CD4+(65%)

A. Precursor T-lymphoblastic lymphoma/leukemia

CD4+8+(25%)
;25@5&32 A..'@)2)>-

Circulating peripheral cell

"
Peripheral CD4+ T-cell

Extrafollicular
CD30+ blasts
HTLV-1-infection

CD2+
CD3+ CD30+
CD3+
CD7+ CD25+/-
CD5+
CD8+/- CD3+/+
CD4+
CD103+ EMA+/-
CD25+
HTLV1 genome

!
BCF
7. Intestinal
7. T-cell lymphoma (<1%)

B. Peripheral T-cell neoplasms

9. Anaplastic large-cell
9. lymphoma ALCL (~2.5%)
8. Adult T-cell lymphoma/
8. leukemia (<1%)
2a) Large granular 2b) Large granular
*+;%22 ,-./0).3(

3) Mycosis fungoides/
!
2a) lymphocyte leukemia 2b. lymphocyte leukemia 3. Sézary syndrome (<1%)
2a) T-cell type (<1%) 2b. NK-cell type
2b. (<1%)
CD2+
CD3+ CD2+ CD2+
CD8+ CD8+/- CD3+
CD16+ CD16+ CD5+
CD57+/- CD56+/- CD7+(35%)
TCRab+ CD57+/- CD4+(95%)

;25@5&32 A..'@)2)>-
Circulating peripheral Peripheral epidermotrope
CD8+ T cell / NK cell CD4+ T cell

Peripheral T cell in different

"
phases of maturation

? ?

NK or T cell? Peripheral T cell CD3+/-

CD2+/-
CD5+/-
CD7-/+
CD4>CD8
4. Peripheral T-cell
Cytokine+++ 4. lymphoma (~10%)
CD3+/- a) Medium cell
CD2+
CD5+/- CD2+/- b) Medium and large cell
CD7+/- CD5+/- c) Large cell
CD3+/+ CD4+/-
d) Lymphoepithelioid
CD56+

6. Angiocentric
6. lymphoma (~1%)
5. Angioimmunoblastic
5. T-cell lymphoma (~1%)
e) Hepatosplenic
e) !" lymphoma
f) Subcutaneous panni-
f) culitic lymphoma !
BCG

"
! 5%/36)-)70&3- 80(%3(%(
!" #$%&'$()$ *+,%-- .'/)$(
!"#$%&'()* +)'"&'"' ),-#%-),. $/"*0/'#/ 1 *"%%'
*&, 2&,)3"'( 4)(5 (5" *%),)*&% $)*(0/" #3 &*0("
%62$5#7%&'()* %"08"2)& 4)(5 7#," 2&//#4 ),9
3)%(/&()#, &,+ %"08"2)* 7%##+ $)*(0/": ;, *5)%9
+/",< (5" +)'"&'" )' 3/"=0",(%6 *5&/&*("/)>"+
76 (02#/#0' '4"%%),. #3 %62$5 ,#+"' &,+
'8), ),3)%(/&()#,< 4)(5 #/ 4)(5#0( 7#," 2&//#4
),-#%-"2",(: ;, (5" %&(("/ *&'"< (5" %"08"2)*
*#0/'" &''#*)&("+ 4)(5 7#," 2&//#4 ),3)%(/&9
()#, +"-"%#$' ), (5" %&("/ '(&."': ?5" (02#/
*"%%' "@$/"'' 19*"%%9'$"*)3)* &,().",'< '0*5 &'
ABCD< *6(#$%&'2)* ABEE< &,+ ABFD&: ;, 2&,6
*&'"'< ABCGH*#22#, IJJ &,().", )' &%'# $#')9
()-": ?5)' *#//"'$#,+' (# & '07./#0$ #3 %"08"9
,-090&3- ://'9)-)7;
2)&' 4)(5 & /"%&()-"%6 3&-#/&7%" $/#.,#')' ),
*5)%+/",< 70( ,#( ), &+0%(': ?5" "@$/"'')#, #3
'0/3&*" )220,#.%#70%),' 76 (5" %62$5#2&H
%"08"2)& *"%%' /"3%"*(' & -"/6 $##/ $/#.,#')':
?/&,'%#*&()#,' ),-#%-),. *5/#2#'#2"' C &,+
CD &,+H#/ *5/#2#'#2"' D &,+ EE #/ *5&,."'
), *5/#2#'#2" CC= &/" &%'# &''#*)&("+ 4)(5
& -"/6 $##/ $/#.,#')':
*" #%$012%$3- *+,%-- 4%)1-3(/(
" ! I/#0,+ KG L #3 &%% ,#,9M#+.8),N' %62$5#9
2&' &/" $"/)$5"/&% 19*"%% ,"#$%&'2': B)'9
"&'"' '0*5 &' *5/#,)* %62$5#*6()* %"08"2)&
O19AJJP #/ $/#%62$5#*6()* %"08"2)& O19QJJP
0'0&%%6 $/#+0*" %&/." ,027"/' #3 %"08#*6("'
), (5" $"/)$5"/&% 7%##+ &,+ "@(",')-" 7#,"
2&//#4 ),3)%(/&()#,: ?5" %62$5 ,#+"'<
'$%"",< &,+ %)-"/ 2&6 7" ),-#%-"+: R#'( 19
AJJ (02#/ *"%%' &/" '2&%% %62$5#*6("'
4)(5 /#0,+ ,0*%"): QJJ *"%%' &/" %&/."/ &,+
5&-" & $/#2),",( *",(/&% ,0*%"#%0': Q/#9
%62$5#*6()* %"08"2)& )' &''#*)&("+ 4)(5
'"-"/" '$%",#2".&%6 &,+ &../"'')-" 7"5&9
-)#/< 45"/"&' *5/#,)* %62$5#*6()* %"08"2)&
#3(", 5&' & '%#4%6 $/#./"'')-"< ),+#%",(
*#0/'": AJJ *"%%' "@$/"'' (5" *%&'')*&% 19*"%%
2&/8"/' ABCD< ABEG< &,+ ABEE< 70( &%'# (69
$)*&%%6 "@$/"'' ABES &,+ ABT O& ?9*"%%9&''#9
*)&("+ &,().",P: U0/3&*" )220,#.%#70%),'
&/" #,%6 4"&8%6 "@$/"''"+: AJJ )' 0'0&%%6 +)9
&.,#'"+ 76 7%##+ '2"&/ &,+H#/ 7#," 2&/9
/#4 *6(#%#.6: ;(' 5)'(#%#.)*&% *#//"%&()-" ),
!
(5" %62$5 ,#+" )' %62$5#*6()* %62$5#2&:
A5/#2#'#2" CS +"%"()#, #/ (/)'#26 CE #*9
*0/' ), &$$/#@)2&("%6 SG L #3 *&'"': B"%"()#,
#3 *5/#2#'#2" CF$ )' &''#*)&("+ 4)(5 & $##/
$/#.,#')':
<=> " !"#$%&'"()' $*+,#+'"(&)- *"#$%&#+, O)#.
#/0&'"(&#+,P &/)'" 3/#2 '2&%% %62$5#)+
*"%%' (5&( 5&-" 7".0, (# +)33"/",()&(" ),(#
$%&'2& *"%%': R#'( *&'"' *#//"'$#,+ (# (5"
*%),)*&% $)*(0/" #3 V&%+",'(/#W2N' 2&*/#9
.%#70%),"2)& O'"" $: CXS#P: I**#/+),.%6< &,
;.R *%&'' 2#,#*%#,&% $&/&$/#("), )' #3(",
3#0,+: R#'( (02#/ *"%%' &/" '2&%% %62$5#9
*6("' 4)(5 & +)'(),*( 7&'#$5)%)* *6(#$%&'2<
70( (5"/" )' & -&/)&7%" ,027"/ #3 $%&'2&
*"%%': ?5"'" %62$5#2&' &/" (6$)*&%%6 &''#9
*)&("+ 4)(5 (5" $/"'",*" #3 ),(/&*6(#$%&'2)*
)220,#.%#70%),' O*6(9;.P: B"%"()#,' #3 *5/#9
2#'#2" CC< CS< #/ CF &/" (5" 2#'( *#22#,
."," /"&//&,."2",(': I '07'"( #3 $&()",('
5&' *5/#2#'#2&% (/&,'%#*&()#, (ODYCXP ),9
-#%-),. (5" $+1.2 .",":
$ 3+0(*4 '4** *"#$%&#+ %&/."%6 *#//"'$#,+' (#
*",(/#*6()* %62$5#2& &' +"3),"+ 76 (5" Z)"%
*%&'')3)*&()#,: ?5" (02#/ *"%%' &/" '2&%% (#
2"+)029')>"+ %62$5#*6("' 4)(5 & ,#(*5"+
,0*%"0' &,+< ), '#2" *&'"'< %&/."/ ,0*%"#%):
?5" *"%%' "@$/"'' '0/3&*" )220,#.%#70%),'
&,+ ?9*"%%9&''#*)&("+ &,().", ABT: [-"/"@9
$/"'')#, #3 *6*%), BC< & *"%% *6*%"9&''#*)&("+
$/#("),< #**0/' +0" (# (/&,'%#*&()#, #3 *5/#9
2#'#2"' CC &,+ CX: ?5" +)'"&'" 2&),%6 &39
3"*(' #%+"/ 2", &,+ )' #3(", +)''"2),&("+ 76
(5" ()2" #3 +)&.,#')': ?5" $/#.,#')' )' $##/<
4)(5 &, &-"/&." '0/-)-&% ()2" #3 S\T 6"&/':
% I =0&/("/ #3 &%% !MJ &/" 546#)0+* '40(46 *"#.
$%&#+,< 45)*5 &/)'" 3/#2 ."/2),&% *",("/ 1
*"%%'< *",(/#*6("'< &,+ *",(/#7%&'(': R", &,+
4#2", &/" "=0&%%6 &33"*("+: ?5" *#,(",( #3
*",(/#*6("' &,+ *",(/#7%&'(' -&/)"'< 70( *",9
(/#*6("' &/" 0'0&%%6 3&/ 2#/" $/"+#2),&,(: I
+)330'" ./#4(5 $&(("/, )' &''#*)&("+ 4)(5 &
$##/"/ $/#.,#')': ?5" (02#/ *"%%' &/" $#')9
()-" 3#/ '0/3&*" )220,#.%#70%),' &,+ 3#/
ABCG: ?5" &,()9&$#$(#()* ."," 7'*.8 )' &*()9
-&("+ 76 CX]CK (/&,'%#*&()#,< 45)*5 %"&+'
(# (5" &**020%&()#, #3 %#,.9%)-"+ *",(/#9
*6("':
& 3+65)0+* 9&04 *"#$%&#+, OR^JP &/" 7/#8",
+#4, ),(# (4# '07(6$"'] "@(/&,#+&% &,+ ,#9
+&%: _@(/&,#+&% R^J O'P *#,')'( #3 1 *"%%'
3/#2 20*#'&9&''#*)&("+ %62$5#)+ ()''0"
ORIJ?P: ?5"6 *#2$/)'" &$$/#@)2&("%6 TG L
#3 &%% .&'(/)* %62$5#2&'< *&: XG L #3 &%% #/7)(&%
%62$5#2&'< &,+ (5" 2&`#/)(6 #3 %62$5#2&'
#3 (5" %0,.'< (56/#)+< &,+ '&%)-&/6 .%&,+': ?5"
.&'(/)* %62$5#2&' &/" 0'0&%%6 &''#*)&("+
4)(5 :4*)'&7+'(46 $"*&6) ),3"*()#,< 45)*5 $/#9
-)+"' (5" '()20%&(#/6 &,().", /"'$#,')7%" 3#/
(5" $/#%)3"/&()#, #3 20*#'&% %62$5#*6("':
I,()7&*("/)&% (/"&(2",( *&, &*5)"-" %62$5#9
2& /"./"'')#,: !#+&% 2&/.),&% >#," %629
 $5#2&' O(P &/)'" 3/#2 2#,#*6(#)+ 1 *"%%'
), (5" 2&/.),&% >#," #3 (5" %62$5 ,#+"':
*+,%-- ?;/12)/3(

)' '(/#,.%6 7&'#$5)%)*: ;,3)%(/&()#, 4)(5

?5" ),*)+",*" #3 (5"'" %62$5#2&' )' ),9
*/"&'"+ ), $&()",(' 4)(5 U`#W./",N' '6,+/#2"
O'"" $: CDGP: !#+&% R^J &/" ),+#%",( %62$5#9
2&': ?5" *"%%' &/" $5",#(6$)*&%%6 ')2)%&/ (#
(5#'" #3 "@(/&,#+&% R^J:
) ;$*40)' #+65)0+* 9&04 *"#$%&#+, OUR^JP
&/)'" 3/#2 '2&%% 2"2#/6 1 *"%%' (5&( $#'')7%6
0,+"/.# 2&%).,&,( (/&,'3#/2&()#, ), (5"
'$%"", &3("/ ."/2),&% *",("/ +)33"/",()&()#,
5&' (&8", $%&*": ?5"'" %62$5#2&' 0'0&%%6
),3)%(/&(" (5" 7#," 2&//#4: ?5" (02#/ *"%%'
*)/*0%&(" ), (5" $"/)$5"/&% 7%##+ &' '5&..6<
-)%%#0' %62$5#*6("': R#'( '$%",)* 2&/.),&%
2&*/#$5&."' (5&( $5&.#*6()>" &$#$(#()* (09
!
2#/ *"%%' %"&+' (# (5" (6$)*&% b'(&//6 '86c &$9
$"&/&,*" #7'"/-"+ ), 5)'(#%#.6: 10/8)((N'
%62$5#2&' 3/"=0",(%6 #**0/ ), *5)%+/",: ;,
&+0%('< (5"6 (",+ (# 7" &''#*)&("+ 4)(5 )29
20," +"3"*('< $&/()*0%&/%6 M;d ),3"*()#,':
10/8)((N' %62$5#2& )' ",+"2)* (# I3/)*&<
45"/" 2&,+)70%&/ ),-#%-"2",( )' (6$)*&%:
?5" +)'"&'" 0'0&%%6 ),-#%-"' (/&,'%#*&()#,
#3 (5" *9#"' ."," 3/#2 *5/#2#'#2" K (#
(5" 5"&-6 *5&), ."," /".)#, #, *5/#2#'#2"
CX: ?/&,'%#*&()#, #3 *9#"' (# (5" %).5( *5&),
/".)#, ), E]K #/ K]EE (/&,'%#*&()#, )' %"''
*#22#,:

,-090&3- ://'9)-)7;
>#," %62$5#2&' $/#./"'' -"/6 '%#4%6: !! Q/#%)3"/&(),. $"/)$5"/&% 1 *"%%' 2&6 ),+0*" &
J#,.9("/2 /"2)'')#, *&, 7" &*5)"-"+ 4)(5 5).59./&+" 2&%).,&,( @/6<)((.*)<4 *"#$%&#+:
'$%","*(#26: ?5" 2#/$5#%#.6 &,+ )220,#(6$" #3 (5"'"
* :+)6" '4** *4/<4#)+ )' *5&/&*("/)>"+ 76 (5" %62$5#2&' /"'"27%" (5#'" #3 10/8)((N' %629
$/"'",*" #3 *"%%' 4)(5 -)%%#0' $/#`"*()#,'< $5#2&< 70( *9#"' (/&,'%#*&()#, +#"' ,#( #*9
&, #-&% ,0*%"0'< &,+ & 7/#&+ 2&/.), #3 *6(#9 *0/: ;,'("&+< (/&,'%#*&()#, #3 (5" 7'*.8 .","
$%&'2: ?5)' +)'"&'" )' (6$)*&%%6 *5&/&*("/)>"+ #**0/' ), SG L #3 *&'"':
76 '$%",#2".&%6 &,+ $&,*6(#$",)&: R&/8"+
3)7/#')' #3 (5" 7#," 2&//#4 )' &%2#'( ),-&/)9
&7%6 $/"'",(< 45"/"&' %62$5 ,#+" ),-#%-"9
2",( )' /&(5"/ 0,0'0&%: ?5" 1 *"%%' &/"
'(/#,.%6 $#')()-" 3#/ ABEE &,+ "@$/"'' '0/9
3&*" )220,#.%#70%),': Q#')()-)(6 3#/ ABCGS
)' *5&/&*("/)'()*: ?5)' +)'"&'" /"'$#,+' -"/6
4"%% (# $0/)," &,&%#.0"' &,+ ),("/3"/#,:
+ ?5" a_IJ *%&'')3)*&()#, O'"" $: CSGP +"3),"'
"
$%&'2&*6(#2& &,+ 20%()$%" 26"%#2& O'""
$: CXTP &' 19*"%% ,"#$%&'2' 7"*&0'" (5"6
*&, &%'# &/)'" 3/#2 %62$5#)+ ()''0" &' '#%)9
(&/6 (02#/':
, =)>>/,4 *+654.'4** *"#$%&#+, &/" /"%&()-"%6
*#22#, O*&: SG L #3 &%% !MJP: ?5"6 2&),%6
&33"*( &+0%('< 70( *&, &%'# #**0/ ), *5)%+/",:
?5"'" %62$5#2&' &/)'" 3/#2 $"/)$5"/&%
1 *"%%' &( +)33"/",( '(&."' #3 2&(0/&()#,:
B)330'"< %&/."9*"%% %62$5#2&' &/" -"/6 &.9
./"'')-"< 70( &/" $/),*)$&%%6 *0/&7%" 4)(5
&../"'')-" *5"2#(5"/&$6: _@(/&,#+&% 2&,)9
3"'(&()#,< ":.:< ), (5" '(#2&*5< A!U< 7#,"< 8)+9
,"6'< &,+ ("'()*%"'< )' *#22#,: I/#0,+ SG L
#3 *&'"' ),-#%-" (/&,'%#*&()#, #3 (5" 7'*.8
."," &,+ #3 (5" 7'*.? .","< 45)*5 *#+"'

!
3#/ & (/&,'*/)$()#,&% /"$/"''#/ .",": ?/&,'%#9
*&()#, #3 *9#"' 5&' &%'# 7"", #7'"/-"+ ),
'#2" *&'"':
!- @/6<)((A, *"#$%&#+ &/)'"' 3/#2 1 %62$5#9
*6("' )22#/(&%)>"+ 76 (5" .",#2" #3 (5" _$9
'("),\1&// -)/0': ?5" (02#/ *"%%' &/" 2"+9
)029')>"+ 2#,#2#/$5)* *"%%' 4)(5 & /#0,+ <=@

"
,0*%"0' &,+ 20%()$%" ,0*%"#%): ?5" *6(#$%&'2
! 5%/36)-)70&3- 80(%3(%(

<1% 1. Chronic lymphatic

1. leukemia / prolympho-
1. cyte leukemia / lympho-
1. cytic lymphoma (~7%)
CD10+/-
CD19+
–Bone marrow
CD19+
TdT
CD22 cyt –Blood CD20+
CD79a –Lymph nodes CD22 cyt
CD5+
Bone marrow CD23 +
SlgM (+)
A. Precursor B-lymphoblastic lymphoma/leukemia SlgD (+)
Deletions in chromosome 13
11. High-malignancy trisomy 12
Burkitt-like lymphoma
,-090&3- ://'9)-)7;

11. (~2.5%)
CD19+
CD19+ CD20+ PANB+ Recirculating
CD20+ CD22 cyt CD5+-CD23+ B cell
CD22+
Slg+/-
CD10+/-

Translocation of
bcl-2 in 30%

" Peripheral B cell in different

phases of differentiation ?

EBV infection

Translocation of c-myc gene

t(8;14), t(2;8), t(8;22)
CD19+
CD19+ CD20+
CD19+
CD20+ CD22++
CD20+
CD22+ SlgM+
CD22+
SlgM+ CD11c+
SlgM+
CD10++ CD25+
cyt lg +/-
CD103+
CD43-/+

!
<AB
10. Burkitt’s lymphoma (<1%)

B. Peripheral B-cell neoplasms

7. Hairy cell leukemia (<1%) 6. Marginal zone lymphoma
6.of the spleen (<1%)
2. Lymphoplasmocytoid 3. Mantle cell lymphoma
*+,%-- ?;/12)/3(

4. Follicle center lymphoma

!
2. lymphoma/immuno- (~6%) 4. (~25%)
2. cytoma (~2%)

CD19+ CD19+
CD20+ CD20+ CD10+/-
CD22 cyt CD22(+) CD19+
SlgM + CD5+ CD20+
SlgD -/+ CD10 +/- CD22 cyt
cit lg+ SlgM+ SlgM,G,A+

t(9;14) deletions in t(11;14) rearranged t(14;18) overexpression

chromosomes 13, 11, 17 bcl-1 gene (cyclin) of bcl-2 proteins

,-090&3- ://'9)-)7;
Peripheral B cell CD5+–CD23- cell Germinal center cells
maturing into plasma cell of follicular mantle

"
Peripheral B cell in different Marginal zone of Marginal zone of mucosa-
phases of differentiation lymph nodes associated lymphoid tissue

Translocation of: bcl-2 (30%) Antigen stimulation

bcl-6 (30%) e.g., Helicobacter pylori
CD19+
CD19+ CD19+ CD20+
CD20+ CD20+ CD22+
CD22+ CD22+ SlgM,G+
CD10-/+ SlgM+ cyt lg +/-
CD30-/+ cyt lg +/- CD43-/+
Slg+/- CD43-/+

9. Diffuse large-cell
9. lymphoma (~30%)
5b) Nodal marginal zone
5b. lymphoma (monocytoid
5b. lymphoma) (~2%)
5a) Extranodal marginal
5a. zone lymphoma
5a. (MALT-Type) (~8%) !
<A<

"
! >5.)6$%$<2')% @2+5)+5+
!" #$%&'%$()% *+" ,$($'%$()%
-)..)/-%$01%2( #3$%2453)62$(
!"#$%&'( )*&'+,#$&" %( - .(/)0&,(#12 $2 2+%3
41,# #& *15+.6#$&" %( 7 ,1..28 701 )*$/6*( 4&% &9
6"#$%&'$12 $2 #& )*&#1,# #01 %&'( 9*&/ $"91,#$&"2
%( %6,#1*$6: ;$*+212: &* )6*62$#128 <$",1 16,0
)6#0&51"$, &*56"$2/ *1)*121"#2 6 /$=#+*1 &9
'$991*1"# 6"#$51"2: !"#$%#"&'# -3,1.. 2#$/+.6#$&"
6.>6(2 #6?12 ).6,18 @6,0 -3,1.. ,.&"1 )*&'+,12
6"#$%&'$12 #06# #6*51# 6 2)1,$9$, 6"#$51"8 A&*13
&;1*: '$991*1"# 6"#$%&'$12 &9 #01 ;6*$&+2 $//+3
"&5.&%+.$" ,.62212 6*1 )*&'+,1': *12+.#$"5 $" 6
/$=#+*1 &9 $//+"&5.&%+.$"28 B" )*&#1$" 1.1,3
#*&)0&*12$2: #0$2 $2 *19.1,#1' 62 6 %*&6'3%621'
$",*1621 &9 56//635.&%+.$"28 A6.$5"6"# '13
=%2(2')% A..1($%$<&
51"1*6#$&" &9 - ,1..2 &* '191,#$;1 73,1.. *15+.63
#$&" ,6" .16' #& #01 +",&"#*&..1' )*&.$91*6#$&"
&9 6" $"'$;$'+6. - ,1.. ,.&"18 701 $",*1621'
)*&'+,#$&" &9 2#*+,#+*6..( 0&/&51"1&+2
$//+"&5.&%+.$"2 ,6" %1 $'1"#$9$1' $" 21*+/
1.1,#*&)0&*12$2 %( #01 )*121",1 &9 2&3,6..1'
/(1.&/63622&,$6#1' &* /6,*&5.&%+.$"1/$63623
2&,$6#1' CAD )*&#1$" ,&/)&"1"#2: >0$,0 6)3
)16* 62 "6**&>3%621' 2)$?12 &" #01 56//63
5.&%+.$"2 ,+*;1 C/&"&,.&"6. 56//&)6#0(D8
"
!"( "1&).62/ ,6+21' %( /6#+*1 - ,1..2 ,6"
#01&*1#$,6..( .16' #& 6 /&"&,.&"6. 56//&)63
#0( >0$,0 &9#1" *1/6$"2 +"'1#1,#1' '+1 #& 6
.&> $//+"&5.&%+.$" ,&"#1"#8 A )*&#1$" ,&/3
)&"1"#2 >1*1 20&>" #& &,,+* $" 6*&+"' E F &9
6.. $"'$;$'+6.2 &;1* GH (16*2 &9 6518 B" #0121
)6#$1"#2: $# $2 "&# )&22$%.1 #& )*1'$,# >01#01*
6 ).62/6 ,1.. '$2&*'1* C1858: /+.#$).1 /(1.&/6:
I6.'1"2#*&J/K2 /6,*&5.&%+.$"1/$6: &* 016;(
,06$" '$21621D >$.. '1;1.&)8 L1",1: #01 '$65"&3
2$2 20&+.' %1 #06# &9 M/&"&,.&"6. 56//&)6#0(
&9 +"?"&>" 2$5"$9$,6",1 CANO<DP $"2#16' &9
#01 9&*/1* '$,#$&" M%1"$5" /&"&,.&"6. 56/3
/&)6#0(8P ! )&*#$&" &9 #0121 $"'$;$'+6.2 >$..
'&+%#.122.( '1;1.&) ).62/6 ,1.. '(2,*62$6: %+#
/6"( &9 #01/ >$.. '$1 &9 &.' 651 %19&*1 #01 '$23
1621 %1,&/12 ,.$"$,6..( /6"$912#8
7" 8)%95(+63$
: .;+ ,)'3$<%$01%2(5.2)
A6,*&5.&%+.$"1/$6 $2 /6$".( 6 '$21621 &9 #01
1.'1*.(8 B# $2 ,6+21' %( #01 )*&.$91*6#$&" &9 2/6..
).62/6,(#&$' .(/)0&,(#12 >$#0 6 ;6*$6%.1 9*6,3
!
#$&" &9 /&*1 /6#+*1 ).62/6 ,1..28 701 6%"&*/6.
,1..2 $"$#$6..( $"9$.#*6#1 #01 %&"1 /6**&>: 6"'
01)6#&/156.( 6"' .(/)06'1"&)6#0( '1;1.&)
62 #01 '$21621 )*&5*122128 ! .1+?1/$, *1.1621
&9 #01 ,1..2 $"#& )1*$)01*6. %.&&' &,,+*2 $"
BCD #01 6';6",1' 2#6512 &9 #01 '$216218 701 ,1..2 213
,*1#1 .6*51 Q+6"#$#$12 &9 /&"&,.&"6. B5A /&.13
,+.12: >0$,0 5*16#.( $",*1621 #01 ;$2,&2$#( &9 #01
%.&&' '+1 #& #01$* )1"#6/1*$, 2#*+,#+*18 !2 6
*12+.#: 6 0()1*;$2,&2$#( 2("'*&/1 >$#0 622&3
,$6#1' ,$*,+.6#&*( '$2&*'1*2 /6( '1;1.&)8 70$2
/6( *12+.# $" '6/651 #& #01 *1#$"6: .16'$"5
#& $/)6$*1' ;$2$&" &* %.$"'"122: &* /6( ,6+21
,1*1%*6. 21$R+*12: ,&/6: &* '6/651 #& #01 ,&*3
&"6*( 6*#1*$12 C$2,01/$, 016*# '$21621: 016*#
96$.+*1D8 701 '1)&2$#$&" &9 A )*&#1$"2 $" #01
/(1.$" 2016#0 &9 "1+*&"2 ,6" $"'+,1 )&.(3
"1+*&)6#0(8 L1/&**0651 /6( 6.2& '1;1.&):
12)1,$6..( $" #01 2?$" &9 #01 .&>1* 1=#*1/$#$128
S62,+.$#$, ,06"512 /6( 6.2& &,,+* '+1 #& #01
)*1,$)$#6#$&" &9 $//+"1 ,&/).1=12 $" #01 ;123
21. >6..28
=" >5)*& =?)2( @2+5)+5
L16;( ,06$" '$21621 CLTUD $2 6 *6*1 ,&"'$#$&"
,06*6,#1*$R1' %( #01 21,*1#$&" &9 /&"&,.&"6.
)*&#1$"2 ,&"2$2#$"5 &9 $",&/).1#1 016;( ,06$"2
&9 #01 $//+"&5.&%+.$"28 ('))'*+,- $2 622&3
,$6#1' >$#0 #01 $",*1621' )*&'+,#$&" &9 /&"&3
,.&"6. ! ,06$"2 &9 B5N8 70$2 2+%#()1 +2+6..( )*13
21"#2 >$#0 .(/)06'1"&)6#0( 6"': $"9*1Q+1"#.(:
>$#0 &2#1&.(2$28 .#!/'*+,- CMA1'$#1**6"16"
.(/)0&/6PD $2 ,06*6,#1*$R1' %( #01 )6#0&.&5$3
,6. 21,*1#$&" &9 B5! %( /+,&26. ).62/6 ,1..2 &9
#01 $"#12#$"128 70$2 .16'2 #& #01 '1;1.&)/1"# &9
6 /6.6%2&*)#$&" 2("'*&/1 622&,$6#1' >$#0
'$6**016 6"' 6%'&/$"6. )6$"8 -&>1. &%2#*+,3
#$&" &* )1*9&*6#$&" ,6" &,,+* '+*$"5 #01 ,&+*21
&9 #01 '$216218 70$2 2+%#()1 /6$".( 6991,#2 ,0$.3
'*1" 6"' (&+"5 6'+.#28 01*+,- &,,+*2 $" ,&"3
4+",#$&" >$#0 .(/)0&)*&.$91*6#$;1 '$216212:
12)1,$6..( -3TVV8 701 %&"1 /6**&> $2 #()$,6..(
$"9$.#*6#1' >$#0 ;6,+&.6#1' ).62/6 ,1..28 V$50#
,06$"2 6*1 6.2& )*&'+,1' $" /6"( )6#$1"#2
>$#0 "3016;( ,06$" '$21621: 62 $2 *19.1,#1' %(
#01 )*121",1 &9 2&3,6..1' -1",1 W&"12 )*&#1$"2
$" #01 +*$"1 C211 )8 XEE!D8
 TH
#%)+.)/=5%% @&+'3)+2)+
!
TR

Bacteria, Poyclonal
antigen mixture B-cell stimulation Hypergammaglobulinemia

Malignant
transformation “spike”
(M-component)

=%2(2')% A..1($%$<&
Defective T-cell Monoclonal
regulation B-cell proliferation
Monoclonal gammopathy
A. Polyclonal vs. monoclonal gamma-globulin increase
Bone marrow
TS TH
Hepatosplenomegaly Neurological
Lymphadenopathy symptoms

CD19
CD20
Blood
Impaired vision,
blindness "
cyt/IgM++ Congestive
heart failure

Bleeding
Lymphoplasma-
cytoid B cells Viscosity

B. Waldenström’s macroglobulinemia

Lymphadenopathy,
! chains rarely osteolytic lesions
(Franklin’s disease)

Malabsorption,
Overproduction " chains diarrhea, intestinal

!
of heavy chains
lymphadenopathy

µ chains In the context of CLL

C. Heavy chain disease
BCE

"
! 6).$%'3'(,/$3 7,+)$+)+

!"#$%# &'"" (')*"#$%$ +$+#"", %#(-.'$/ #$

0-$$'%-(#/'0 1)(' %#22)3 "'$-)($ 4!"#$%&#'
!('#)!*56 1+/ -(.2'7+'(/", %#(-.'$/ #$ $)"-/#2,
'8/2#%'0+""#2, /+%)2$ &"#$$-.-'0 #$ *"#$%#&,9
/)%#$ )2 *"#$%#&,/)-0 ",%*:)%#$; <'$*-/'
/:-$ 0-..'2'(&'6 /:' /'2%$ =%+"/-*"' %,'")%#>
#(0 =*"#$%#&,/)%#> #2' )./'( +$'0 $,()(,9
%)+$",; !"#$%# &'""$ +$+#"", $'&2'/' ?@A 4&#;
BC D5 )2 ?@E -%%+()@")1+"-($ 4FC D56 1+/ 2#2'",
?@< -%%+()@")1+"-($ 4GHF D5; I'(&' J)('$ *"#$9
%#&,/)%#$ 4GKHFC D5 #2' &:#2#&/'2-L'0 1, /:'
'8&"+$-M' $'&2'/-)( ). "-@:/ &:#-($; N:' &)%9
*"'/' #1$'(&' ). -%%+()@")1+"-( $,(/:'$-$
)2 2'"'#$' 4()($'&2'/)2, *"#$%#&,/)%#5 -$
2#2' 4"'$$ /:#( G D ). &#$'$5;
83,*,/$3 9..2*'3'(5
). %+"/-*"' %,'")%# -$ &:#2#&/'2-L'0 1, /:'
*2'$'(&' ). %+"/-*"' )$/')",/-& "'$-)($ /:#/ 0'9
M'")* 0+' /) -(&2'#$'0 )$/')&"#$/ #&/-M-/,; ?O9G!
#(0 N\]9" :#M' 1''( -0'(/-.-'0 #$ )$/')&"#$/9
#&/-M#/-(@ .#&/)2$; N:' -(&2'#$-(@ 0'@2'' ).
1)(' 0'$/2+&/-)( "'#0$ /) /:' 2'"'#$' ). &#"9
&-+%6 2'$+"/-(@ -( :,*'2&#"&'%-#;
N:' )$/')",/-& "'$-)($ #2' +$+#"", .)&#" #(0
)&&+2 #/ M#2-)+$ $-/'$6 '$*'&-#"", -( 1)('$
3-/: :'%#/)*)-'/-& %#22)36 .)2 '8#%*"'6 -(
/:' 2-1$6 $/'2(+%6 M'2/'12#'6 &"#M-&"'6 $Q+""6 $&#9
*+"#6 *'"M-$6 #(0 *2)8-%#" $'@%'(/$ ). /:' .'9
%+2 #(0 :+%'2+$ 4!5; N:', #**'#2 )( 2#0-)9
@2#*:$ #$ =:)"'9*+(&:> "'$-)($ 4"5; N:'
*#/-'(/$ &)%*"#-( ). 1)(' *#-(6 #(0 *#/:)")@-9

&#" .2#&/+2'$ .2'7+'(/", )&&+2; <-..+$' -(M#$-)(

!" #$%&'()*)+,+ $*- #$%&'.)/&$*,+.+ ). /:' M'2/'12#' &#( %-%-& )$/')*)2)$-$; Z+"/-9
'0 123%,43) 15)3'.$ *"' %,'")%# -$ &:#2#&/'2-L'0 1, /:' *2)"-.'2#9
/-)( ). *"#$%# &'""$ 3-/:-( /:' 1)(' %#22)3
?O9B -$ '$$'(/-#" .)2 /:' @2)3/: ). *"#$%#
4#5; N:' *"#$%# &'"" &)(/'(/ ). /:' 1)(' %#22)3
&'""$; E+/)&2-(' *2)0+&/-)( ). ?O9B 1, %,'")%#
-$ ()2%#"", KHGC D6 1+/ &#( -(&2'#$' &)($-0'29
&'""$ -$ *)$$-1"'6 1+/ ?O9B #(0P)2 ?O9B9"-Q' %)"'9
#1", -( /:' *2'$'(&' ). -(.'&/-)($; U'(&'6 #( -(9
&+"'$ &#( #"$) 1' *2)0+&'0 1, $/2)%#" &'""$
&2'#$' ). *"#$%# &'""$ 3-/:-( /:' 1)(' %#22)3
3-/:-( /:' 1)(' %#22)3; N:' *)/'(/-#" 2)"'
$:)+"0 ()/ 1' -(/'2*2'/'0 #$ 0-#@()$/-& ). %+"9
). R#*)$-S$ $#2&)%#9#$$)&-#/'0 :'2*'$ M-2+$
/-*"' %,'")%# +("'$$ # %)()&")(#" -%%+()9
/,*' T 4UUV9T5 -( /:' 0'M'")*%'(/ ). %+"/-*"'
@")1+"-( -$ #"$) 0'/'&/'0; !"#$%# &'"" *2)"-.'2#9

"
%,'")%# -$ $/-"" +(&"'#2;
/-)( -$ )./'( 0-..+$' #(0 &#( /:'2'.)2' 1'
W-(&' "#2@' 7+#(/-/-'$ ). %)()&")(#" *2)/'-(
0'/'&/'0 1, 1)(' %#22)3 #$*-2#/-)( 4&,/)")@,5;
#2' +$+#"", *2'$'(/6 /:' M-$&)$-/, ). /:' 1"))0
U)3'M'26 # 1-)*$, -$ 2'7+-2'0 .)2 0-#@()$-$ ).
&#( -(&2'#$'6 /:'2'1, &#+$-(@ # :,*'2M-$&)$-/,
.)&#" 1)(' %#22)3 -(.-"/2#/-)( 4:-$/)")@,5;
$,(02)%' 4$'' *; GXY!5; N:-$ %)$/ &)%%)(",
N:' #**'#2#(&' ). *"#$%# &'""$ &#( M#2, @2'#/",
)&&+2$ -( ?@E %,'")%#$ 1'&#+$' ?@E -%%+()9
0'*'(0-(@ )( /:' 0'@2'' ). %#/+2#/-)( )2 %#9
@")1+"-( /'(0$ /) .)2% *)",%'2$ M-# $+".-0'
"-@(#(/ /2#($.)2%#/-)( ). /:' &'""$; O#2@' *"#$9
1)(0$; I'(&' J)('$ *"#$%#&,/)%#$ #2' &:#2#&9
%#1"#$/$ 3-/: (+&"')"- 0)%-(#/' /:' %)2*:)9
/'2-L'0 1, '8&"+$-M' "-@:/ &:#-( $,(/:'$-$; ?( /:'
")@-&#" *-&/+2' ). *))2", 0-..'2'(/-#/'0 *"#$%#
'"'&/2)*:)2'$-$6 Z @2#0-'(/$ #2' ()/ .)+(0
&'""$;
$-(&' "-@:/ &:#-($ #2' '8&2'/'0 3-/: +2-('; U)39
N2'#/%'(/ ). *"#$%#&,/)%# +$+#"", &)($-$/$
'M'26 "-@:/ &:#-($ *2)/'-($ 4I'(&' J)('$ *2)9
). #"Q,"#/-(@ #@'(/$ 4';@;6 %'"*:#"#(5 #(0 &)2/-9
/'-($5 #2' #"$) .)+(0 -( /:' +2-(' ). #1)+/
&)$/'2)-0$; N:' 0-$'#$' :#$ # *))2 *2)@()$-$
XC D ). *#/-'(/$ 3-/: &"#$$-&#" ?@A )2 ?@E *"#$9
#(0 &#(()/ 1' &+2'0 1, &)(M'(/-)(#" &:'9
%#&,/)%#; N:', +"/-%#/'", #&&+%+"#/' -( /:'
%)/:'2#*,; ^)+(@'2 *#/-'(/$ %#, 1' &)($-09
2'(#" /+1+"'$ #$ :,#"-(' -(&"+$-)( 1)0-'$6 /:'2'9
'2'0 .)2 1)(' %#22)3 /2#($*"#(/#/-)(;
1, &#+$-(@ # *2)@2'$$-M' 0'&2'#$' -( Q-0(',
.+(&/-)(;
N:'2' -$ # 7+#(/-/#/-M' -(&2'#$' -( /:' -%%+9
()@")1+"-( &)(&'(/2#/-)( -( /:' 1"))0 ). %,'9
")%# *#/-'(/$6 1+/ #"" ). /:' -%%+()@")1+"-($
:#M' -0'(/-&#" $*'&-.-&-/, #(0 /:'2'.)2' 0) ()/
&)(/2-1+/' /) -%%+(' 0'.'($'; N:' &)(&'(/2#9

!
:;;
/-)( ). ()2%#" -%%+()@")1+"-($ -$ +$+#"", 0'9
&2'#$'0 4$'&)(0#2, #(/-1)0, 0'.-&-'(&,5 0+' /)
/:' 0-$2'@+"#/-)( ). ()2%#" I &'""$ #(0 N &'""$;
[,/)/)8-& N &'""$ #(0 &,/)Q-('$ $'&2'/'0 1, %,'9
")%# &'""$ -(:-1-/ '2,/:2)*)-'$-$ -( /:' 1)('
%#22)36 /:'2'1, "'#0-(@ /) #('%-#; N:' *-&/+2'
 123%,43) 15)3'.$
!
IL-6 Autocrine
IL-6-like production
factor
Viral infection Stromal cell Plasma cell

Immunglobulins Cytokines: TNF IL-1 (osteoclast-activating factors)

Large amounts of Unbalanced Suppression Suppression Activation

83,*,/$3 9..2*'3'(5
monoclonal synthesis of of normal of hemato- of osteo-
proteins light chains Ig-production poiesis clasts

Plasma !/"-chains in urine Decrease of Bone marrow Osteolysis

"
viscosity (Bence Jones normal
(esp. IgA) proteinuria) antibodies

Hyperviscosity Nephropathy Frequent Cytopenias Hypercalcemia

syndrome infections

A. Pathogenesis and pathomechanisms of multiple myeloma

Histology Buckshot skull

B. Localization
B. of osteolysis
Cytology

C. Bone marrow findings

Osteolysis, decalcification

D. Radiographic findings
!
:;<

"
! 9):$%'4'(,/$4 .,+)$+)+
!" #$%&'()*)+,+
!"#$%&$'(&)*+ !"# $#"%& '"()#*+$ ),!) -*$$(./#
!) 01 !2 !+- '"#3*'*)!)# !) .(4#" )#&'#"!)%"#$5
6,# &(.#3%.!" 7!$*$ (8 3"9('"#3*'*)!)*(+ ,!$ 9#)
)( 7# #:'.!*+#-5 ; 3,!+<# *+ ),# 3!"7(,9-"!)#
3(+)#+)= ),!) *$= ! "#-%3)*(+ *+ ),# $*!.*3 !3*-
3(+)#+)= ,!$ 7##+ '"('($#- !$ ! '($$*7.# 3!%$#5
-" .)%)/%,'* '0 123'(4'564,*+
6,# -#)#3)*(+ (8 3"9(<.(7%.*+$ *+ ),# 7.((- "#>
?%*"#$ ),# %$# (8 '"#4!"&#- $9"*+<#$5 6,# $'#>
3*&#+$ &%$) 7# *&&#-*!)#.9 3#+)"*8%<#- !)
01 !2 )( @##' ),# 3"9(<.(7%.*+$ 8"(& '"#3*'*)!)>
*+< 4*), ),# 3#.. $#-*&#+)5 6,# $#"%& &%$)
14,*,/$4 ;::6*'4'(3
),#+ 7# '"(&').9 "#&(/#- !+- $)("#- !) A !2
8(" !) .#!$) 1B ,(%"$5 ;8)#" $%7$#?%#+) 3#+)"*8%>
<!)*(+ *+ 3!'*..!"9 )%7#$= ),# '"#3*'*)!)*+< 3"9(>
<.(7%.*+$ $#'!"!)#= 8("&*+< ,"#$-".,)-)/0/.5
1" 14$++,0,/$%,'* $*7 14,*,/$4 8)$%62)+
! 69'# C 3"9(<.(7%.*+$ 3(+$*$) (8 ! $*+<.#
&(+(3.(+!. *&&%+(<.(7%.*+ 3(&'(+#+)
!+- !"# 8(%+- *+ BD E (8 !.. 3"9(<.(7%.*+#>
&*!$5 6,#9 (33%" *+ &%.)*'.# &9#.(&!=
" F!.-#+$)"(G&H$ &!3"(<.(7%.*+#&*!= 3,"(+*3
.9&',(39)*3 .#%@#&*! I2JJK= !+- (),#" +(+>
L(-<@*+H$ .9&',(&!$ IMLJK5 2"9(<.(7%.*+$
!"# 8"#?%#+).9 '"#$#+) *+ &%.)*'.# &9#.(&!=
4,#"#!$ C<N !+)*7(-*#$ '"#-(&*+!)# *+ ),#
(),#" -*$#!$#$5 C+ &%.)*'.# &9#.(&! !+-
F!.-#+$)"(G&H$ &!3"(<.(7%.*+#&*!= !"(%+-
OD E !+- BD E= "#$'#3)*/#.9= (8 ),# N '"()#*+$
7#,!/# !$ 3"9(<.(7%.*+$5 6,# $9&')(&$ !"#
'"*&!"*.9 3!%$#- 79 ),# *&'!*"#- (" 3(&'.#>
)#.9 !7$#+) 3*"3%.!)*(+ *+ ),# 3!'*..!"*#$ (8
),# $@*+P ),# .(4 )#&'#"!)%"# (+ ),# $@*+
$%"8!3# .#!-$ )( ),# *+)"!/!$3%.!" '"#3*'*)!>
)*(+ (8 3"9(<.(7%.*+$ !+- *+3"#!$#$ ),# $#">
%& /*$3($*)95 6,*$ &!9 "#$%.) *+ 8%.. /!$3%.!"
(33.%$*(+5 Q!9+!%-H$ ',#+(&#+(+ *$ ! 3(&>
&(+ 8#!)%"# I$## '5 ORRK= !$ !"# +#3"($*$ (8
),# #:)"#&*)*#$= !3"(39!+($*$= /!$3%.!" '%">
'%"!= !+- '(.9+#%"('!),*3 %.3#"$ (8 ),#
!+@.#$5
" 69'# CC 3"9(<.(7%.*+$ ,!/# ! &(+(3.(+!.
*&&%+(<.(7%.*+ 3(&'(+#+) I%$%!..9 C<N
!
7%) "!"#.9 C<; (" C<SK !+- ! '(.93.(+!. C<S
3(&'(+#+)5 ;''"(:*&!)#.9 ADE (8 !.. 3"9(>
<.(7%.*+#&*!$ 3(""#$'(+- )( ),*$ )9'#5 6,#
&(+(3.(+!. 3(&'(+#+) #:,*7*)$ "#!3)*/*)9
)( ),# TI!7KB 8"!<&#+) (8 ),# '(.93.(+!. *&>
<=> &%+(<.(7%.*+ I",#%&!)(*- 8!3)(" !3)*/*)9U
$## '5 O1BK5 N(+(3.(+!. *&&%+(<.(7%.*+$
%$%!..9 ,!/# ! .*<,) 3,!*+$= 7%) "!"#.9 " .*<,)
3,!*+$5 M( %+-#".9*+< -*$#!$# 3!+ 7# *-#+)*>
8*#- *+ !"(%+- (+#>),*"- (8 ),# '!)*#+)$
I#$$#+)*!. &*:#- 3"9(<.(7%.*+#&*!K5 L#'!)*>
)*$ *$ 3(&&(+ *+ ),#$# '!)*#+)$ I%$%!..9
3,"(+*3 ,#'!)*)*$ 2 /*"%$ *+8#3)*(+ *$ 3(+$*->
#"#- )( 7# ),# )"*<<#" (8 ),# -*$#!$#K=
4,#"#!$ 3(++#3)*/# )*$$%# -*$#!$#= (),#"
!%)(*&&%+# -*$("-#"$= !+- .9&',('"(>
.*8#"!)*/# -*$#!$#$ !"# "!"#5
# 69'# CCC 3"9(<.(7%.*+$ 3(+$*$) (8 '(.93.(+!.
*&&%+(<.(7%.*+$= %$%!..9 C<N= -*"#3)#-
!<!*+$) '(.93.(+!. C<S !+- C<; &(.#3%.#$
I&*:#- '(.93.(+!. )9'#K5 ;7(%) AD E (8 !..
3"9(<.(7%.*+$ 7#.(+< )( ),*$ <"(%'5 69'# CCC
3"9(<.(7%.*+$ )#+- )( !"*$# *+ !$$(3*!)*(+
4*), /!"*(%$ *+8#3)*(+$ !+- !%)(*&&%+#
-*$#!$#$= 7%) #$$#+)*!. 3"9(<.(7%.*+#&*!
!.$( (33%"$ *+ ),*$ <"(%'5
C+ &*:#- 3"9(<.(7%.*+#&*!$= *&&%+(<.(7%.*+>
*&&%+# 3(&'.#:#$ '"#3*'*)!)# *+ ),# /#$$#.
4!..$= ),#"#79 '"(/(@*+< !+ *+8.!&&!)("9
"#$'(+$# I/!$3%.*)*$K5 6,# &($) '"(&*+#+)
$9&')(& *$ /!$3%.!" '%"'%"! I'%+3)*8("& ("
$'()>.*@# ,#&("",!<#$ (+ ),# .(4#" #:)"#&*>
)*#$K5 V.3#"!)*(+$ &!9 -#/#.(' *+ ),# "#<*(+
(8 ),# !+@.#$5 N()(" !+- $#+$("9 '(.9+#%"(>
'!),*#$ 3!+ &!+*8#$) !$ '!"#$*$ (" '!"#$),#$*!5
;"),"!.<*!= #$'#3*!..9 *+ ),# ,!+-$= @+##$= !+>
@.#$= !+- #.7(4$= (33%"$ *$ WDX1D E (8 '!)*#+)$5
6,*$ 3!+ .#!- )( "#-+#$$ !+- $4#..*+<= 7%) Y(*+)
-#8("&*)9 -(#$ +() (33%"5 N("# ),!+ ZD E (8
),#$# '!)*#+)$ -#/#.(' @*-+#9 -*$#!$# (/#"
),# 3(%"$# (8 )*&#5 6,# ,*$)(.(<*3!. '*3)%"# *$
%$%!..9 (+# (8 '"(.*8#"!)*/# <.(&#"%.(+#',"*)*$
3!%$#- 79 ),# -#'($*)*(+ (8 *&&%+(<.(7%.*+$
!+- 3(&'.#&#+) I$## '5 BBZ= BB1K5
6,# '"(<+($*$ (8 3"9(<.(7%.*+#&*! /!"*#$ *+
!33("-!+3# 4*), ),# $#/#"*)9 (8 ),# %+-#".9*+<
-*$#!$#5 ;'!") 8"(& !/(*-*+< ),# 3(.-= ),# -*$>
#!$# 3!+ 7# )"#!)#- 4*), 3(")*3($)#"(*-$= *&&%>
+($%''"#$$!+)$= !+- *+)#"8#"(+>#5 C+ '!")*3%.!"=
*+)#"8#"(+># ,!$ 7##+ %$#8%. 8(" ),# )"#!)&#+)
(8 '!)*#+)$ 4*), ,#'!)*)*$>!$$(3*!)#- 3"9(<.(>
7%.*+#&*!= #/#+)%!..9 *+ !$$(3*!)*(+ 4*), !+)*>
/*"!. $%7$)!+3#$ I#5<5= "*7!/*"*+K5 C+ !3%)# 3"*$#$=
3"9(8*.)"!)*(+ 3!+ 7# '#"8("&#- )( ?%*3@.9
"#&(/# .!"<# ?%!+)*)*#$ (8 3"9(<.(7%.*+$ 8"(&
),# 3*"3%.!)*(+5
 +37°C +4°C
123'(4'564,*):,$

+4°C
!
Centrifuge Collect Cryo-
immediately at 37°C serum precipitate
A. Behavior of cryoglobulins B. Determination of cryoglobulins in the blood

In
– plasmacytoma
– Waldenström’s syndrome
– CLL

14,*,/$4 ;::6*'4'(3
– NHL

Purpura Poly- Trophic

neuropathy ulcers

Monoclonal
IgM, IgG or Impaired blood circulation
IgA, !, "

"
1. Type I (monoclonal immunglobulin)

Rheumatoid factor activity

Monoclonal Immune complex Polyclonal

precipitation
IgM IgA IgG IgM IgM
+ + + + +
IgG IgG IgG IgG IgA
Polyclonal Polyclonal

– Essential mixed – Infections

- cryoglobulins (hepatitis C !!) - (HCV, HBV, HIV, syphilis,
– Connective tissue diseases - borreliosis)
– Lymphoproliferative – Essential cryoglobulins
- diseases Vasculitis – Connective tissue diseases

Polyneuropathy Arthralgia

2. Type II (mixed cryoglobulins including one

monoclonal immunglobulin)

C. Classification of cryoglobulinemia
Nephritis

3. Type III (mixed polyclonal

cryoglobulins)
Purpura

!
<=?

"
! 7)0$%'2'(,9$2 6,+)$+)+
!" #$%&'()*)+,+
!"#$ %&'("'( )*+,(''(' "*( ,-"*",.(*&/(% 0$
.-( &#1&2.*".&+# +1 .&''3( 4&.- " -+5+6(#(+3'7
(+'&#+)-&2&, 5".(*&"2 4-&,-7 2&8( '."*,- 9!"#$%&
: '."*,-;7 &' '."&#(% 0$ &+%&#(< =-('( >"5$2+&%?
%()+'&.' ,+#'&'. +1 1&0*&22"* )*+.(&#' %(*&@(%
1*+5 )+2$5(*&/(% )().&%( 1*"65(#.' 9&553A
#+62+032&# 2&6-. ,-"&#'7 "5$2+&% B )*+.(&#7
!CA5&,*+62+032&#7 .*"#'.-$*(.&#7 !A)*+.(&# BD7
,$'.".&#7 )*+,"2,&.+#&#7 "#% "A#".*&3*(.&, )()A
.&%(;< =-( "#.&)"*"22(2 "5$2+&% 1&0*&2' 1+*5
.4&'.(% !A)2(".(% '-((.'7 4-&,- "))("* 6*((#
3#%(* )+2"*&/(% 2&6-. "1.(* '."&#&#6 4&.- E+#6+
*(%< B*+3#% FGHI J +1 .-( "5$2+&% %()+'&.' ,+#A
'&'. +1 .-( #+#1&0*&22"*$7 )(#."6+#"2 ",3.(A)-"'(
/2,*,9$2 >00<*'2'(1
)*+.(&#7 '(*35 "5$2+&% K 9LBK;7 4-&,- &' )*+A
%3,(% &# -()".+,$.('<
-" .,(&% /&$,* !012',3'+,+
4!. !012',3'+,+5
K*&5"*$7 #+#A-(*(%&."*$ 2&6-. ,-"&# 9BM; "5$A
2+&%+'&' &' ,-"*",.(*&/(% 0$ .-( %()+'&.&+# +1
1&0*&2' 1*+5 1*"65(#.' +1 &553#+62+032&# 2&6-.
,-"&#' 9N(#,( O+#(' )*+.(&#'P '(( )< HDD;< BM
"5$2+&%+'&' +,,3*' &# )2"'5" ,(22 %$',*"'&"'7
"
(')(,&"22$ 532.&)2( 5$(2+5" +* Q"2%(#'.*+R5S'
5",*+62+032&#(5&"< B))*+T&5".(2$ CI J +1 "22
2&6-. ,-"&#' .(#% .+ 1+*5 "5$2+&%7 " '30,2"''
+1 # ,-"&#' 9#UV; &' +1.(# &#@+2@(%< L(*35 "5$A
2+&% K )*+%3,(% 0$ -()".+,$.(' 0&#%' #+#')(A
,&1&,"22$ .+ .-( "5$2+&% 1&0*&2'<
/" !012',3 ! !012',3'+,+
4!! !012',3'+,+5
L(,+#%"*$ +* *(",.&@( '$'.(5&, "5$2+&%+'&'
5"$ %(@(2+) "' " ,+5)2&,".&+# +1 ,-*+#&, &#A
1(,.&+# 9.30(*,32+'&'7 0*+#,-&(,."'&'7 ,-*+#&,
+'.(+5$(2&.&';7 ,-*+#&, &#12"55".+*$ %&'("'(
9*-(35".+&% "*.-*&.&'7 E*+-#S' %&'("'(;7 %*36
"03'(7 +* ,"#,(*< V# BB "5$2+&%+'&'7 .-( "5$2+&%
1&0*&2' ,+#."&# "5$2+&% B7 4-&,- 1+*5' "1.(*
)*+.(+2$.&, ,2("@"6( +1 .-( ",3.(A)-"'( )*+.(&#
'(*35 "5$2+&% B 9LBB;< LBB &' )*+%3,(% &#
-()".+,$.(' +* 5",*+)-"6(' %3*&#6 "# &#12"5A
5".&+#<
6" 7)0'3,$21+,+8!++'9,$%)3 !012',3'+,+
! 4!7 !012',3'+,+5
N(."ACA5&,*+62+032&# 9!C5P '(( )< DW; &' '.*3,A
.3*"22$ '&5&2"* .+ 2&6-. ,-"&# &553#+62+032&#7
.-( )*(,3*'+* '30'."#,( +1 BM "5$2+&%< E(22'
?@A +1 .-( &553#( '$'.(5 "#% -()".+,$.(' "*(
.-( 5"&# '+3*,(' +1 ,&*,32".&#6 !C5< !C5 &'
)*+,(''(% 0$ 62+5(*32"* 1&2.*".&+# "#% .3032"*
*("0'+*).&+#< B' " *('32.7 !C5 2(@(2' &# )2"'5"
"*( &#,*("'(% DIGXIA1+2% &# )".&(#.' 4&.- *(#"2
1"&23*(< L&#,( .-( !C5 5+2(,32( &' .++ 0&6 .+ )"''
.-*+36- 5+'. %&"2$'&' 5(50*"#('7 &. ,+#.&#3('
.+ ",,3532".(7 %(')&.( -(5+%&"2$'&'< Y(4(*
%&"2$'&' 5(50*"#(' "*( #+4 "02( .+ (2&5&#".(
.-('( 5+2(,32('<
:" /2,*,9$2 ;)$%<=)+
B5$2+&%+'&' 5+'. ,+55+#2$ &#%3,(' *(#"2
'$5).+5' *"#6&#6 1*+5 )*+.(&#3*&" .+ *(#"2
1"&23*(< B%*(#+,+*.&,"2 &#'311&,&(#,$ &' "2'+
,+55+#< E"*%&", &#@+2@(5(#. &' 1+3#% &#
WIGZI J +1 )".&(#.' 4&.- BM "5$2+&%+'&'< B5$A
2+&% %()+'&.' ,"# 2("% .+ *&6&% .-&,8(#&#6 +1 .-(
5$+,"*%&35 4&.- ,"*%&", &#'311&,&(#,$ "#% "*A
*-$.-5&"< M&@(* 13#,.&+# 3'3"22$ &' #+. &5)"&*(%
%(')&.( 5"''&@( -()".+5(6"2$< L)2(#+5(6"2$
3'3"22$ *(5"&#' "'$5).+5".&,< [()+'&.' &#
.-( ,"*)"2 .3##(2 2&6"5(#.' 5"$ ,+5)*(''
.-( 5(%&"# #(*@( "#% ,"3'( )"*('.-('&" +1
.-( -"#%'< \"'.*+&#.('.&#"2 &#@+2@(5(#. &' +0A
'(*@(% &# "22 1+*5' +1 "5$2+&%+'&'< =$)&,"2 1("A
.3*(' &#,23%( .-&,8(#&#6 +1 .-( .+#63( 95",*+A
62+''&"; "#% 5+.&2&.$ %&'+*%(*' "''+,&".(% 4&.-
+0'.*3,.&+#7 5"2"0'+*).&+#7 "#% %&"**-("< B5$A
2+&% %()+'&.' &# .-( .*",-(+0*+#,-&"2 .*(( 5"$
,"3'( 0*+#,-&.&, '$5).+5'<
K(*&)-(*"2 #(*@+3' '$'.(5 &#@+2@(5(#. &'
,+55+# &# @"*&+3' 1+*5' +1 1"5&2&"2 "5$2+&%+A
'&'< !3.".&+# +1 .*"#'.-$*(.&#7 " .-$*+T&#(A0&#%A
&#6 "#% *(.&#+2A0&#%&#6 )*+.(&#7 &' 1*(]3(#.2$
+0'(*@(%< =-( ,2&#&,"2 (T"5&#".&+# *(@("2' '(#A
'+*$ %&'+*%(*' "''+,&".(% 4&.- &#%+2(#. 32,(*'
+* 5+.+* %&'+*%(*'< =-( ",,3532".&+# +1 "5$A
2+&% &# .-( "3.+#+5&, #(*@+3' '$'.(5' 5"#&A
1('.' "' %$'-&%*+'&'7 &#,+#.&#(#,(7 "#% &5)+A
.(#,(< =-( EYL &' "11(,.(% +#2$ &# " 1+*5 +1
"5$2+&%+'&' ,"22(% >'(#&2( "5$2+&%+'&'<? =-&'
(#.&.$ 2("%' .+ .-( %()+'&.&+# +1 .-( !A)*+.(&#
BD7 4-&,- &' ,+%(% 0$ " 6(#( 2+,".(% +# ,-*+A
5+'+5( CH< V# '+5( 1+*5' +1 B2/-(&5(*S' %&'A
("'(7 5&''(#'( 53.".&+#' &# .-( 6(#( ,+%&#6 1+*
"5$2+&% )*(,3*'+* )*+.(&# -"@( 0((# 1+3#%<
=-( "0#+*5"2 )().&%( &' )*+#( .+ 1+*5 )2"]3('
&# .-( 0*"&#<
=-( %&"6#+'&' +1 "5$2+&%+'&' &' ('."02&'-(%
0$ 0&+)'$ +1 .-( "11(,.(% +*6"#'< ^(,."2 0&+)'$
"#% .-( "')&*".&+# +1 "0%+5&#"2 1". 5"$ 2("% .+
.-( %&"6#+'&' +1 '$'.(5&, "5$2+&%+'&'<
- Immunglobulin
- light chain
10 nm
!012',3'+,+
!
- Protein AA

1000nm
- !2-Microglobulin
- Transthyretin
- ! Protein A4
- Cystatin
- Procalcitonin
- "-Natriuretic Degradation
- peptide of proteins Polymeri- Amyloid Polymerized
A. Pathogenesis or precursors zation fibrils polypeptides

IL-1, IL-6,TNF-"
Myeloma, Waldenström’s
plasma cell macro-
dyscrasia globulinemia Chronic infections

/2,*,9$2 >00<*'2'(1
Monoclonal Ig
light chain
surplus
Hepatocytes Serum amyloid
A = SAA
Amyloid P
component Chronic inflammations
AL-fibrils (serum amyloid Accumulation:
P = SAP) AA fibrils
B. AL amyloidosis
B. (primary, nonhereditary amyloidosis) C. AA amyloidosis (secondary amyloidosis)

Cells of the
immune system
Hepatocytes
Accumulation of AA fibrils in tissue

Macroglossia
Dementia,
vasculopathy

Peripheral and
"
autonomous
!2-micro- neuropathy:
globulin Cardiomegaly, polyneuro-
congestive pathy,
heart failure incontinence,
impotence
Glomerular
filtration
Tubular Hepatomegaly Bronchitis,
absorption diffuse or
nodular
Adrenal gland
infiltration
insufficiency
of the lung

Glomerular Splenomegaly
damage,
proteinuria,
azotemia

Reduced filtration in long-

term renal failure

D. AH amyloidosis
C. (hemodialysis-associated)
!2-m
fibrils
Carpal
tunnel
syndrome

E. Clinical features
Hypomotility,
malabsorption,
obstruction !
?@B

"
! ,-.&/ 2..-(&5&'6
!"# $%#&'()* )+ ,"#'"#- (..%*)&%-/#(001*2#
131(*&' '%.)-& '-%04 #5(&'& (& &'(00 %*&)0/#67 8129
'#-(1 1*6 /(-%&#&: ,"(2" 21* ;# #++#2'(/#04 -#9
2)3*(<#6 1*6 2)*'-)00#6 ;4 '"# (..%*# &4&9
'#.: 2)*&(&' )+ 1 /1-(#'4 )+ +)-#(3* =-)'#(*&7
!%.)- 2#00&: )* '"# )'"#- "1*6: 6(++#- )*04
&0(3"'04 +-). *)-.10 2#00&7 >).#'(.#&: '-%*9
21'#6 )- .%'1'#6 =-)'#(*& 1-# =-#&#*': ;%'
)'"#-,(&# '"# 2#00& %&# *)-.10 ;()2"#.(210
=1'",14&7 ?/#* (+ &).# =-)'#(*& 1-# #5=-#&&#6
1' 0#/#0& "(3"#- '"1* *)-.10: )- (+ +#'10 1*'(3#*&
1-# #5=-#&&#6: '"#&# 1-# (* .)&' 21&#& *)-.10
2#00%01- =-)'#(*&7 @* .1*4 21&#&: (+ .%'1'#6
=-)'#(*& 1-# =-#&#*': )*04 +#, =#='(6#& 21*
;# =)'#*'(1004 -#2)3*(<#6 1& +)-#(3*7 A *%.;#-
75)()%45 2..-(&5&'6
)+ +(*6(*3& (*6(21'# '"1' (..%*)&%-/#(001*2#
131(*&' '%.)-& (& *)' )*# )+ '"# =-(.1-4 '1&B&
)+ '"# (..%*# &4&'#.7 C1'(#*'& ,('" &#/#-#
(..%*# 6#+#2'&: &%2" 1& D@E: "1/# 1* (*2-#1&#6
(*2(6#*2# )+ /(-%&91&&)2(1'#6 '%.)-&: ;%' 6)
*)' #5"(;(' 1* (*2-#1&# (* '"# .)&' 2)..)*
21*2#- '4=#&7 F%-'"#-.)-#: *%6# .(2# '"1'
012B +%*2'()*10 ! 2#00& 6) *)' 6#/#0)= '%.)-&
;%' -1'"#- 6(# )+ (*+#2'()*&7 G)*#'"#0#&&: '"#
+(*6(*3& )+ #5=#-(.#*'10 1*(.10 &'%6(#& 1*6
20(*(210 &'%6(#& 6) H%&'(+4 ")=# '"1' .1*(=%019
"
'()* )+ '"# (..%*# &4&'#. ,(00 #/#*'%1004
-#&%0' (* #++#2'(/# (..%*)'"#-1=4 &'-1'#3(#&
(* '"# +%'%-#7
!" #$%&'()*)&( &+ ,-.&/ !(*)'$(0
I#&#1-2"#-& "1/# 1''#.='#6 ') .1*%+12'%-#
1*'(;)6(#& 131(*&' '%.)- 2#00& &(*2# .)*)20)9
*10 1*'(;)64 #*3(*##-(*3 '#2"*($%#& ,#-# 6#9
/#0)=#6 1;)%' JK 4#1-& 13)7 !"(& (*/)0/#& '"#
(..%*(<1'()* )+ .(2# ,('" '%.)- 2#00&7 A+'#-
-#=#1'#6 1==0(21'()*: '"# &=0#*(2 2#00& 1-# (&)9
01'#6 1*6 +%&#6 ,('" .4#0).1 2#00& +-). 1*
L(..)-'10M .4#0).1 2#00 0(*# ;4 166('()* )+
=)04#'"40#*# 3042)0 NC?OP7 Q%# ') 1* #*<4.#
6#+#2': %*+%&#6 .4#0).1 2#00& 6(# ,"#* =012#6
(* 1 .#6(%. 2)*'1(*(*3 "4=)51*'"(*#: 1.(9
*)='#-(*: 1*6 '"4.(6(*# NDA! .#6(%.P N!P7
R*04 '")&# 2#00& '"1' (*"#-('#6 (..)-'10('4
+-). '"# .4#0).1 2#00& 1*6 DA! -#&(&'1*2#
+-). '"# &=0#*(2 2#00& ,(00 &%-/(/#7 A=1-' +-).
DA! -#&(&'1*2#: '"# +%&()* 2#00& N"4;-(6).1
2#00&P 10&) (*"#-(' 1*'(;)64 &=#2(+(2('4 +-).
!
'"# &=0#*(2 2#00&7 D4;-(6).1 2#00& '"1' =-)6%2#
1*'(;)6(#& 131(*&' '%.)- 2#00& 1-# &%;H#2'#6 ')
1 =-)2#&& B*),* 1& L0(.('(*3 6(0%'()*7M !"#4 1-#
'"#* -#=#1'#604 20)*#6 ') );'1(* 1 2#00 0(*# 1-(&9
(*3 +-). 1 &(*30# 2#00 '"1' =-)6%2#& 1*'(;)6(#&
89:
)+ 1 &(*30# &=#2(+(2('4 N.)*)20)*10 2#00 0(*# )-
"4;-(6).1P7
R* '"# )'"#- "1*6: ! 2#00& 1-# =)'#*'(1004 1;0#
') -#2)3*(<# '%.)- 1*'(3#*& N"P7 A+'#- (*'-12#09
0%01- 6#3-161'()*: &%2" 1*'(3#*& N#737: .%'1'#6
=-)'#(*&P 21* ;# =-#&#*'#6 ') SQTU 24')')5(2 !
2#00& 1& VDS 201&& @9;)%*6 =#='(6#&7 !"# !92#00
-#&=)*&# (& DWA9-#&'-(2'#6: '"1' (&: (' 6#=#*6&
)* ,"#'"#- '"# .%'1'#6 '%.)- =#='(6# +('&
(* '"# 1*'(3#*9=-#&#*'(*3 &('# )+ '"# DWA .)0#9
2%0# N&## =7 XYP7 !%.)- 2#00& 1-# *)' #++#2'(/#
1*'(3#*9=-#&#*'(*3 2#00& ;#21%&# '"#4 012B (.9
=)-'1*' 2)9&'(.%01')-4 .)0#2%0#& N&## =7 ZYP7
1" 23$(*)+)%4*)&( &+ ,-.&/ !(*)'$(0
!92#00 20)*#& '"1' &=#2(+(21004 04&# '1-3#' 2#00&
21* ;# (&)01'#6 ;4 20)*(*3 '#2"*($%#& N&## =7
[JP7 @* )-6#- ') (6#*'(+4 '"# QGA &#$%#*2# )+
'"# 2)--#&=)*6(*3 '%.)- 1*'(3#*: '"# ')'10
QGA )+ '"# '%.)- 2#00& (& =-#=1-#6: &#=1-1'#6
(*') .%0'(=0# &.100 +-13.#*'&: 1*6 (*&#-'#6
(*') /#2')-& N!P7 !"# +-13.#*'9;#1-(*3 /#2')-&
1-# '"#* '-1*&6%2#6 ') 2#00& ,('" '"# &1.#
DWA -#&'-(2'()* 1& '"# '%.)- 2#00&7 R*04 '")&#
2#00& 2)*'1(*(*3 '"# -#0#/1*' QGA +-13.#*'
=-#&#*' (' (* '"# VDS .)0#2%0#&7 !"#4 21*
'"#-#+)-# ;# -#2)3*(<#6 1*6 04&#6 ;4 '"#
!92#00 20)*#&7
A* 10'#-*1'(/# .#'")6 (& '"# #0%'()* )+
=#='(6# +-). '%.)- 2#00&7 @* )-6#- ') +(*6 )%'
,"(2" )+ '"# =#='(6#& =-#&#*'#6 ;4 1 2#00 1-#
'%.)-9&=#2(+(2: 100 =#='(6#& (* '"# VDS .)0#9
2%0# 1-# +(-&' 6(&&)0/#6 ;4 ;-(#+ 12(6 '-#1'.#*'
N"P7 !"# 6(&&)0/#6 =#='(6#& 1-# &#=1-1'#6 ;4
"(3"9=#-+)-.1*2# 0($%(6 2"-).1')3-1="4 NDCWSP7
!"# (*6(/(6%10 =#='(6# +-12'()*& 1-# '"#* (*2%9
;1'#6 ,('" 1 !AC96#+(2(#*' 2#00 0(*# N&## =7 \XZP7
!"# 2#00 0(*#& (& *)' 1;0# ') &%==04 VDS .)0#9
2%0#& ,('" =#='(6#&7 L?.='4M VDS .)0#2%0#&
)* '"# 2#00 .#.;-1*# 1-# %*&'1;0# 1*6 6#9
3-16#6 $%(2B047 !"# #5'#-*10 166('()* )+ #512'04
.1'2"(*3 =#='(6#& &'1;(0(<#& '"#.: 1*6 '"#
VDS .)0#2%0#& 1-# '"#* 1;0# ') =-#&#*' '"#
;)%*6 =#='(6#&7 @+ )*# )+ '"# =#='(6# (& '%9
.)-9&=#2(+(2: '"# 2)--#&=)*6(*3 =-#&#*'(*3
2#00 (& 04&#6 ;4 '"# '%.)-9&=#2(+(2 !92#00 20)*#7
F%-'"#- 2"1-12'#-(<1'()* )+ '"# =#='(6#& (&)9
01'#6 +-). '"# VDS .)0#2%0#& 21* ;# 12"(#/#6
;4 .1&& &=#2'-).#'-47
 ;$*$%*)&( 4(3 23$(*)+)%4*)&( &+ ,-.&/ !(*)'$(0

Myeloma
cell
!
Cloning

Spleen
cell
Immunization Spleen Fusion
with tumor cells removal (+PEG)

Hybrid
cell

Myeloma HAT-sensitive Culture in Reactivity test Hybridoma

cell line mutant HAT medium against tumor cells clones

75)()%45 2..-(&5&'6
1. Production of monoclonal antibodies against tumor antigens

E.g., Tumor cell CD8

mutated
protein
ER
Tumor-
Proteasome specific
T-cell
MHC I TCR

"
TAP Tumor-
specific
2. Antigen recognition by T cells peptide

A. Recognition of tumor antigens

Tumor CD8 CD8

peptide Tumor
T cell
Tumor cell T cell cell
clone
(e.g., clone
HLA-A2) MHC I TCR TCR Tumor
peptide
Acid elution of
DNA Fractionation MHC-bound
extraction by HPLC peptides
DNA columns
fractionation

Insertion of
DNA fragments
in vectors

Insert in
HLA-A2+ cells
Peptide loading
of cell line with
empty MHC I

!
T-cell clone only lyses
cells with molecules
tumor antigen-coding DNA T-cell
Lysis by
clone
T-cell clone
1. Identification of genes 2. Identification of peptides

B. Identification of tumor antigens

898

"
! #$%&' /%%$(&8&+9
!" #$%&' !()*+,(-
!"#$%%&' $ ()*+, $-(./#- 01+)%" 2# #34,#00#"
+-%& 2& ()*+, 5#%%0 $-" -+( 2& -+,*$% 5#%%0
.- +,"#, (+ 2# ,#5+/-.6#" $0 7+,#./- 2& (1# .*8
*)-# 0&0(#*9 !- ,#$%.(&' *+0( ()*+,8$00+5.$(#"
$-(./#-0 $,# +:#,#34,#00#" .- ()*+, 5#%%0 2)(
$,# $%0+ #34,#00#" .- 0*$%%#, $*+)-(0 .- -+,8
*$% 5#%%09 ;1# #-6&*# (&,+0.-$0#' 7+, #3$*4%#'
.0 #34,#00#" .- $%% -+,*$% *#%$-+5&(#0' 2)(
*)51 1./1#, 5+-5#-(,$(.+-0 +55), .- *#%$-+8
*$ 5#%%09 ;&,+0.-$0#804#5.7.5 ; 5#%%0 (1$( ,#5+/8
-.6# $-" <.%% *#%$-+*$ 5#%%0 5$- 2# 7+)-" .-
(1# 2%++" +7 0+*# *#%$-+*$ 4$(.#-(09 ;1#0#
; 5#%%0 $,# .-"##" ,#04+-0.2%# 7+, (1# "#4./8
*#-($(.+- +7 (1# 0<.- =:.(.%./+> .- 0+*# *#%$8
:8*(*238 /%%$(&8&+9
-+*$ 4$(.#-(09 ;1# +55),,#-5# +7 :.(.%./+ 7,#8
?)#-(%& 5+,,#%$(#0 @.(1 $ ,#04+-0# (+ (1#,$4&9
A-5+7#($% $-(./#-0' 0)51 $0 $%41$87#(+4,+8
(#.- $-" 5$,5.-+#*2,&+-.5 $-(./#- =BCD>' $,#
4,#0#-( .- ()*+,0 +7 (1# %.:#, $-" /+-$"0
$-" .- :$,.+)0 $"#-+5$,5.-+*$09 ;1#0# $-(.8
/#-0 $,# 0(,+-/%& #34,#00#" "),.-/ 7#($% "#:#%8
+4*#-(' 2)( $,# -+,*$%%& +-%& @#$<%& #38
4,#00#" .- $")%(09 A-5+7#($% $-(./#-0 5.,5)%$(#
$0 0+%)2%# 4,+(#.-0 .- (1# 2%++" +7 ()*+, 4$8
"
(.#-(0 $-" $,# (1#,#7+,# )0#7)% $0 .-".5$(+,0
+7 ()*+, 4,+/,#00.+- =()*+, *$,<#,0>9
!- E85#%% $-" ;85#%% %&*41+*$0 $-" %#)<#8
*.$0' 5%+-#804#5.7.5 "#(#,*.-$-(0 =.".+(&4#0>
+7 (1# .**)-+/%+2)%.-0 $-" +7 (1# ;85#%% ,#5#48
(+, ,#4,#0#-( .-".:.")$% $-" 04#5.7.5 ()*+,
$-(./#-09 F#-5#' -+ ,#$5(.:.(& @.(1 +(1#, (.08
0)#0 .0 (+ 2# #34#5(#"9
G)($(#" 4,+(#.-0 $,.0.-/ 7,+* 51,+*+0+*$%
(,$-0%+5$(.+-0 +, 4+.-( *)($(.+-0' +- (1# +(1#,
1$-"' ,#4,#0#-( 5+*4%#(#%& -#@ $-(./#-0
=!"#$!%&'"!(>9 !- (=HIJJ> )*+,-). (,$-0%+5$(.+-
+7 BGK' 7+, #3$*4%#' $ 7)0.+- 4,+(#.- "#:#%+40
2#(@##- (1# -+,*$% )*+ $-" -). /#-#09 L#48
(."#0 @.(1 0#?)#-5#0 7+,*#" 2& $*.-+ $5."0
+7 2+(1 +7 (1#0# /#-#0 5$- 7)-5(.+- $0 (,)# ()8
*+, $-(./#-09 L+.-( *)($(.+-0' @1.51 5+*8
*+-%& +55), .- ()*+, 0)44,#00+, /#-# /01
$-" +(1#, 5#%% 5&5%#8,#/)%$(.-/ 4,+(#.-0' 0)51
$0 /23 $-" /42' $%0+ %#$" (+ (1# "#:#%+4*#-(
+7 -#@ ()*+,804#5.7.5 4#4(."#0 (1$( "+ -+( +58
5), .- -+,*$% 5#%%09 F+@#:#,' (1#0# 4#4(."#0
*)0( 7.( .-(+ (1# FKD *+%#5)%#0 +7 (1# ()*+,
! 5#%%0 .- +,"#, (+ 2# ,#5+/-.6#" 2& (1# .**)-#
0&0(#*9 F#-5#' .( .0 4+00.2%# (+ 1$:# ()*+,0
@1#,# 0)51 ()*+,804#5.7.5 4#4(."#0 $,# 4,#0#-(
2)( -+( 4,#0#-(#" (+ (1# .**)-# 0&0(#* 2& (1#
.-".:.")$% GFB *+%#5)%#09 ;,)# :.,$% 4,+(#.-0
;<= 4,+")5#" 2& F;KMN .- ;85#%% %#)<#*.$ $-" C48
0(#.-OE$,, :.,)0 .- 0+*# *$%./-$-( %&*41+*$0
$,# ,#04+-0.2%# 7+, *$%./-$-( (,$-07+,*$(.+-
$-" $,# 4,+")5#" 2& ()*+, 5#%%09 ;1#,# .0 5%#$,
#:."#-5# (1$( (1#0# :.,$% 4,+")5(0 5$- 2# 0)58
5#007)%%& ,#5+/-.6#" 2& (1# .**)-# 0&0(#*9 !-
5+-(,$0( (+ 0.-/%# *)($(#" 4,+(#.-0' (1#0# :.,$%
4,+(#.-0 )0)$%%& 5+-($.- $ %$,/# -)*2#, +7 4#48
(."#0 (1$( $,# 4+(#-(.$%%& .**)-+/#-.5' $-"
(1#,# .0 $ /,#$( 51$-5# (1$( 0+*# +7 (1#*
@.%% 2.-" (+ (1# GFB *+%#5)%#0 +7 (1# 1+0( 5#%%09
." /%%$(, 01-234, 5,263(*-%-7
;1#,# $,# $ -)*2#, +7 ,#$0+-0 7+, (1# $20#-5#
+7 $- #77#5(.:# .**)-# ,#04+-0# (+ ()*+,09
C$51 $)(+%+/+)0 4,+(#.- .0 "#/,$"#" @.(1.-
(1# 5&(+4%$0* (+ 7+,* 4#4(."#0 5+-0.0(.-/ +7
HONJ $*.-+ $5."09 ;1#0# 4#4(."#0 $,# 5+-:#&#"
2& $ (,$-04+,( 0&0(#* 5$%%#" P(,$-04+,(#, $00+8
5.$(#" @.(1 $-(./#- 4,+5#00.-/ =;DL>Q (+ (1# #-8
"+4%$0*.5 ,#(.5)%)* =CR>' @1#,# (1#& $,#
2+)-" 2& 5%$00 ! GFB *+%#5)%#0 $-" 4,#0#-(#"
(+ BSTU ; 5#%%0 +- (1# 5#%% 0),7$5# =0## 49 VW>9
X+*# ()*+,0 *$& -+( 1$:# ()*+, 4#4(."#0
(1$( 7.( .-(+ (1# 2.-".-/ 0.(#0 +7 (1# 4$(.#-(Y0
GFB *+%#5)%#0 =!>9 !- ()*+, 5#%%0 @.(1 "#7#58
(.:# $-(./#- 4,+5#00.-/ *$51.-#,& =#9/9' ;DL
"#7.5.#-5&>' ()*+, 4#4(."#0 $,# -+( (,$-04+,(#"
(+ (1# #-"+4%$0*.5 ,#(.5)%)* ="> $-" $,# -+(
4,#0#-(#" +- (1# 5#%% 0),7$5#9 !- *$-& 5$0#0'
(1#,# .0 $ %$5< +7 GFB 5%$00 ! *+%#5)%#0 +-
(1# 0),7$5# +7 (1# ()*+, 5#%%0 ")# (+ (1# "+@-8
,#/)%$(.+- +7 GFB /#-#09 D0 $ 5+-0#?)#-5#' (1#
()*+, $-(./#-0 5$--+( 2# ,#5+/-.6#" 2& 5&(+8
(+3.5 ; 5#%%0 =#>9
;)*+, 5#%%0 $,# -+( 4,+7#00.+-$% $-(./#-8
4,#0#-(.-/ 5#%%09 ;1#& %$5< 5+80(.*)%$(+,& *+8
%#5)%#0 BSTZ $-" BSTW -##"#" 7+, ;85#%% $5(.8
:$(.+-9 [.(1+)( 5+80(.*)%$(.+-' (1# 4,#0#-($8
(.+- +7 $ 4#4(."# :.$ (1# GFB\;BR 5+*4%#3
%#$"0 (+ ;85#%% $-#,/& $-" (+%#,$-5# =$>9 X+*#
()*+, 5#%%0 $%0+ 0(+4 4,+")5.-/ ()*+, $-(./#-
(+ #05$4# $- .**)-# ,#04+-0# =%>9 D%(#,-$8
(.:#%&' (1# ()*+, *$& 4,+")5# .**)-+0)48
4,#00.:# 0)20($-5#0' 0)51 $0 !K8NZ $-" (,$-08
7+,*.-/ /,+@(1 7$5(+, 2#($ ! =;]^8!> =&>' $-"
.- 0+*# 5$0#0' GFB !8%.<# *+%#5)%#0 (1$( .-(#,8
$5( @.(1 .-1.2.(+,& %./$-"0 +- ; 5#%%0 $,# #38
4,#00#" 2& ()*+, 5#%%09 R#5#-(%&' ,#/)%$(+,&
; 5#%%0 =BS_! BSJV! > 1$:# 2##- 01+@- (+ 0)48
4,#00 .**)-+,#$5(.:.(& .- 4$(.#-(0 @.(1 0+%."
()*+,09
 /%%$(, 1-234, 5,263(*-%- &> #$%&' !()*+,(-

Normal Gene Products

!
Differentiation antigens Fetal antigens Clonal antigens
overexpressed in tumor cells Fetal liver Fetal bowel B cell T cell

Normal
melanocyte
Tyr mIg TCR
!-Fetoprotein Carcino-
Tyrosinase (AFP) embryonic Clonal proliferation
peptide antigen (CEA)
B-cell T-cell
lymphoma lymphoma

Tyr
Tyr Tyr
Melanoma
Tyr cell
Tyr Hepatic/testicular Bowel cancer Idiotypic antibody orTCR

:8*(*238 /%%$(&8&+9
cancer AFP+++ CEA+++ sequences
Mutated or Abnormal Proteins Viral proteins
Chromosomal translocations Point mutations
9 22
p21 p53 p16 HTLV1
t 9;22 Cell cycle-regulated proteins

BCR BCR-

"
ABL Infected
ABL
Point mutations T cell
BCR ABL
Fusion gene
Adult
T-cell
BCR-ABL protein
leukemia
(ATL)
Normal Tumor- Viral
Fusion peptide = tumor specific peptide specific peptide
peptide
A. Tumor antigens

Normal Tumor cells:

cells: MHC I
TAP
express expression
MHC I absent or
molecules reduced
1. Tumor peptide does not bind to MHC 2. Downregulation of MHC molecules

CD8
T-cell
TCR T-cell anergy,
Empty
tolerance
Defective TAP MHC I
molecule CD28
3. Defective antigen-processing machinery 4. Absence of co-stimulatory molecules
IL-10, TGF-", prostaglandins

!
Tyr Tumor antigen
no longer T-cell
T-cell anergy/
Tyr synthesized/
Tyr expressed apoptosis
FAS ligand FAS
5. Antigen modulation 6. T-cell-inhibitiory molecules, cytokines
B. Immune recognition escape mechanisms
;<?

"
! 72)+< 1))2$+:+=3

!" #$%&$'()($* +, -+$./('0,0' 1))2$0*3

!"#$%& '() )%& #* '() +,'( -)%'$"./ '() !0)"1
2-3% 4$"5)#% 6277230 8#7). 9)53% '# 2%:)-' -3%1
;#44297) '# 2%&$-) 3 4;)-2*2- K1-)77 ")4;#%4)
'# '() '$0#" 9. 3&02%24')"2%5 2""3&23')& 3$'#1
7#5#$4 '$0#" -)774 #" '$0#" -)77 7.43')4 H"J?
VA)% $%&)" 2&)37 -#%&2'2#%4 <()") '() '$0#"
-)" ;3'2)%'4 <2'( '$0#" -)77 7.43')4 '(3' <)")
-)774 ;")4)%' '$0#" 3%'25)% '# '() K -)774/ 3 4$*1
-#%'302%3')& <2'( 93-')"23 &$) '# '() 73-= #*
*2-2)%' 3%'2'$0#" 200$%) ")4;#%4) 24 %#' #91
4')"27) ;");3"3'2#% ')-(%2>$)4? @$";"242%57./
4)"A)& 9)-3$4) '() '$0#" -)774 73-= '() ")1
4#0) '$0#" ")5")442#% <34 #94)"A)&? B3')"
>$2")& -#14'20$73'#". 0#7)-$7)4/ 4$-( 34 IQ
2% '() CD'( -)%'$"./ '$0#" A3--2%3'2#% <34
H8WXDYXZJ H4)) ;;? OZ 3%& +[OJ? ! %$09)" #*
')4')& 3532%/ 9$' '() $4) #* $%0#&2*2)& '$0#"
'"2374 24 9)2%5 ;)"*#"0)& 2% <(2-( '$0#" -)774
-)774 37#%) &2& %#' 2%&$-) 425%2*2-3%' ")4;#%4)4?
3") 5)%)'2-377. 0#&2*2)& '# )M;")44 '() IQ 3%'21
!&:$A3%'4 <)") 4##% 3&&)& 2% 3'')0;'4 '# )%1
5)% 2% #"&)" '# 2%-")34) '()2" 200$%#5)%2-2'.
(3%-) '() '$0#"14;)-2*2- 200$%) ")4;#%4)? !'1
H!J? !%#'()" <3. '# 2%&$-) 3% 200$%) ")1
')%$3')& 0.-#93-')"237 4'"32%4/ 4$-( 34 93-277$4
4;#%4) '# ;##"7. 200$%#5)%2- '$0#" -)774 24
8370)'')EF$)G"2% HI8FJ #" !"#$%&'()*&#+,-
'# 377#< ;"#*)442#%37 3%'25)%1;")4)%'2%5 -)774
.(#/,-/ <)") ;"203"27. $4)&? K() L)<-34'7)
9:0$0'&: 1))2$+:+=3

H!\8J '# ;")4)%' '() '$0#" 3%'25)%4 H#J? K()

&24)34) A2"$4 (34 374# 9))% $4)& 2% 0#") ")-)%'
;"#*)442#%37 !\84 )M;")44 377 20;#"'3%' 4'20$1
)M;)"20)%'4? @#0) -72%2-37 4'$&2)4 934)& #%
73'#". 0#7)-$7)4 %))&)& '# 2%&$-) 3% )**)-'2A)
'(24 4'"3')5. 3") 4'277 2% ;"#-)44? !7'(#$5( %#
K1-)77 ")4;#%4)? !--#"&2%57./ &)%&"2'2- -)774
4<));2%5 4$--)44)4 -3% 9) )M;)-')& *"#0 '()4)
5)%)"3')& )M A2A# -3% '()")*#") 9) 7#3&)&
'"2374/ 4#0) ;#42'2A) ")4$7'4 2%&2-3') '(3' 201
H.,34&0J <2'( '$0#" -)77 7.43')4/ ;$"2*2)& '$0#"
;"#A)& A3--2%3'2#% 0)'(#&4 025(' 9) 4$--)441
3%'25)%4/ #" 4;)-2*2- '$0#" ;);'2&)4? K() ")4$7'4
*$77. &)A)7#;)& 2% '() *$'$")?
#* ;")7202%3". -72%2-37 '"2374 3") ;"#0242%5?
N% '() ;34' OEP .)3"4/ '$0#" -)774 (3A) 9))%
K() 7#-37 2%4'2773'2#% #* 8370)'')EF$)G"2% 931
0#&2*2)& 9. 5)%) '"3%4*)" '# 4)7)-'2A)7. 2%&$-)
-277$4 3*')" 7#-37 ")4)-'2#% #* -3"-2%#03 #* '()
K1-)7710)&23')& 200$%) ")4;#%4)4? K() 5#37 24
973&&)" 24 3 4;)-237 *#"0 #* 200$%#'()"3;.?

"
'# 4'20$73') '() 7#-37 5"#<'( #* K -)774 #" &)%1
I8F '")3'0)%' ;")A)%'4 '() &)A)7#;0)%' #* ")1
&"2'2- -)774 9. '() 4)-")'2#% #* -.'#=2%)4/ 4$-( 34
-$"")%-)4 2% 3 (25( ;)"-)%'35) #* -34)4? N%4'271
NB1C/ NB1P/ NB1Q/ 3%& FR18@S/ 2% '() (#;) #* 3-1
73'2#% #* '() 93-277$4 03. '"255)" 2%*73003'#".
'2A3'2%5 '$0#"14;)-2*2- K -)774?
;"#-)44)4 2% <(2-( 3-'2A3')& 3%'25)%1;")4)%'1
8.'#=2%)4 -3% 374# 9) 3&02%24')")& 4.4')021
2%5 -)774 3") 397) '# -3;'$") 3%'25)%4 *"#0 ")1
-377.? T#<)A)"/ #%7. 2%')"*)"#%1! HNSL1!J 3%& NB1
032%2%5 '$0#" -)774 3%& )**)-'2A)7. ;")4)%'
C (3A) 9)-#0) )4'39724()& 2% 3 *)< '.;)4 #* '$1
'()0 '# '() 200$%) 4.4')0?
0#"4 H!J? N% 3&&2'2#% '# 2'4 200$%#4'20$73'#".
)**)-'/ NSL1! 374# (34 3 &2")-' 3%'2;"#72*)"3'2A)
)**)-' '(3' 03. 9) ")4;#%4297) *#" 4#0) #*
'() '()"3;)$'2- )**)-'4? U)%37 -)77 -3"-2%#034
3%& 03725%3%' 0)73%#034 3;;)3" '# ")4;#%&
9)'')" '(3% #'()" '$0#"4 '# 200$%#'()"3;)$1
'2- ")520)%4/ 9$' '() ")34#% *#" '(24 24 4'277 $%1
=%#<%? K$0#" %)-"#424 *3-'#"1! HKLS1!J 24 374#
$4)& 2% ;3'2)%'4 <2'( 43"-#034 3%& 0)73%#034
2% 7209 ;)"*$42#% '#5)'()" <2'( 3%'2%)#;734'2-
&"$54 '# )%(3%-) '$0#" -)77 &3035)?

4" 1$52'*0+$ +, & 6/('0,0' 789(:: ;(./+$.(

N% 03%. ;3'2)%'4/ 4$"52-37 )M-242#% -3% 4$--)441
*$77. )7202%3') '() ;"203". '$0#" 3' '() '20) #*

!
&235%#424? T#<)A)"/ 3 ;"#;#"'2#% #* '()4) ;31
'2)%'4 <277 73')" &)A)7#; &24'3%' 0)'34'34)4 #"
7#-37 ")-$"")%-)4? K(24 24 <(. (01,/(%* *2&#(.$
24 ;)"*#"0)& 2% ;3'2)%'4 <2'( -)"'32% "24= *3-1
'#"4 H'$0#" '.;)/ &)5")) #* 03725%3%-./ &);'(
>?@ #* '$0#" 2%A342#%/ 7.0;( %#&) 2%A#7A)0)%'/
)'-?J? L#%)'()7)44/ 2% 0#4' -34)4/ 2' 4'277 24 %#'
 Addition of adjuvants:
BCG, Corynebacterium
1))2$+*%(<&/(2*0' 6*<&*(=0(. A1B
!
parvum

s.c. or c.v.
administration
of cytokines

Interferon-! – Chronic
- myelocytic
Postoperative - leukemia
– Plasmocytoma
Tumor removal, injection (s.c.)
– Lymphoma
tumor cell isolation – Melanoma
– Renal cell
- carcinoma

9:0$0'&: 1))2$+:+=3
Interleukin-2 – Renal cell
IL-2
- carcinoma
IL-7 – Melanoma
IL-4 – Leukemias
Insert cytokine-encoding GM-CSF
TNF-! – local perfusion of
genes into tumor cells
- sarcomas/melanomas
(retroviruses, adenoviruses, physical methods)

1. Vaccination with adjuvants, cytokine-producing cells 2. Cytokine therapy

A. Enhancement of nonspecific immunity

Irradiation
B7 gene

CD28
B7
"
Tumor Post- Tolerance T-cell
removal, Tumor operative activation
tumor cell lysate injection
cell isolation s.c., c.v. 2. Direct antigen presentation
CD80 gene

Phagocytosis
of tumor proteins
CD80+ tumor
cells
CD4

APC
Tumor
cell lysate

!
Defined tumor KSQSSALRK CD8
antigen/ Pulse with
tumor peptide purified T-cell
antigen, peptide activation
Autologous
1. Vaccination strategies APC 3. Indirect antigen presentation
B. Induction of a specific T-cell response
>??

"
! 0'1%$ >11'+%=%.9

!" #$%&'()*%+ %, -+.*+//$/&

0'1%$234/(*,*( 0563
!"#$ %&'()* ")+ +,%+#*-.+/$ -#0-/%)"%+1 2$ /$'3
45(6$%+*7 8&'()3-#0-/%)"%-#9 /$'45(6$%+* :8;<=
&*+1 %( 2+ )+'(.+1 0)(' *&)9-6"/ *4+6-'+#*>
+*4+6-"//$ 0)(' '+/"#('"* "#1 )+#"/ 6+// 6")3
6-#('"*> %5+# -*(/"%+1 "#1 )+%)"#*0&*+1 "0%+)
4)(/-0+)"%-(#7 ?(@+.+)> %5+ )+*&/%* @+)+ )"%5+)
1-*"44(-#%-#97 ;% -* #(@ 4(**-2/+ %( -1+#%-0$
%5+ ABC *+D&+#6+* (# %5+ .")-"2/+ 1('"-#*
(0 %5+ ! "#1 " 65"-#* (0 %5+ 836+// )+6+4%()*
(0 8;<7 E*-#9 .-)"/ .+6%()*> 9+#+%-6"//$ +#9-3
#++)+1 8 /$'45(6$%+* %5"% *4+6-0-6"//$ )+"6%
@-%5 %5+ %&'() 6"# 2+ 4)(1&6+17 C1(4%-.+
%5+)"4$ 6(&/1 %5+# 2+ 4+)0()'+1 2$ "1'-#-*3
5=*+*(;= >11'+%=%.9
"#%-2(1-+* ")+ "# -'4)(.+'+#% (0 %5-* *%)"%+9$
:#=7 85+*+ ")+ 9+#+%-6"//$ +#9-#++)+1 "#%-2(1$
1+)-."%-.+* %5"% 6(#*-*% (#/$ (0 %5+ /-95% "#1
5+".$ 65"-# (0 %5+ .")-"2/+ )+9-(# :N.= (0 %5+
'(#(6/(#"/ C27 U-#9/+ 65"-#* 0)(' %@( 1-00+)3
+#% "#%-2(1-+* 6"# 2+ 6(##+6%+1 2$ " 2-#1-#9
0)"9'+#% :*4"6+)=7 C/%+)#"%-.+/$> *-#9/+365"-#
"#%-2(1-+* %5"% )+6(9#-L+ " %&'() +4-%(4+
6"# 2+ /-#P+1 %( %5+ # 65"-#> @5-65 4/"$* "# -'3
4()%"#% )(/+ -# %5+ %)"#*1&6%-(# (0 8FH *-9#"/*7
8 6+//* 6"# 2+ %)"#*0+6%+1 @-%5 *&65 6(#*%)&6%*>
*( %5"% %5+$ 6"# )+6(9#-L+ " %&'() "#%-9+# -#
%5+ *"'+ @"$ "* "#%-2(1-+* 1(> "#1 %5+ *-9#"/
@-// 2+ %)"#*'-%%+1 %( %5+ -#*-1+ (0 %5+ 6+// 2$
%5+ 6(##+6%+1 8FH # 65"-#7 C#%-2(1-+* 1-)+6%+1

"9"-#*% %&'()3"**(6-"%+1 "#%-9+#* 6"# "/*( 2+

%+)-#9 *&65 +, .-.( +,4"#1+1 8 6+//*7 F&))+#%/$>
(#+ (0 %5+ '"G() /-'-%"%-(#* -* %5+ 1-00-6&/%$ (0
9+#+ %)"#*0+) -# #()'"/ 8 6+//*> 2&% -'4)(.+1
'+%5(1* ")+ 2+-#9 9+#+)"%+17 C/*(> +#1(9+#3
(&* 8FH '&*% 2+ 1(@#)+9&/"%+17
7" !+)*8%&9 0:/$;4*/3
!(#(6/(#"/ "#%-2(1-+* :!C2= 5".+ 2++# &*+1
-# 6"#6+) %)+"%'+#% 0() "2(&% IJ $+")* #(@7
!(*% "#%-2(1-+* 5".+ 2++# 9+#+)"%+1 -#
/-#P+1 %( -''&#(%(,-#* () )"1-(-*(%(4+*
:$%&=7 ;# -''&#(%(,-#*> %5+ %(,-6 6('4(#+#%*
%5"% 2/(6P %5+ *$#%5+*-* (0 HBC ")+ )+/+"*+1
"0%+) -#%+)#"/-L"%-(# (0 %5+ "#%-2(1$7 ;# )"1-(3
/"2+/+1 -''&#(6(#G&9"%+*> " )"1-("6%-.+ *&23
*%"#6+ :&*&"//$ )"1-("6%-.+ $%%)-&' () -(1-#+=
-#1&6+* %5+ /$*-* (0 %")9+% 6+//* 2&% "/*( (0
"1G"6+#% 6+//* :*(36"//+1 K2$*%"#1+) +00+6%M=7
5" </(:;+*313 %, <%+%(=%+;= !+)*8%&9

" '-6+7 8)+"%'+#% @-%5 '&)-#+ !C2 /+"1* %(

%5+ 0()'"%-(# (0 5&'"# "#%-3'&)-#+ "#%-2(3
1-+* :?C!C=> @5-65 )+1&6+ %5+ +00-6"6$ (0 '&)3
-#+ !C2> %5+)+0()+ K5&'"#-L+1M '(#(6/(#"/
"#%-2(1-+* @+)+ 1+.+/(4+1 :!=7 ;# 5&'"#-L+1
'(#(6/(#"/ "#%-2(1-+*> %5+ 9)+"%+) 4()%-(# (0
0:/$;49
C '(#(6/(#"/ "#%-2(1$ 6"# -'-%"%+ () 2/(6P %5+
#"%&)"/ /-9"#1* (0 " )+6+4%()7 C# "#%-3FAVW "#%-3
2(1$ 6"#> 0() +,"'4/+> "6%-."%+ %5+ N"*XCYZ3[
)+6+4%() :FAVW=> %5+)+2$ %)-99+)-#9 "4(4%(*-*
:!=7 Z# %5+ (%5+) 5"#1> "#%-2(1-+* 6"# "6%-."%+
%5+ '(/+6&/+ -* (0 5&'"# ()-9-#> "#1 (#/$
6('4/+'+#% "#1 %5&* -#1&6+ 4()+ 0()'"%-(# -#
%5+ N:"2= 0)"9'+#% () %5+ .")-"2/+ )+9-(# (0
%5+ 6+// '+'2)"#+ :"=7 ;# "#%-2(1$31+4+#1+#%
N:"2= -* (0 '&)-#+ ()-9-#7 ?&'"#-L+1 '(#(3
6+//3'+1-"%+1 6$%(%(,-6-%$> N6 )+6+4%()32+")-#9
6/(#"/ "#%-2(1-+* 5".+ " *-9#-0-6"#%/$ /(#9+)
#"%&)"/ P-//+) 6+//* )+6(9#-L+ %5+ N6 0)"9'+#% (0
5"/03/-0+ -# %5+ 4"%-+#%O* 2/((1 "#1 %5+$ "6%-."%+
" 6+//32(&#1 "#%-2(1$ "#1 %5&* )+/+"*+ 6$%(3
%5+ -''&#+ +00+6%() 6+//* '()+ +00-6-+#%/$
4/"*'-6 9)"#&/+* 6(#%"-#-#9 6$%(%(,-6 4+)0()-#*
%5"# '&)-#+ '(#(6/(#"/ "#%-2(1-+*7 8@( 5&3
"#1 9)"#L$'+* :#> *++ "/*( 47 TV=7
'"#-L+1 '(#(6/(#"/ "#%-2(1-+* 5".+ "65-+.+1
C* '+#%-(#+1> '&)-#+ C2 6"# -#1&6+ ?C!C7
)+'")P"2/+ )+*&/%* -# %5+ 4"*% %5)++ $+")*Q %5+
U('+ (0 %5+*+ "#%-3'&)-#+ "#%-2(1-+* '"$ 2+
FAIJ "#%-2(1$ H-%&,-'"2 :H-%&,"#!= 5"* "6%-.3
1-)+6%+1 "9"-#*% %5+ *4+6-0-6 -1-(%$4-6 2-#1-#9
-%$ "9"-#*% R36+// /$'45('"*> "#1 %5+ "#%-2(1$
)+9-(# (0 '&)-#+ C2 :&=7 ;# %5-* 6"*+> %5+
%)"*%&L&'"2 :?+)6+4%-#!= 1-)+6%+1 "9"-#*%
"#%-3-1-(%$4-6 "#%-2(1-+* -'-%"%+ %&'() "#%-3
5&'"# +4-1+)'"/ 9)(@%5 0"6%() )+6+4%() I
9+#* "#1 6"# *+).+ "* " %&'() *&))(9"%+ -#
:?SHI= -* "6%-.+ -# 2)+"*% 6"#6+)7 C #&'2+)
."66-#+*7 Z# %5+ (%5+) 5"#1> %5+$ 6"# "/*(
(0 (%5+) "#%-2(1-+* "44+") 4)('-*-#97 KR-*4+6-3
/+"1 %( %5+ 0()'"%-(# (0 "#%-3"#%-3-1-(%$4-6
0-6M "#%-2(1-+* ")+ "#(%5+) #+@ 1+.+/(4'+#%
'(#(6/(#"/ "#%-2(1-+*> @5-65\/-P+ '&)-#+

!
:"=7 85+$ ")+ 4)(1&6+1 2$ 0&*-(# (0 %@( 5$3
!C2*\)+6(9#-L+ %5+ %&'() "#%-9+#7 85+ +00+6%
2)-1('"*> +"65 (0 @5-65 *+6)+%+* " *4+6-0-6
(0 %5+ '&)-#+ '(#(6/(#"/ "#%-2(1-+* -* +#3
'(#(6/(#"/ "#%-2(1$7 85+ 5$2)-1('"* 2-#1 *-3
5"#6+1 2$ %5-* 6"*6"1+7
'&/%"#+(&*/$ %( %5+ +4-%(4+ (0 %5+ %&'() 6+//
"#1 %( 8 6+//* :FAT=7 85+ 8 6+//* ")+ %5+)+0()+
?@A 2)(&95% -# 6(#%"6% @-%5 %5+ %&'() 6+//* "#1
")+ "6%-."%+1 2$ FAT7 U$#%5+%-6 *-#9/+365"-#
 Tumor
>11'+%):/$;4/')*( B)$;)/.*/3 C>>D
!
peptide Gene transfer in
Cloning the DNA lymphocytes,
sequence of TCR from expansion of
tumor-infiltrating T cells with
lymphocytes tumor -reactive TCR

MHC-I TCR DNA expression in Adoptive

vectors immune therapy

A. Production of tumor-specific TCR by gene modification

1. Human Murine Fc + part of Fab = Anti-APO-1 1.

Fc Fab human Fas

Apoptosis

5=*+*(;= >11'+%=%.9
APO-1
Fas

Murine mono- “Humanized Only variable Antibody imitates the natural

clonal anti- antibody” sequence is ligand of a molecule:
body (MAb) murine “agonistic effect”
2. Monospecific CD3 Tumor-associated 2.
antibodies antigen
Pore formation
Tumor

"
T cell
cell

Fusion of hybridomas Bispecific

(quadromas) antibody
Bispecific antibodies Activation of the complement cascade

3. Fv protein Variable E.g., Chimeric Fc-receptor 3.

part of !-chain T-cell receptor
antibody of TCR Necrosis,
Perforins, apoptosis
granzymes

Only variable part Transfection

of antibody of T cells Antibody-dependent cellular
Genetically produced antibody derivatives cytotoxicity (ADCC)

4. Toxin Tumor 4.
antigen

Production
of human

!
anti-mouse
Murine Ab antibodies
Radioisotope MAb therapy (HAMA),
which
Immunotoxins - immunoconjugates imitate the
antigen
B. Antibody therapies C. Mechanisms
?@E

"
! !"#$%&'#$(#()*$ >55-$*'*.B

!"#$%&'#$(#()*$ *+ ,-(*'*.*-% /*$0

1#""*23405#(*&*)0()6 7(05 80''%
!"#$ %&'()*+ ,*-,./"00$ 0,&1,'/"* "#2 0$'3
-4('"*+ ."# 5, ,0/'/#"%,2 6/%4 *&77/./,#%0$
4/84 2(*,* (7 .4,'(%4,)"-$ "#2 )"2/(%4,)"-$9
:4, %(;/./%$ (7 %4, %4,)"-$ /* " 0/'/%/#8 7".%()
5,."&*, /)),<,)*/50, 2"'"8, %( %4, 4,'"%(3
-(/,%/. 5(#, '"))(6 ='$,0("50"%/(#> ."# (.3
.&)9 :4, %)"#*7&*/(# (7 ?@@AB@@ '0 (7 5(#,
'"))(6 50((2 7)(' " 4,"0%4$ 2(#() 6/00 *&77/.,
7() ),.(#*%/%&%/(# (7 %4, 4,'"%(-(/,%/. *$*%,'
="00(8,#,/. 5(#, '"))(6 %)"#*-0"#%"%/(#+ "00(3
8,#,/. C!:>9 C(#, '"))(6 7&#.%/(# ."# "0*( 5,
),.(#*%/%&%,2 5$ ),%)"#*7&*/#8 "&%(0(8(&* 5(#,
'"))(6 ),'(<,2 D&*% -)/() %( "50"%/<, %4,)"-$
8')$)6#' >55-$*'*.B
64,# .)$(-),*,)<,2 *%,' .,00* "), ),/#7&*,2
(# .('-0,%/(# (7 .4,'(%4,)"-$9 S&00 ),.(#*%/3
%&%/(# (7 %4, 4,'"%(-(/,%/. *$*%,' *&5*,3
K&,#%0$ (..&)*9
89 >$=)6#()*$%
L&%(0(8(&* 4,'"%(-(/,%/. *%,' .,00 %)"#*-0"#3
%"%/(# =LTJE:> () 5(#, '"))(6 %)"#*-0"#%"%/(#
/* "0*( -,)7()',2 /# " #&'5,) (7 4,'"%(0(8/."0
2/*,"*,* "#2 /# /*(0"%,2 *(0/2 %&'()*+ ,*-,./"00$
8,)'/#"0 .,00 %&'()*9 :4, -)(.,2&),* "), "0*(
/#2/."%,2 /# 8,#,%/. ,#8/#,,)/#8 (7 *%,' .,00*
7() %),"%',#% (7 .(#8,#/%"0 ',%"5(0/. () /'3
'&#, 2,7,.%*9 !(), ),.,#%0$+ 4/8432(*, .4,3
'(%4,)"-$ 7(00(6,2 5$ *%,' .,00 ),/#7&*/(#

="&%(0(8(&* C!:>9 4"* "0*( 5,,# -,)7()',2 /# %4,)"-$3),*/*%"#%

,9 7(05 80'' 4#":0%()$.
C(#, '"))(6 50((2 /* 4")<,*%,2 5$ ),-,"%,2
-&#.%&), (7 %4, /0/". .),*% 6/%4 %4, -"%/,#% &#3
2,) 7&00 "#,*%4,*/"9 :4, 7,6 EFGHI *%,' .,00*
-),*,#% /# %4, 4")<,*% "), ),*-(#*/50, 7() ),3
.(#*%/%&%/(# (7 4,'"%(-(/,*/*9 J&.4 .,00* "),
#(% (#0$ -),*,#% /# %4, 5(#, '"))(6+ 5&%
"0*( ./).&0"%, /# *'"00 K&"#%/%/,* /# %4, -,)/-43
"&%(/''&#, 2/*,"*,*9 EFGHI .,00* "), "0*(
"50, %( 2/77,),#%/"%, /#%( 2,#2)/%/. .,00* () /'3
'&#, ,77,.%() .,00* /# </%)(9 U# %4/* ."*,+ %)"#*3
-0"#%"%/(# ."# 5, -,)7()',2 /# .(#D&#.%/(#
6/%4 /''&#(%4,)"-$9
?9 @-".)$. (A0 ,-(*("#$%&'#$(
U# "&%(0(8(&* %)"#*-0"#%"%/(#+ %4,), /* " )/*1
%4"% %4, %)"#*-0"#% '"$ .(#%"/# .(#%"'/#"%/#8

" ,)"0 50((29 :4, .,00* ."# %4,),7(), 5, ,;%)".%,2

5$ 0,&1"-4,),*/*+ " -)(.,** /# 64/.4 '(#(#&.3
0,") .,00*+ /#.0&2/#8 *%,' .,00*+ "), 4")<,*%,2 5$
*,0,.%/<, .,#%)/7&8"%/(# (7 %4, 50((29 L)(&#2 BA
MN 0/%,)* (7 50((2 .(#%/#&(&*0$ 70(6 %4)(&84 %4,
.,00 *,-")"%() (<,) " -,)/(2 (7 OAN 4(&)*9 :4/*
$/,02* "--)(;/'"%,0$ GN@ '0 (7 50((2 6/%4 ,#3
)/.4,2 *%,' .,00*+ 64/.4 "), .)$(-),*,)<,2 7()
0"%,) &*,9 :4, '/#/'&' ),K&/),',#% (7 EFGHI
.,00* 7() *&..,**7&0 ),.(#*%/%&%/(# (7 %4, 4,'"3
%(-(/,%/. *$*%,' /* ")(&#2 O!M@P EFGHI .,00*Q18
5(2$ 6,/84%9
/9 1*;)')<#()*$ *+ 405#(*&*)0()6 7(05
80''% #$= 8*-"%0 *+ !"#$%&'#$(#()*$
:4, #&'5,) (7 EFGHI *%,' .,00* /# %4, -,)/3
-4,)"0 50((2 /* 0(6+ 5&% ."# 5, /#.),"*,2 5$
"2'/#/*%,)/#8 ),.('5/#"#% 4,'"%(-(/,%/.
8)(6%4 7".%()*+ *&.4 "* R3EJS () R!3EJS9
C(#, '"))(6 ,;%)".%/(# () 0,&1"-4,),*/* /*
*&5*,K&,#%0$ -,)7()',29 :4, 4")<,*%,2 %)"#*3
-0"#% ."# 5, .)$(-),*,)<,2 7() "* 0(#8 "* #,.,*3
%&'() .,00*9 :4, %)"#*-0"#% '"%,)/"0 /* %4,),3
7(), *&5D,.%,2 %( " -&)/7/."%/(# -)(.,2&), ."00,2
!"#$%&$9 J/#., %4, EFGH "#%/8,# /* #(% ,;3
-),**,2 (# %4, *&)7"., (7 *(0/23%&'() .,00*+ -(3
*/%/<, *,0,.%/(# (7 EFGHI .,00* /* -(**/50,9 U# %4,
-),*,#., (7 5/(%/#$0"%,2 "#%/3EFGH "#%/5(2/,*+
%4, EFGHI .,00* "), 5(&#2 %( " .(0&'# -".1,2
6/%4 "</2/# "#2 0"%,) *,-")"%,29 :4, -&)/%$ (7
EFGHI .,00* 4")<,*%,2 5$ %4/* ',%4(2 /* ")(&#2
V@ W9 S&)%4,) ),'(<"0 (7 .(#%"'/#"%/#8 %&'()
.,00* /* ".4/,<,2 5$ #,8"%/<, *,0,.%/(#9 :4/* /*
2(#, &*/#8 /)(# 5,"2* .("%,2 6/%4 "#%/5(2/,*
"8"/#*% %&'() "#%/8,#*9 E,00* 5,")/#8 %4, %&'()
"#%/8,# "), %4,# ),'(<,2 5$ "--0$/#8 " '"83
#,%/. 7/,029
:4, .(#%)/5&%/(# (7 .(#%"'/#"%/#8 %&'()
.,00* %( ),0"-*, (7 %4, %&'() "7%,) 4/8432(*,
.4,'(%4,)"-$ /* *%/00 " '"%%,) (7 2,5"%,9 X)(53
"50$ '(*% (7 %4, ),0"-*,* "), 2&, %( " -,)*/*3
%,#., (7 %&'() .,00* /# %4, 5(2$ )"%4,) %4"#
/# %4, %)"#*-0"#%9

!
*")$9 T/8432(*, .4,'(Q)"2/(%4,)"-$ 0,"2* %(
5(#, '"))(6 "-0"*/" =2,.),"*, /# %4, #&'5,)
(7 ,)$%4)(.$%,*+ 8)"#&0(.$%,*+ "#2 %4)('5(3
.$%,* /# %4, -,)/-4,)"0 50((2>+ 64/.4 6(&02
5, /)),<,)*/50, 6/%4(&% %4, ),/#7&*/(# (7 *%,'
CDE .,00*9 :4, "-0"*/" -4"*, 0"*%* (#0$ M@AMN 2"$*
 !"#$%&'#$(#()*$ *+ ,-(*'*.*-% /*$0 1#""*23405#(*&*)0()6 7(05 80''%

Bone marrow
!
0.5% ~850 ml
BM blood CD34+
CD34+
cells

Bone marrow (BM) aspiration

Peripheral blood

0.1%
CD34+ ~350 ml
leuka- CD34+
cells
pheresis
product
Stem cell graft
A. Stem cell harvesting Leukapheresis

8')$)6#' >55-$*'*.B
BM-aspiration Cryo- Stem cell
leukapheresis conser- reinfusion
-196ºC vation
Cytokine Reconstitution
stimulation by graft

mG-CSF
GM-CSF

20000
5000
1000
Leukocytes
Myeloablative
therapy
± radiotherapy

Aplasia 10–20 days

"
0
B. Mobilization of hematopoietic stem cells and transplantation schedule

– Acute leukemias – Immune defects

– Hodgkin’s lymphoma – Hemophilia
– Non -Hodgkin’s lymphoma – Immune therapy of cancer
– Breast cancer – Gene modification
– Germ cell tumors - of stem cells

1. Enhancement of the chemotherapeutic effect 2. Genetic and experimental therapy

C. Indications

Avidin Cobalt– Bead with iron core

MAb samarium
magnet
Biotin CD34

Enrichment MAb Depletion of

CD34 of CD34+ cells CD34+

!
contaminating
tumor cells
~90% purity
CD34+
Stem cell

D. Purging of the autograft

CDF

"
! #$%&'()%&*%*+,& 966>&,),.B
!" #$%&'()%&*%*+,& ,- !)),./&/+0 1,&/
2%$$,3 %&4 5/6%*,(,+/*+0 7*/6 8/))'
! "#$%&'()*+ ,#-#. $/0' )+ &1&(*&)*+ 2#. &- &*3
*#4+-+(" '.&-0%*&-'&'(#-5 6+*&'(1+0 7('8 (,+-'(3
"&* 9:! &-'(4+-0 &.+ 2(.0' 0#/48' (- '8+ ($$+,(3
&'+ 2&$(*;5 <8+ %.#)&)(*('; #2 2(-,(-4 & 2/**;
9:!3"#$%&'()*+ ).#'8+. #. 0(0'+. =&** 9:! &-'(3
4+-0 $&'"8+,> (0 ?@A5 B2 '8+.+ (0 -# ,#-#. (- '8+
2&$(*;C #. (- $#.+ ,(0'&-' .+*&'(1+0 =+545C &/-'0C
/-"*+0C "#/0(-0>C (-'+.-&'(#-&* ,&'&)&0+0 &.+
0+&."8+, 2#. 9:!3"#$%&'()*+ ,#-#.05 D#-+
$&..#7 #. %+.(%8+.&* 8+$&'#%#(+'(" 0'+$ "+**0
&.+ /0+, &0 '.&-0%*&-'5 E#., )*##, "&- &*0# )+
/0+,F (' 8&0 *&.4+ G/&-'('(+0 #2 EHIAJ < "+**0 &-,
#-*; & 2+7 $&'/.+ < "+**05 <8+ .+"(%(+-' (0 /0/&*3
8)+&+0%) 966>&,),.B
*; K"#-,('(#-+,L %.(#. '# '8+.&%;C +545C 7('8 &
"#$)(-&'(#- #2 8(483,#0+ &*M;*&'(-4 &4+-'0
&-, '#'&*3)#,; (..&,(&'(#- =?NO?A P;>5 <8(0 ,+3
0'.#;0 '/$#. "+**0 &-, %.#,/"+0 0/22("(+-' ($3
$/-#0/%%.+00(#- '# %.+1+-' '8+ .+Q+"'(#- #2
'8+ 2#.+(4- )#-+ $&..#7R0'+$ "+**05
1" 9&4+0%*+,&'
B- $&*(4-&-' ,(0+&0+0C '8+ '.&-0%*&-'&'(#- (0
%+.2#.$+, #-*; ,/.(-4 & "#$%*+'+ .+$(00(#-C
" '8&' (0C &2'+. '8+ $&Q#.('; #2 '/$#. "+**0 8&1+
)++- +*($(-&'+, ); "#-1+-'(#-&* "8+$#'8+.3
&%;5 !**#4+-+(" )#-+ $&..#7 '.&-0%*&-'&'(#-
(0 & "/.&'(1+ '.+&'$+-' 2#. "8.#-(" $;+*#(,
*+/M+$(&5 B- &"/'+ $;+*#(, *+/M+$(& &-, &"/'+
*;$%8#(, *+/M+$(&C '.&-0%*&-'&'(#-0 &.+ %+.3
2#.$+, #-*; (- '8#0+ %&'(+-'0 7('8 & 8(48
.(0M #2 .+"/..+-"+5 S'8+. (-,("&'(#-0 (-"*/,+ 0+3
1+.+ &%*&0'(" &-+$(&0C %&.#T;0$&* -#"'/.-&*
8+$#4*#)/*(-/.(&C 0+1+.+ "#$)(-+, ($$/-+
,+2+"'0C &-, '8&*&00+$(&5 <8+ .#*+ #2 &**#3DU<
(- 0#*(, '/$#.0 (0 /-"*+&.@ +-"#/.&4(-4 .+0/*'0
&.+ )+(-4 &"8(+1+, (- .+-&* "&-"+.5
8" 8,6()+0%*+,&'
9(483,#0+ "8+$#'8+.&%; #. .&,(#'8+.&%;
"&/0+0 ,&$&4+ '# 1&.(#/0 #.4&-0 =!>5 H&$&4+
'# $/"#0&* *(-(-40 7('8 /*"+.&'(#- &-,C (-
0#$+ "&0+0C 0+1+.+ ,(&..8+& "&- #""/. &-;3
78+.+ (- '8+ 4&0'.#(-'+0'(-&* '.&"'5 V+-#3#""*/3
0(1+ ,(0+&0+ =VSH> (0 & *(2+3'8.+&'+-(-4 "#$%*(3
"&'(#- 7('8 0(4-0 .&-4(-4 2.#$ $(*, ,&$&4+
!
'# '8+ %#0'"&%(**&.; 1+-/*+0 #2 '8+ *(1+. '# *(1+.
2&(*/.+5 B-'+.0'('(&* %-+/$#-(& (0 -#' /-"#$3
$#-5 B-2+.'(*('; (0 /0/&**; /-&1#(,&)*+C )/'
'8+ 0%+.$ #2 $&*+ %&'(+-'0 "&- )+ 2.#W+- )+2#.+
'8+.&%;5 X+1+.+ 8+$#..8&4(" ";0'('(0 "&- #""/.
CDE &0 & 0(,+ +22+"' #2 ";"*#%8#0%8&$(,+5 X+"#-,&.;
-+#%*&0$0 "&- #""/. &0 *&'+ 0+G/+*&+5 B-2+"3
'(#-0 ); $/*'(.+0(0'&-' 0'&%8;*#"#""(C %0+/,#3
$#-&,0C &-, 2/-4( &.+ +0%+"(&**; ,&-4+.#/0
,/.(-4 '8+ &%*&0(& %8&0+ =">5 E;'#$+4&*#3
1(./0+0 =EUV0>C 78("8 "&- (-,/"+ 0+1+.+ %/*3
$#-&.; &-, 4&0'.#(-'+0'(-&* (-2+"'(#-0C &.+
'8+ $#0' ($%#.'&-' 1(.&* %&'8#4+-05 D+"&/0+
%*&'+*+' .+%*&"+$+-' (0 0#$+'($+0 ,(22("/*'
,/+ '# '.&-0%*&-'3.+*&'+, &**#($$/-(W&'(#-C
'8+.+ (0 & .(0M #2 8+$#..8&4+5
P.&2'31+.0/038#0' ,(0+&0+ =PV9H> =#>C #-+ #2
'8+ $&(- "&/0+0 #2 $#.)(,('; &-, $#.'&*(';
&2'+. &**#4+-+(" '.&-0%*&-'&'(#-C (0 "&/0+, );
,#-#. < *;$%8#";'+0 7('8(- '8+ '.&-0%*&-' &'3
'&"M(-4 ,(22+.+-' '(00/+0 #2 '8+ .+"(%(+-'5 B-
9:!3"#$%&'()*+ '.&-0%*&-'&'(#-0C '8+ PV9H
.+0%#-0+ (0 ,(.+"'+, &4&(-0' !"#$% &"'($)$!*
+,("-"."(/ ,#("01#'5 !-'(4+-3%.+0+-'(-4 "+**0 #2
'8+ .+"(%(+-' %.+0/$&)*; %.+0+-' '8+ 2#.+(4-
'(00/+ &-'(4+-0 '# '8+ ,#-#. < *;$%8#";'+05
<8(0 0++$0 +0%+"(&**; *(M+*;C 0(-"+ '8+ &"'(1(';
#2 '8+ !YE (0 (-".+&0+, ,/+ '# ";'#M(-+0 (-3
,/"+, ); "8+$#R.&,(#'8+.&%;C +545C B:3?C B:3ZC
&-, <[\3!5 PV9H $&(-*; &22+"'0 '8+ 0M(-
=0$&**30%#''+, +T&-'8+$&>C *(1+. ="8#*+0'&'("
8+%&'('(0>C &-, )#7+* =,(&..8+&>5 H.;-+00 #2
'8+ $/"#0&+ &-, "#--+"'(1+ '(00/+ =0(""& 0;-3
,.#$+> &-, $;#0('(0 $&; &*0# #""/.5 PV9H
%.#%8;*&T(0 "#-0(0'0 #2 ($$/-#0/%%.+00(1+
'8+.&%; 7('8 ";"*#0%#.(-+C 78("8 "&- &*0# )+
4(1+- (- "#$)(-&'(#- 7('8 $+'8#'.+T&'+C $;3
"#2+-#*&'+ $#2+'(*C '&".#*($/0C &-, "#.'("#0'+.3
#(,0C (2 -+"+00&.;5
:" #;8/)) :/()/*+,& %&4 <$%-*;=/$'>';
?/>@/6+% A--/0*
<8+ .(0M #2 PV9H "&- )+ .+,/"+, ); ,+%*+'(-4
'8+ < *;$%8#";'+0 (- '8+ '.&-0%*&-'5 <8+ ,.&73
)&"M (0 &- (-".+&0+, .(0M #2 '.&-0%*&-' .+Q+"'(#-
&-, #2 '/$#. .+"/..+-"+ )+"&/0+ '8+ ,#-#. <
*;$%8#";'+0 $+,(&'+ '8+ )+-+2("(&* 4.&2' 1+.3
0/0 *+/M+$(& =PV:> +22+"'5 <# $&(-'&(- '8+
PV: +22+"' 78(*+ .+,/"(-4 '8+ .(0M #2 PV9HC
'8+ < "+**0 "&- )+ %&.'(&**; ,+%*+'+, 2.#$ '8+
'.&-0%*&-' &-, ,#-#. < *;$%8#";'+0 .+(-2/0+,
&""#.,(-4 '# & 4.&,/&'+, 0"8+$+5
Search for
an HLA-
#$%&'()%&*%*+,& ,- !)),./&/+0 1,&/ 2%$$,3F5/6%*,(,+/*+0 7*/6 8/))'

Alternatives
!
compatible – CML
donor within – AML
the family Cord blood
– Aplastic anemia
– SCID
Unrelated donor – PNH
– Fanconi’s anemia
– Thalassemia
– Aggresive
lymphomas?
Myelo- – Solid tumors?

8)+&+0%) 966>&,),.B
ablative
Patient therapy
A. Allogeneic BM transplantation Graft B. Indications

Hemorrhagic
cystitis
Interstitial,
toxic
pneumopathy Bleeding HSV, CMV

Veno- occlusive
disease (VOD)
1. Chemotherapy-induced complications
Infertility Aspergillus, Candida Coccus, Pseudomonas
2. Aplasia-induced complications

CTLs
"
Host APC Donor
lymphocytes

Chemo- TNF-! IL-2

therapy IL-1 IFN-"
IL-6
Adhesion
molecules ,
Irradiation
APC–T-cell
interaction NK cell
3. Immunological complications: GVHD
C. Complications of allogeneic transplantation

BM donor

Reinfusion
Decresed of T/NK

!
risk of cells after
GVHD , 4,8,12
increased risk weeks
of relapse
T-cell depletion Anti-leukemia
effect
D. T-cell depletion and graft-versus-leukemia effect
CDC

"
! #$%&'()%&*%*+,& ;55<&,),3-

!" #$%&'()%&*%*+,& #-(.'

!"#$# %$# &'((#$#)* *+,#- .( .$/%) *$%)-,0%)*%1
*'.)-2 !"#$%$&$"' *$%)-,0%)*- 3#2/24 -5')6 %$#
*$%)-,0%)*4 $#%:*'<%*'.) .( KLJ ')(#:*'.)4 %)&
*"# )#,"$.*.A':'*+ .( -.7# '77=).-=,,$#-1
-'<# &$=/- 3:+:0.-,.$')#6 %$# 7%S.$ :.7,0':%1
*'.)-2
*$%)-(#$$#& ($.7 .)# -'*# *. %).*"#$ 8'*"')
K.$)#%0 /$%(*')/ 35#$%*.,0%-*+6 :%) 9# ,#$1
*"# -%7# .$/%)'-72 ()*&+*+,- *$%)-,0%)*- %$#
(.$7#& %- % 0%7#00%$ ,$.:#&=$# 9+ *$%)-,0%)*1
*$%)-(#$$#& 9#*8##) '&#)*':%0 37.).;+/.*':6
')/ .)0+ *"# #,'*"#0'=7 %)& -*$.7%4 .$ %- % ,#$1
*8')-2 !%%$&+*+,- *$%)-,0%)*- %$# *$%)-(#$$#& 9#1
(.$%*')/ ,$.:#&=$# ') 8"':" *"# ,.-*#$'.$
*8##) /#)#*':%00+ &'((#$#)* ')&'<'&=%0-4 %)& .+/
#)&.*"#0'=7 '- %0-. /$%(*#& 3"62 !"# *$%)-,0%)*
*$&+*+,- *$%)-,0%)*- %$# *$%)-(#$$#& 9#*8##)
8'00 ).* 9# $#S#:*#& %- 0.)/ %- '* '- ).* <%-:=0%$1
%)'7%0- .( &'((#$#)* -,#:'#- 3#2/24 7.)5#+- *.
';#& 3W-#>=#-*#$#& %)*'/#)-4X -## ,2 YV#62
"=7%)-62
9" :.&,*$%&'()%&*%*+,&
/" 0$+*.$+% 1,$ 2$3%& 4.5,6%)
!"# 0'7'*#& -=,,0+ .( &.).$ .$/%)- '- -*'00 *"#
!"# 7%') ,$#$#>='-'*# (.$ .$/%) $#7.<%0 '-
,$'7%$+ ,$.90#7 ') %00 *$%)-,0%)*%*'.)-2 !"#
0)+&+=%) ;55<&,),3-

&'--.:'%*#& 9$%') &#%*" .( *"# &.).$4 8"':" '-

,.*#)*'%0- .( A#).*$%)-,0%)*%*'.) 3#2/24 ($.7
&#(')#& %- *"# %9-#):# .( %00 9$%') 8%<#- 3(0%*
,'/- *. "=7%)-6 "%<# *"#$#(.$# 9##) ')*#)1
??@64 *"# '$$#<#$-'90# 0.-- .( -,.)*%)#.=- $#1
-'<#0+ $#-#%$:"#&2 Z.7# .( *"# 7%') ,$.90#7-
-,'$%*'.) %)& $#(0#A#-4 %)& *"# %)/'./$%,"':%00+
') A#).*$%)-,0%)*%*'.) %$# '77#&'%*# $#S#:*'.)
:.)('$7#& %9-#):# .( :#$#9$%0 90..& (0.82 !"#
&=# *. *"# ,$#-#):# .( ,$#(.$7#& %)*'9.&'#-
&.).$ %)&B.$ &.).$C- (%7'0+ 7=-* :.)-#)* *.
%)& :.7,0#7#)*4 *"# >=#-*'.)%90# #((':%:+ .(
*"# &.)%*'.)2 D):# *"# .$/%) .$ .$/%)- "%<#
-=$$./%*# (=):*'.)4 *"# ,.--'90# *$%)-7'--'.)
9##) $#7.<#&4 *"# &.)%*#& *'--=# '- *+,#& 9+
.( <'$=-#- ,%*"./#)': *. "=7%)-4 %)& #*"':%0
%)%0+;')/ *"# EFD 90..& /$.=, %)& GHE
%-,#:*- .( *"# ,$.:#&=$#2
*+,#2 !"# ,$#-#):# .( GIJ %)& KLJ ')(#:*'.)-
I) .$&#$ *. ,$#<#)* "+,#$%:=*# $#S#:*'.)-
7=-* %0-. 9# #A:0=&#&2 E $#:','#)* -#%$:" '-

"
&=# *. :.7,0#7#)* %:*'<%*'.)4 $#-#%$:"#$-
*"#) ,#$(.$7#& 9+ *$%)-,0%)*%*'.) :..$&')%1
%$# %**#7,*')/ *. ,$.&=:# *$%)-/#)': ,'/-
*'.) :#)*#$-4 -=:" %- ?=$.*$%)-,0%)*2 !"# ,$'.$1
8'*".=* %)*'/#)- (.$ ,$#(.$7#& %)*'9.&'#-
'*+ .( GHE :.7,%*'9'0'*+ '- -#>=#):#& %-
9=* *"%*4 ')-*#%&4 #A,$#-- :.7,0#7#)* $#/=0%1
MNOFOEOK2 E 0"%%/1$"'+ 23#-1 .::=$- ') .)0+
*.$- *"%* 0'7'* :.7,0#7#)*1')&=:#& 0+-'-2 !"#
PQ R .( :%-#-2 K$.--1*#-*')/ .( &.).$ :#00-
*%$/#* :.7,0#7#)* $#/=0%*.$- %$# *"# 7#71
8'*" *"# $#:','#)*C- -#$=7 -".=0& %0-. *=$)
9$%)# ')"'9'*.$ .( $#%:*'<# 0+-'- 3LINH6 KMU[4
.=* )#/%*'<#2
*"# &#:%+1%::#0#$%*')/ (%:*.$ 3ME\6 KMUU4 %)&
I77=).-=,,$#--'<# *"#$%,+ '- ,#$(.$7#&
*"# 7#79$%)# :.(%:*.$ 3LK]6 KMTY2 ]$#1
%(*#$ %00 %00./#)#': .$/%) *$%)-,0%)*%*'.)- *.
(.$7#& %)*'9.&'#- :%)4 ') ,%$*4 9# $#7.<#&
,$#<#)* *$%)-,0%)* $#S#:*'.)2 4)5+63-"#+ 6+7+-/
9+ ,0%-7%,"#$#-'- .$ 9+ ')S#:*')/ -.0=90# ')"'1
#,$* .::=$- 8'*"') *"# ('$-* (#8 7')=*#- *. *"$##
9'*.$+ (%:*.$-2
&%+- %(*#$ *$%)-,0%)*%*'.)2 !"'- *+,# .( $#S#:*'.)
$#%:*'.) '- &=# *. ,$'.$ ".-* -#)-'*';%*'.) %)& '-
$#-'-*%)* *. *"#$%,+2 !-"#+ 6+7+-#,$* 7%+ .::=$
8'*"') TOU &%+- .( *$%)-,0%)*%*'.)4 9=* 7.-*
:.77.)0+ .::=$- ') *"# P)& *. V$& ,.-*.,#$%1
*'<# 8##52 E:=*# $#S#:*'.) '- % :$'*':%0 :.)&'*'.)4
9=* :%) 9# 7%)%/#& 8#00 9+ &$=/ *"#$%,+2
816$*,- 6+7+-#,$* 3&#<#0.,- 8'*"') 7.)*"- *.
+#%$-6 '- :"%$%:*#$';#& 9+ *"# &#<#0.,7#)* .(
-#<#$# <#--#0 :"%)/#-2 !"#-# $#S#:*'.) $#%:*'.)-
$#-,.)& ,..$0+ *. "'/"1&.-# '77=).-=,,$#-1

!
-%)*-2

0" 78%5().' ,1 2$3%& #$%&'()%&*%*+,&'

M'%0+-'-1&#,#)&#)* :"$.)': $#)%0 (%'0=$# '- %)
')&':%*'.) (.$ 5'&)#+ *$%)-,0%)*%*'.) 3!62 N#%:1
>?@ *'<%*'.) .( *"# ,$'7%$+ &'-#%-# 8'*"') *"#
 0)+&+=%) !'(.=*' ,1 2$3%& #$%&'()%&*%*+,&
!
Identical twins

Autologous Syngeneic Allogeneic Xenogeneic

A. Transplantation types

Irreversible
areflexia
(pupils,
cornea)
Organ donor’s written Approval of family

0)+&+=%) ;55<&,),3-
consent members
24 h
2. Conditions
Isoelectric EEG
Irreversible
absence of
spontaneous breathing - ABO blood group
2 x angiography: - HLA test: DR>B>A>C
absence of cerebral
blood flow - Test for cross-reactivity
- HIV exclusion, CMV status
30 min
1. 2.
1. Dissociated brain death 3. Testing
B. Criteria for organ transplantation

Vena cava Aorta

Lamellar
keratoplastic
surgery
Ciliary body
Iris
Lens
"
Ureter Anterior eye
Perforating chamber
Pelvic
vessels Bladder keratoplastic Epithelium
surgery Endothelium
Stroma
1. Kidney 2. Cornea
C. Transplantable organs: Examples

Complement Knock Out Plasma- Soluble

regulators For antigens pheresis inhibitory
For preformed factors of
antibodies complement
lysis CD35
DAF (CD55)
MCP (CD46)
MIRL (CD59) !-Galactosyl
compounds

Transgenic pig

D. Xenogeneic transplantation
Host !
>?A

"
! 012&3452&,2,*'& #$$%&'5'(-

!" #$$%&'()&*+*,- '. ,/) 012&3452&,

!""#$%&'$()(*+ ,'-)*(%$. /(,')*'/ -&-($.* -
*,-$.01-$* -,' *,(&&','/ 2+ 345 )%"01'6'.
%$1+ -)*(>-*'. = )'11. *7-* /% $%* ,')%&$(;'
345 "%1')#1'. ($ *7' &,-8*9
7 8).,&'( 34'5) %6 +)((#('& &)*)+,-%./ A)*(:
>-*'/ = )'11. ($8(1*,-*' 0',(>-.)#1-, *(..#'
($ *7' &,-8*9 51-.. ! 345 "%1')#1'. -$/ *7' 0'0:
-$/ *7' *(..#' -,%#$/ -$*(&'$:0,'.'$*($&
*(/'. 0,'.'$*'/ 2+ *7'" "-+ 2' ,')%&$(;'/ -.
)'11.9 =7' =4O 0%0#1-*(%$ 0,'/%"($-*'.9
8%,'(&$ 2+ *7' ,')(0('$*<. (""#$' .+.*'" /#'
=7' ,'1'-.' %8 )+*%J($'. 7-. /(,')*? *%6() '8:
*% &'$'*() 0%1+"%,07(."9 =7' 0'0*(/'. %,(&(:
8')*. %$ *7' .#,,%#$/($& *(..#'.9 3%,'%>',? (*
$-*' 8,%" )+*%01-."() 0,%*'($. )1'->'/ 8,%"
($/#)'. *7' ,'),#(*"'$* %8 -//(*(%$-1 = )'11.
-$ '$;+"' )%"01'6? *7' 0,%*'-.%"'9 =,-$.:
-. F'11 -. K )'11.? "-),%07-&'.? -$/ &,-$#:
0%,*:-..%)(-*'/ 0,%*'($. @=ABC )%$>'+ *7'"
1%)+*'.9 =7' -)*(>-*'/ '88')*%, )'11. ,'1'-.'
*% *7' '$/%01-."() ,'*()#1#" @DEC? F7','
0,%:)%-&#1-*%,+ "'/(-*%,.? J($($.? -$/ '()%:
*7'+ 2($/ *% )1-.. ! 345 "%1')#1'.9 E')%&$(*(%$
.-$%(/.9 P$/', *7' ($81#'$)' %8 *7' )+*%:
%8 *7' 0'0*(/'G)1-.. ! 345 )%"01'6 2+ *7'
J($'.? -$ ($),'-.'/ '60,'..(%$ %8 -/7'.(%$
*,-$.01-$* ,')(0('$*<. 1+"07%)+*'. *,(&&',.
"%1')#1'. -$/ 345 "%1')#1'. %))#,. ($
2%*7 )'11#1-, -$/ 7#"%,-1 (""#$' ,'.0%$.'.9
95*&*+25 #$$%&'5'(-

*7' .#,,%#$/($& *(..#'9

B'0*(/'. %,(&($-*($& 8,%" %*7', )'11 )%"0-,*:
=7' (""#$%"%/#1-*%,+ 0,%)'..'. *7-* %))#,
"'$*. -,' -1.% *,-$.0%,*'/ *% *7' DE? 2%#$/
($ *,-$.01-$* ,')(0('$*. F(*7 1%$&:*'," &,-8*
*% )1-.. ! 345 "%1')#1'.? -$/ 0,'.'$*'/ %$
*%1',-$)' -,' )%"01'6 -$/ %$1+ 0-,*(-11+ #$/',:
*7' )'11 .#,8-)'9 =7'.' .%:)-11'/ H$%$:345
.*%%/9 !8 *7' .')%$/ .(&$-1 8,%" *7' )%:.*("#1-:
-$*(&'$.I ($/#)' - &'$',-11+ F'-J', (""#$'
*%,+ 1(&-$/ >(- 5NQR (. -2.'$*? *7' -)*(>-*(%$ %8
,'.0%$.' -$/ -)*(>-*' %$1+ - ."-11 $#"2', %8
$-(>' = )'11. F(11 2' ($)%"01'*'9 =7(. )%$/(*(%$?
=:)'11 )1%$'.9 =7' ,')%&$(*(%$ %8 21%%/ &,%#0
)-11'/ !"#$%&? (. )7-,-)*',(;'/ 2+ *7' -2.'$)' %8
-$*(&'$. 2+ *7' ,')(0('$* -. 8%,'(&$ (. -$%*7',
!S:Q -$/ - /'.*,#)*(>' =:)'11 ,'-)*(%$9 =%1',-*'/
)-#.' %8 (""#$' ,'-)*(%$. *% *,-$.01-$*.9 =7'
-11%&'$'() *,-$.01-$*. -,' %8*'$ ($8(1*,-*'/ F(*7
AKL 21%%/ &,%#0 .+.*'" 7-. 0,'8%,"'/ -$*(2%:
=4Q )'11. F7()7 0%..(21+ ($7(2(* *7' =4O )'11.

"
/('. *7-* "-+ 1'-/ *% - 7+0',-)#*' ,'M')*(%$ ,':
*7','9 T#,*7',"%,'? *7'(, )+*%J($'. !S:OU -$/
-)*(%$9
=VT:! )-$ ,'/#)' *7' '60,'..(%$ %8 *7' )%:.*(:
"#1-*%,+ 1(&-$/. 5NRU -$/ 5NRW9
6" 7)8)+,*'& 7)2+,*'&3
! "#$%&'( &)*)+,-%./ A$*(2%/+:"'/(-*'/
*,-$.01-$* ,'M')*(%$ "-+ 2')%"' -$ ("0%,:
*-$* 8-)*%,? '.0')(-11+ ($ )-.'. F7',' 0,(%,
.'$.(*(;-*(%$ %8 *7' ,')(0('$* 7-. %))#,,'/?
'9&9? /#,($& 0,'&$-$)+ %, 21%%/ *,-$.8#.(%$9
B,'8%,"'/ -$*(2%/('. -,' 0,("-,(1+ /(,')*'/
-&-($.* *7' '$/%*7'1(#" %8 *7' *,-$.01-$*
@/%$%,C9 =7'(, 0,'.'$)' *,(&&',. *7' -)*(>-:
*(%$ %8 *7' )%"01'"'$* .+.*'"? *7','2+
)-#.($& )%"01'"'$*:"'/(-*'/ '$/%*7'1(-1
/-"-&'? -&&,'&-*(%$ %8 *7,%"2%)+*'.? &,-$:
#1%)+*'.? -$/ "%$%)+*'.? -$/ ($*,->-.)#1-,
)%-&#1-*(%$ /#' *% *7' ,'1'-.' %8 "'/(-*%,.9
A$*(2%/+:/'0'$/'$* )'11:"'/(-*'/ )+*%:
*%6()(*+ @AN55C "-($1+ 01-+. -$ ("0%,*-$*
,%1' ($ )7,%$() ,'M')*(%$9
0 1'&(2 34'5) %6 +)((#('& &)*)+,-%./ D-,1+ ,':
M')*(%$ ,'-)*(%$. -,' "'/(-*'/ 2+ 0,%8'.:
.(%$-1 -$*(&'$:0,'.'$*($& )'11. @AB5.C9

!
:;<
AB5. ($ *7' &,-8* )-$ "(&,-*' -$/ /(,')*1+ -):
*(>-*' 7%.* = )'11.? F7()7 *7'$ 2')%"' .0':
)(8() 8%, 345 "%1')#1'. ($ *7' &,-8*9 A$*(&'$.
($ *7' *,-$.01-$* "-+ -1.% 2' 07-&%)+*%.'/
-$/ 0,%)'..'/ 2+ 7%.* -$*(&'$:0,'.'$*($&
)'11.9 4%F'>',? 0,'.'$*-*(%$ %$ .'18:345
 MHC antigens
#$$%&'5'(*+25 !34)+,3 '. =1(2& 012&3452&,2,*'&

Non-MHC antigens
!
Anti-A

MHC I
MHC I
A

Poly-
morphic Proteasome
protein
TAP Golgi

95*&*+25 #$$%&'5'(-
Proteins
derived from other ER
ABO blood group system
cell compartments
A. Immunogenicity of the graft

Donor endothelium
Complement system

Fc"R C5–C9 C3b C3a, C5a Mast cells

ADCC

1. Humoral rejection

Processing
(indirect)
Cell lysis

APC
Cell activation

Rejection
Chemotaxis

MHC II
Histamine, serotonin

Endothelial lesion, intravascular coagulation

Tolerance
MHC II
"
co-stimulatory co-stimu-
ligands latory
Adhesion Adhesion
signal
molecule molecule
missing

APC Ø IL-2

Migration Donor IL-2 Anergy

(direct) Host

TH2
CD8
Donor,
MHC-specific
CD80
CD4
CD86
PAF IL-10
MHC II MHC I TGF-!

!
TH1 TH2
LFA3, ICAM1
Kinins

Rejection Eicosanoids Tolerance

IL-2, IFN-", TNF-# IL-4, IL-10
2. Early phase 3. Central phase
B. Rejection reactions
:;>

"
! <,.',$/.=*$*+($ >%.*(.*.

!"#$%&'()* &+'"+)'), !"#$ %&'()*% +(,-.'/&'*/*01

*0 /&2 3(0/ %(33() 4*02.02 (5 /&2 6(*)/07 8/ .59
52%/0 %.7 :;< = (5 /&2 +(+>,./*()7 # %./.,(? (5 %'*9
/2'*. @.0 42A2,(+24 B- /&2 #32'*%.) C(,,2?2 (5
"&2>3./(,(?- !#C"1 /( %,.00*5- /&*0 4*02.02 +*%9
/>'27 #/ ,2.0/ 5(>' (>/ (5 02A2) %'*/2'*. 3>0/ B2
32/ !022 D.B,2 : (5 /&2 .++2)4*E17
!" #$%&%'($ )*(+,-*. /0 12*,3(+/%4
!-+2-%+%.
"&2>3./(*4 .'/&'*/*0 *0 . 0-0/23*% 4*02.02 /&./
(5/2) (%%>'0 @*/& 2E/'.9.'/*%>,.' 3.)*520/.9
/*()07 "# >0>.,,- B2?*)0 .5/2' .?2 FG .)4 +'24(9
3*).)/,- .552%/0 @(32) !'./*( (5 HI:17 8) 3(0/
%.020J "# B2?*)0 *)0*4*(>0,-J >0>.,,- @*/& .
#$%&%'($ ?33,&/$/@A
B>/.B,2 /( A.0%>,*/*0 @*/& %()02%>/*A2 +,2>'*/*0
(' +2'*%.'4*/*0 !'.'2,- %,*)*%.,,- 4*.?)(0.B,217
T/&2' '.'2 2E/'.9.'/*%>,.' 3.)*520/./*()0 .'2
%>/.)2(>0 A.0%>,*/*0J +>,3().'- 5*B'(0*0J 3*/'.,
A.,A2 4252%/0J .)4 3-(%.'4*/*07 8)A(,A232)/ (5
/&2 2-2J @*/& 0>%& 3.)*520/./*()0 .0 0%,2'*/*0 ('
2+*0%,2'*/*0 .)4 02%()4.'- L6(V?'2)W0 0-)4'(32
!022 +7 :XY1 *0 %&.'.%/2'*0/*% (5 "#7
D&2 02'(,(?*%., 52./>'20 (5 "# *)%,>42 2E/2)9
0*A2 %&.)?20 *) /&2 ?2)2'., +.'.32/2'0 (5 *)9
5,.33./*() !2'-/&'(%-/2 024*32)/./*() './2J
ZL"J .)4 C9'2.%/*A2 +'(/2*)J C"N17 ZE/2)0*A2 .%9
/*A*/- *)4*%./20 /&2 +'202)%2 (5 .)23*. .)4
/&'(3B(%-/(0*07 8?K '&2>3./(*4 5.%/('0 .'2
5(>)4 *) .'(>)4 XG = (5 +./*2)/0J .)4 &0')/0$/

.1#&+ &0')2(*)#, .'2 5(>)4 *) HG =7

+(,-.'/*%>,.' .)4 0-332/'*%., +.//2') (5 *)A(,9
A232)/J 20+2%*.,,- (5 03.,, 6(*)/0 *) /&2 +2'*+&9
2'-7 K.)- +./*2)/0 %(3+,.*) (5 ?2)2'., 3.,.*027
L-)(A*., %.+0>,.' /&*%M2)*)? .)4 5>0*5('3 6(*)/
!"# $%&'(%&) *+% $,)--&*&$)'&+. +* #!
0@2,,*)? 3(0/ %(33(),- .552%/ /&2 324*., .)4
+'(E*3., *)/2'+&.,.)?2., 6(*)/0 !N8N1 (5 /&2 5*)9 #-%+*-%/&
?2'0 .0 @2,, .0 /&2 @'*0/0 .)4 /&2 32/.%.'+(9
+&.,.)?2., 6(*)/0 !KCN1 (5 /&2 /(207 O(%/>')., 5 /+%.&.0 -'&**.(--
.//.%M0 (5 +.*) .)4 3(')*)? .'/&'.,?*.0 @*/&
+2'0*0/2)/ 3(')*)? 0/*55)200 .'2 .,0( (B02'A247 6 !%'1%&'&- &. '1%(( +% 2+%( 3+&.' %(0&+.-

"
P(*)/ *)5,.33./*() 0+'2.40 *) . %2)/'*+2/., +./9
/2')7 D&2 4*0/., *)/2'+&.,.)?2., 6(*)/0 (5 /&2 5*)9 7 !%'1%&'&- &. '1( 3+&.'- +* '1( 1).45 6%&-'-7
?2'0 >0>.,,- '23.*) >).552%/247 /"8-7 898-
8''2A2'0*B,2 425('3*/*20 /&./ ,*3*/ 6(*)/ 3(9
B*,*/- (%%>' *) /&2 .4A.)%24 0/.?20 (5 4*02.02J 8 :;22('%&$), -6(,,&.0 <)%'1%&'&-=
20+2%*.,,- *) /&2 03.,, 6(*)/07 Q25('3*/*20 (5
/&2 5*)?2'0 /.M2 /&2 5('3 (5 %&.'.%/2'*0/*% >,).' 9 #1(>2)'+&4 .+4>,(-
42A*./*()0 .)4 0(9%.,,24 B>//()9&(,2 425('3*9
/*20 .)4 0@.)9)2%M 425('3*/*20J @&*%& .'2 : #1(>2)'+&4 *)$'+% &. -(%>2
%.>024 B- ,>E./*() (5 2E/2)0(' (' 5,2E(' /2)9
4()0 *) 0@(,,2) .)4 4.3.?24 /2)4() 0&2./&07 ; #)4&+,+0&$), $1).0(- +* %1(>2)'+&4
D&2'2 .'2 .,0( 420/'>%/*A2 B()2 +'(%20020 /&./ )%'1%&'&-
B2?*) ./ /&2 *)02'/*()0 (5 /&2 6(*)/ %.+0>,20
!022) .0 2'(0*()0 () '.4*(?'.+&017 D&2 /2'3*).,
0/.?2 (5 /&2 4*02.02 *0 %&.'.%/2'*R24 B- 5*B'(>0
.)4 (002(>0 B'*4?20 (A2' /&2 6(*)/ B(4*207 8)9
A(,A232)/ (5 /&2 %2'A*%., 0+*)2 *0 %(33()
.5/2' 3.)- -2.'0 (5 '25'.%/('- 4*02.027 D&*0 *0
%&.'.%/2'*R24 B- 420/'>%/*A2 %&.)?20 *) /&2
./,.)/(42)/., 6(*)/ .)4 +(020 . '*0M (5 B()2
3.''(@ %(3+'200*()7
!"#$%&'()* -&.'(+, !"S1 .'2 (5/2) 5(>)4
@&2) 2E/'.9.'/*%>,.' 3.)*520/./*()0 (%%>'7

!
5::
T)2 (5 /&2 3.*) 52./>'20 *0 /&2 5('3./*() (5 5*9
B'(>0 )(4>,20 () /&2 2E/2)0(' 0*42 (5 /&2 2E/'29
3*/*20J 20+2%*.,,- () /&2 5('2.'37 D&202 +"#$/
%&'()* 0(*$1#, .'2 3.42 (5 )2%'(/*% 3./2'*.,
/&./ *0 0>''(>)424 *) +.,*0.429,*M2 5.0&*() B-
3.%'(+&.?207 U*0%2'., 3.)*520/./*()0 .'2 .//'*9
 Articular
#$%&%'($ )*(+,-*. /0 12*,3(+/%4 !-+2-%+%.

Extra-articular
!
Episcleritis

Cervical spine

#$%&%'($ ?33,&/$/@A
Pericarditis

Elbow

Hand
Pleuritis
"
Rheumatoid nodules

Knees

Vasculitis

Feet

A. Clinical manifestations of rheumatoid arthritis

!
5:;

"
! 3&7+&%,7@$%$*'% A27$'7$7

!" #$%%&%'( )*(&+*&($ ,- *.$ )/0,12'%

3$45('0$
!"#$%&'(') $'% *(++#,- %(-.&'.(#' #/ .0& '#"1
2$++3 -2##.0 -3'#*($+ 2&24"$'& (- $ 50$"$51
.&"(-.(5 /&$.,"& #/ "0&,2$.#(% $".0"(.(-6 7"#+(/1
&"$.(#' #/ .0& +('(') +$3&" #/ 5&++-8 90(50
:"(2$"(+3 5#'-(-.- #/ 2$5"#:0$)&- $'% $5.(1
*$.&% -3'#*($+ /(4"#4+$-.-8 5$' 4& #4-&"*&%6 ;'1
/(+."$.(#' 9(.0 < +32:0#53.&- $+-# #55,"-6 <0&
=>?@ 5&++- $"& :"&%#2('$'.+3 /#,'% (' -.",51
.,"&- "&-&24+(') .0& +32:0$.(5 /#++(5+&6 ;'
-#2& 5$-&-8 .0&3 0$*& 50$"$5.&"(-.(5- -(2(+$"
.# .0#-& #/ )&"2('$+ 5&'.&"-6 ;' 5#'."$-.8 =>A@
< 5&++- %(//,-&+3 ('/(+."$.& .0& 5#''&5.(*& .(--,&6
<0& &B.&'-(*& *$-5,+$"(C$.(#' #/ .0& -3'#*($+
#%202+'% 944&0,%,B/
5&++ .3:& G=>?PDQ@H6 <0& )&"2('$+ 5&'.&"1+(R&
$))"&)$.&- 5#'.$(' $5.(*$.&% ! 5&++- $'% /#++(5,1
+$" %&'%"(.(5 5&++-6 <0&"& $"& $+-# $ ',24&" #/
:+$-2$ 5&++- .0$. :"#%,5& "0&,2$.#(% /$5.#"-
$- 9&++ $- :#+35+#'$+ $'.(4#%(&- #/ *$"(#,- -:&1
5(/(5(.(&-6 <0& :"&%#2('$'. 5&++- $. .0& 5$".(1
+$)&S:$'',- 4#,'%$"3 $"& $5.(*$.&% -3'#*($+
/(4"#4+$-.- .0$. :"#%,5& +$")& T,$'.(.(&- #/ %&1
-.",5.(*& &'C32&-8 -,50 $- 2&.$++#:"#.&$-&-
G5#++$)&'$-& $'% -."#2&+3-('U -&& .$4+&H6 V#'#1
',5+&$" 5&++- 2$('+3 ('/(+."$.& .0& -3'#*($+
2&24"$'&8 90&"&$- $ +$")& ',24&" #/ '&,."#1
:0(+(5 )"$',+#53.&- ('/(+."$.& .0& -3'#*($+ /+,(%6
<0& (2:$5. #/ .0& %(//&"&'. 5&++ -3-.&2- #'
.0& %&*&+#:2&'. #/ "0&,2$.#(% $".0"(.(- (- -.(++

5#'."#*&"-($+6 <0& 2$F#"(.3 #/ "&-&$"50&"- 4&1

2&24"$'& (- $+-# $ .3:(5$+ /&$.,"& #/ .0& :"#1
5&-- #/ -3'#*(.(-6
6" #$%%7 20 *.$ !(*.(2*2+ 8,20*
<0& .3:(5$+ :$.(&'. 9(.0 DE :"&-&'.- 9(.0 -3'#1
*(.(-1"&+$.&% %(-.&'.-#' #/ .0& F#('. 5$:-,+& $'%
.&'%#' -0&$.0- G!H8 90(50 5$' "&-,+. (' .&'%#'
",:.,"& $'% .0& 5#""&-:#'%(') +#-- #/ 2#4(+(.36
IB.&'-(*& +32:0#53.& ('/(+."$.(#' (- $ .3:(5$+
0(-.#+#)(5$+ /('%(')6 <0& ('%(*(%,$+ *(++( 2$('+3
+(&*& .0& (22,'& -3-.&2 (- "&-:#'-(4+& /#"
.0& :$.0#)&'&-(- #/ DE G-&& :6 WPXH6 O#9&*&"8
-#2& 9#"R&"- 03:#.0&-(C& .0$. .0& (22,'#1
+#)(5$+ 2$'(/&-.$.(#'- $"& #'+3 -&5#'%$"3 ('
'$.,"&6 <0&3 :"#:#-& .0$. .0&-& 2$'(/&-.$.(#'-
2$3 #55," $- $ "&-:#'-& .# 5#'.(',$+ ('/+$22$1
.#"3 -.(2,+( 5$,-&% 2$('+3 43 ,'R'#9' ('1
/&5.(#'- #" 43 /$+-&+3 :"#)"$22&% -3'#*($+
/(4"#4+$-.- G."$'-/#"2$.(#'H "&-,+.(') (' %&1
-.",5.(*& $5.(*$.(#' :"#5&--&- G-&& :6 WYW%&#H6

" 5#'-(-. #/ .0& 03:&"."#:0(&% +('(') +$3&" #/ 5&++-

.0$. 5#'.$('- 2$5"#:0$)&- G.3:& E 5&++-H8 /(4"#1
4+$-.- G.3:& ! 5&++-H8 $'% +32:0#53.(5 G"#,'%1
5&++H ('/(+."$.&- G"H6 E 5#'-(%&"$4+& -.$.& #/ $5.(1
*$.(#' #/ .0& 5&++-8 &-:&5($++3 2$5"#:0$)&- $'%
-3'#*($+ /(4"#4+$-.-8 (- #4-&"*&% ,:#' &+&5."#'
Z,".0&" "&-&$"50 %$.$ $"& "&T,("&% /#" $ %&1
/('(.(*& $'-9&" .# .0&-& T,&-.(#'-6

2(5"#-5#:3 G#H6 <0(- .(--,& +&$%- .# .0& %&*&+#:1

2&'. #/ :$'',- GJ$.('K L$ :(&5& #/ 5+#.0MH8
90(50 :&'&."$.&- ('.# .0& 4#'&8 5#*&"- .0& 5$"1
.(+$)&8 $'% ,+.(2$.&+3 %&-."#3- 4#.0 -.",5.,"&-6
N(".,$++3 $++ 5&++- #/ (22,'#+#)(5$+ "&+&*$'5&
$"& +#5$.&% (' .0& -3'#*($+ 2&24"$'& G$H6
O&'5&8 .0& -3'#*(,2 $//&5.&% 43 ('/+$22$.#"3
50$')&- $--,2&- .0& /&$.,"&- #/ $ +32:0#(%
#")$'6 <0& < 5&++- $"& 2$('+3 #/ .0& 2&2#"3

94:,(*'0* ;(,*$,%/*2+ <0=/4$7 20 >.$&4'*,2? !(*.(2*27

<0=/4$ -'42%/ >$:($7$0*'*21$7

!"#$%& '(#"))*+$*#(%,"-(- .!!/0 !!/- 12 32 42 ",5 6

!
CDE
78-#(%,( +$*#(%,"-(-

=($%,( +$*#(%,"-(-

C-+"$#%@ +$*#(%,"-(-
7"#9(+-%,- :2 ;2 ",5 <

>)"-#"-(2 +)"-'%,*?(, "@#%A"#*$2 @"#9(+-%, B

7"#9(+-%, D
 Normal Pathological
)/0,12'% #.'0B$7 20 >.$&4'*,2? !(*.(2*27
!
Enlarged layer of lining cells

Intra-articular space

Normal layer of lining cells

CD4+
T cells

#%202+'% 944&0,%,B/
CD8+
T cells

Connective Increased
1. Synovial membrane
tissue vascularization
with lymphoid
A. Cellular structure of the synovium follicle-like structure

B cells

T cells
"
Bone
Plasma
cells
Cartilage
1. Synovitis
Erosion Synovial fluid Granulo-
cytes
Pannus
NK cells
Lining cell
layer
Dendritic
Synovium cells

Macro-
phages/
monocytes

2. RA: histology
B. Cells in the arthritic joint
3. Activated macrophages:
electron micrograph
Endothelial
cells

4. Cellular
composition
!
CDF

"
! <$%&$,.%=',')2, >*%'2%'%

!" #$%&'()*+*,*)- ). /0'$12).*3 !4)04*)*%

!"#"$%& '(&$)*+ ,-(. (# %/,)*$(#$ *)-" %# $0" 1"2
3"-),/"#$ )' *0"4/($)%1 (*$0*%$%+5 (-$0)460
$0" &)#&)*1(#&" )' $0" 1%+"(+" %+ )#-. &(7
89 : %# %1"#$%&(- $;%#+7 <0%+ 4#1"*-%#"+ $0"
'(&$ $0($ "#3%*)#/"#$(- '(&$)*+5 ,*"+4/(=-. %#2
'"&$%)4+ "3"#$+5 (-+) ,-(. ( 1"&%+%3" *)-" >&'7 ,7
8?9!@7 <0" ABC (++)&%($%)#+ )' DC ;"*" &-"(*-.
"-(=)*($"1 ;0"# $0" E+0(*"1 ",%$)," 0.,)$02
"+%+F ;(+ 1"3"-),"17 <0" 0.,)$0"+%+ +$($"+
$0($ $0" 1%+"(+" %+ #)$ )#-. (++)&%($"1 ;%$0 (
&"*$(%# ABC2GD +,"&%'%&%$.5 =4$ (-+) ;%$0 &)/2
/)# ",%$),"+ )# 3(*%)4+ GD /)-"&4-"+ >"+,"2
&%(--. GDH (#1 GD8@7 I$ ;(+ (-+) +0);# $0($
$0" ,*"+"#&" )' GDH %+ (++)&%($"1 ;%$0 ( ;)*+"
:,*8*&2, ;11$8.,.7-
$0($ +$%/4-($" $0" (&$%3($%)# )' &)/,-"/"#$
$0*)460 %//4#" &)/,-"N"+7 W)*")3"*5 ,*)%#2
'-(//($)*. &.$)L%#"+5 "+,"&%(--. <XY2! (#1
IB285 -"(1 $) $0" %#&*"(+"1 ,*)-%'"*($%)# (#1 (&2
$%3($%)# )' '%=*)=-(+$+7 <0%+ *"+4-$+ %# +.#)3%$%+
;%$0 ,(##4+ ')*/($%)# (#1 %# &)#+"&4$%3"
=)#" (#1 J)%#$ 1(/(6"5 ;0%&0 (,,"(*+ (+ "*)2
+%)#+ (#1 1"')*/%$%"+ )# *(1%)6*(,0+7
:" ;83$&)*.8 .9 /0'$12).*3 !4)04*)*%
C +$%-- 4#L#);# (#$%6"# +$%/4-($"+ $0" (&$%3(2
$%)# )' < -./,0)&.$"+ $0($5 %# $4*#5 (&$%3($" +.2
#)3%(- /(&*),0(6"+7 <0" /(&*),0(6"+ +"&*"$"
$0" 1"&%+%3" &.$)L%#"+5 <XY2! (#1 IB285 ;0%&0
(&$%3($" )+$")&-(+$+ (#1 &0)#1*)&.$"+7 <0%+

&)4*+" )' DC ;%$0 "+,"&%(--. +"3"*" J)%#$ 1"2
+$*4&$%)#5 ,(*$%&4-(*-. ;0"# =)$0 &0*)/)2
+)/"+ &)1" ')* $0%+ /)-"&4-" >E1)4=-" 1)+"F
)' $0" 6"#"@7
K($0)6"#"$%& +$41%"+ +466"+$ $0($ $0" +$%--
4#L#);# ')*"%6# (#$%6"# )* (4$)(#$%6"# $0($
%#14&"+ $0" 1%+"(+" %+ =)4#1 %# $0" ,-"($"1
+0"($0 +$*4&$4*" )' &-(++ II ABC /)-"&4-"+7 I#2
$"*(&$%)# ="$;""# (#$%6"#2,*"+"#$%#6 &"--+
(#1 <20"-,"* &"--+ $(L"+ ,-(&" %# $0" $0%*1 0.2
E$;)2,*)#6"1 ($$(&LF *"+4-$+ %# $0" 1"+$*4&$%)#
)' &(*$%-(6" (#1 =)#"7 <0" &0)#1*)&.$"+ $0"#
="6%# $) ,*)14&" -(*6" V4(#$%$%"+ )' '%=*)=-(+$
6*);$0 '(&$)* >Y!Y@ (#1 !W2ZUY5 ;0%&0 &)/2
,-"$"+ ( 0(*/'4- &.&-" $0($ &(# *"+4-$ %# *"(&$%2
3($%)# )' $0" /(&*),0(6"+7 <0%+ /(. =" $0"
*"(+)# ;0. $0" 1%+"(+" ,*)&"++ +)/"$%/"+ ,"*2
+%+$+ ')* -)#6 ,"*%)1+ )' $%/"5 "3"# ('$"* < &"--+
0(3" =""# 1"+$*)."15 ')* "N(/,-"5 %# /)#)2
&-)#(- (#$%=)1. $0"*(,.7 <0" #"; $0"*(,"4$%&

"
,"*3(*%(=-" *"6%)# )' $0" &-(++ II ABC (#$%6"#5 (,,*)(&0"+ 4+%#6 /)#)&-)#(- (#$%=)1%"+ )*
;0%&0 0(+ ( 0"-%&(- &)#'%64*($%)#7 A"*" (*" 3(*%2 +%/%-(* ;)*L%#6 /)1"-+ (*" =(+"1 )# $0"+"
(=-" (/%#) (&%1 6*)4,+ $0($ (*" &)1"1 %# $0" &)#&",$+ >+"" ,7 [?8@7
*"6%)# )' $0" '%*+$ 1)/(%# )' $0" ABC2GDM8
6"#"7 <0" $(=-" 4#1"*-%#"+ $0" +%/%-(*%$. ="2
$;""# GDH +4=$.,"+ (#1 ="$;""# GD8 (#1
GD?G;8?5 ;0%&0 (*" (-+) (++)&%($"1 ;%$0 *0"42
/($)%1 (*$0*%$%+7 <0" "N&0(#6" )' #"4$*(- (#1O
)* =(+%& (/%#) (&%1+ ')* $0" (&%1%& (/%#) (&%1+
C+, (#1 !-4 ($ ,)+%$%)#+ PQ5 P85 (#1 PH )' $0"
(--"-"+ G;8Q (#1O)* G;8R -"(1+ $) ( -)++ )'
1%+"(+" (++)&%($%)#7 <0"+" ABC /)-"&4-"+ (*"
(,,(*"#$-. 4#(=-" $) =%#1 $0" (*$0*%$)6"#%&
,",$%1" )* ,",$%1"+ ;%$0 +4''%&%"#$ (''%#%$. )*
(*" )$0"*;%+" #)$ *"&)6#%S"1 =. $0" E*%60$F
<2&"-- *"&",$)*7

5" 62)0.7'8'%*% .9 /0'$12).*3 !4)04*)*%

< (#1 M -./,0)&.$"+ /%6*($" '*)/ $0" ,)+$&(2
,%--(*. 3"#4-"+ %# $0" +.#)3%(- /"/=*(#" $) $0"
$%++4" $0*)460 +$%-- 4#L#);# /"&0(#%+/+ >%#2
'"&$%)#5 $*(4/(T@7 U.#)3%(- &"--+ ="(*%#6 (="*2

!
*(#$ &-(++ II ABC (#$%6"#+ (#1 &)2+$%/4-($)*.
/)-"&4-"+ $0"# ,*"+"#$ $0" +$%-- 4#L#);# (*2
$0*%$)6"#%& ,",$%1" $) $0" < &"--+7 U4=+"V4"#$-.5
&.$)L%#"+ +$%/4-($" $0" (&$%3($%)# )' 3(*%)4+
&"-- +.+$"/+7 M &"--+ (*" (&$%3($"1 =. ,)-.&-)#(-
?@A +$%/4-($%)#7 <0"+" (&$%3($"1 M &"--+ ,*)14&" %/2
/4#)6-)=4-%#+5 "+,"&%(--. *0"4/($)%1 '(&$)*+5
 62)0.7'8'%*% .9 /0'$12).*3 !4)04*)*% B;C

Amino acid
!
DRB1 57 69 67 70 71 74 86
DR4Dw4 Asp Glu Leu Gln Lys Ala Gly
DR4Dw10 – – Ile Asp Glu – Val
DR4Dw13 – – – – Arg Glu Val
DR4Dw14 – – – – Arg – Val
DR4Dw15 Ser – – – Arg – –
DR1 Ile – – – Arg – Ala
1. Class II DR6Dw16 Leu – – – Arg – Ala
1. antigen
1. (view from above) 2. Variable amino acid position in the sequence of DR

A. Susceptibility to rheumatoid arthritis

:,*8*&2, ;11$8.,.7-
Post-
capillary
venules

T cells Synovial proliferation

Arthritogenic B cells
peptide

Antigen presentation
by synovial cells
Immunoglobulins
Rheumatoid factor

Immune complexes
Synovitis
Pannus formation
"
Complement
Cytokines activation

Bone and joint damage

B. Pathogenesis of rheumatoid arthritis

Unknown
antigen Pannus tissue

GM-CSF
Synovial
tissue
FGF
Chondrocytes

!
IL-1
T cells Macro- TNF-!
phages Osteoclasts

C. Induction of rheumatoid arthritis

?@?

"
! 4-:&-3/:B%3%'*3 ?(:%*:%:

!" #$% !&'()*'%+ ,$%-.*'/(+ 012/)(*3

4*&5/6$*7%
!"#$% &$'( ) *+(",'-+%./0 #-%12#%.3 $,.4(#5
%'13 /+6'21#* (#-$'",#7./ 89:;< #$. &4$%,.$
-.6%$#* -.** .*.(.6%/ %,#% 1634-. 3./%$4-%1'6=
!$'463 >? @ '& #** -.**/ 16 %,. 16&*#(.3 /+6'21#*
(.(A$#6. #$. '& %,1/ -.** %+".= 9:;/ A.#$ #**
1("'$%#6% ('*.-4*./B %,. CDEF #6%17.60 %,.
&4** /.% '& -*#// GG HI! #6%17.6/ 8D90 DJ0 DK<0
L- $.-."%'$/0 #63 %,. CDF #6%17.6= G6%$#-.**4*#$
9:;/ #$. -,#$#-%.$1M.3 A+ %,. "$./.6-. '&
CDNO #6%17.6= G6 #331%1'6 %' (.(A$#6.5A'463
('*.-4*./0 9:;/ #*/' /.-$.%. 64(.$'4/ (.31#5
%'$/ #63 -+%'P16./0 /4-, #/ )QL5! #63 GI5E0 %'
6#(. # &.R '& %,. ('/% 1("'$%#6% '6./= 9,.45
93(2(&*3 @..-2/3/71
(#%'13 &#-%'$/ R1%, #&&161%+ (#%4$#%1'6 %' $,.45
(#%'13 &#-%'$/ '& %,. G7S -*#//0 R,1-, 6'$(#**+
#$. 6'% 3.%.-%#A*.=
!*%,'47, %,.+ #$. &'463 16 '%,.$ 31/.#/./0
$,.4(#%'13 &#-%'$/ #$. /%1** %,. ('/% 1("'$%#6%
,4('$#* &.#%4$./ '& $,.4(#%'13 #$%,$1%1/= G7;5
9L 1/ .#/+ %' 3.%.-%= Y.-#4/. '& 1%/ &$.. #$(/0 1%
,#/ &$.. $.#-%1'6 "#$%6.$/ 16 %./% /+/%.(/ 8!<=
G7S $,.4(#%'13 &#-%'$/ /%1(4*#%. %,. &'$(#%1'6
'& *#$7. 1((46. -'("*.T./= G6 %,1/ -#/.0 %,.
#4%'#6%1A'31./ A163 R1%, '6. #6'%,.$0 #63 1%
1/ 31&&1-4*% %' /."#$#%. %,.( &$'( %,./. -'(5
"*.T./= ),.$.&'$.0 %,.+ -#66'% A. 3.%.-%.3 16
-*#//1-#* $,.4(#%'13 &#-%'$ %./%/ 8"<=

?" @.6*(5%+ 8A9%33 ,%7-3*'(/2

(#%'13 /+6'21#* (#-$'",#7./ #*/' "$'34-.
-'46%.$5$.74*#%'$+ -+%'P16./ 8(#16*+ )SL5"
#63 GI5E?<0 A4% %,.1$ $.*.#/. 1/ "$'A#A*+ &4%1*.
%' -'46%.$#-% %,. "$'16&*#((#%'$+ -+%'P16./=
G6 %1//4. -4*%4$./0 %,. (#-$'",#7./ #$. 2.$+ #-5
%12. #63 #$. -,#$#-%.$1M.3 A+ 16-$.#/.3 ",#7'5
-+%'/1/ #63 ,.17,%.6.3 -,.('%#T1/=
8" !&'()*'%+ 9%33: (2 '$% ,$%-.*'/(+
012/)(*3 4%.;5*2%
Y.-#4/. '& /%1** 4613.6%1&1.3 31/%4$A#6-./ #% %,.
/%#7./ '& #6%17.6 "$./.6%#%1'6 #63 $.74*#%1'60
Y *+(",'-+%./ #$. /%1(4*#%.3 %' "$'34-.
$,.4(#%'13 &#-%'$/0 R,1-, &'$( *#$7. 1((46.
-'("*.T./= ),1/ #-%12#%./ %,. -'("*.(.6% /+/5
%.( #63 %,. $.*.#/. '& -,.('%#-%1- -'("*.5
(.6% -*.#2#7. "$'34-%/0 *.#3167 %' /4A/%#6%1#*
2#/-4*1%1/= !/ # $./4*%0 -+%'P16./ #63 (.31#%'$/
'& 16&*#((#%1'6 #$. $.*.#/.3 16 %,. %1//4.=

"
),./. ('*.-4*./ #%%$#-% 7$#64*'-+%./ #63
!-%12#%.3 /+6'21#* -.**/ #$. "$./.6%.3 16 %,. 1*5 (#-$'",#7./ %,#% -'6%$1A4%. %' %,. "$'-.//
*4/%$#%1'6/= ),.+ /,'R 8!<0 #6 '*17'3.63$1%1-0 '& %1//4. 3./%$4-%1'6= ),1/ (.-,#61/( "$'A#A*+
-*#// GG HI!5"'/1%12. -.**U 8"<0 # CDEFV 71#6% "*#+/ # 3.-1/12. $'*. 16 %,. 3.2.*'"(.6% '&
-.**0 R,1-, (#+ '--4$ 16 7$#64*'(#5*1P. &'$(#5 .T%$#5#$%1-4*#$ 2#/-4*1%1/5#//'-1#%.3 *./1'6/ 'A5
%1'6/U #63 8#<0 # %+"1-#* /%.**#%. /+6'21#* -.** /.$2.3 16 $,.4(#%'13 #$%,$1%1/=
8!"#$$%"# &#$$< %,#% -'$$./"'63/ %' # /+6'21#* &15
A$'A*#/% #63 A.#$/ #A.$$#6% -*#// GG HI! #6%15
7.6/= :%.**#%. -.**/ /,'4*3 6'% A. -'6&4/.3
R1%, 3.63$1%1- -.**/0 R,1-, #$. #*/' "$./.6% 16
%,. /+6'21#* (.(A$#6. 16 "#%1.6%/ R1%, $,.45
(#%'13 #$%,$1%1/=

9" ,$%-.*'/(+ <*&'/5: =!2'(73/;-3(2:>

9,.4(#%'13 &#-%'$/ #$. 1((46'7*'A4*16/ 315
$.-%.3 #7#16/% %,. L- $.71'6 '& G7S= ),.+ #$.
%,. "$1(. .T#("*. '& #6 #4%'1((46. (#61&./5
%#%1'60 /16-. %,.+ $."$./.6% #6 #6%1A'3+ 31$.-5
%.3 #7#16/% 1%/ 'R6 P163 8W#6%17*'A4*16X<= 9,.45
(#%'13 &#-%'$/ #$. #*/' "$./.6% 16 ,.#*%,+
16312134#*/ 16 *'R #('46%/= ),.1$ /1761&1-#6-.
1/ "$'A#A*+ #%%$1A4%#A*. %' %,. 6'6/".-1&1- .65
,#6-.(.6% '& #6%1A'3+ $.#-%1'6/ 16 16&.-%1'6/0

!
CDE
./".-1#**+ 16 %,. .#$*+ ",#/./ R,.$. %,. /4""*+
'& /".-1&1- 1((46'7*'A4*16/ 1/ 6'% +.% &4**+
('46%.3= ),1/ 1/ #*/' %,. -#/. 16 &1.$-. 1((45
6'*'71-#* -*#/,./0 /4-, #/ 16 .63'-#$31%1/= G6
$,.4(#%'13 #$%,$1%1/0 /%1** 46P6'R6 (.-,#65
1/(/ -#4/. %,. #A6'$(#* "$'*1&.$#%1'6 '& $,.45
 PGE2, CD4 CD14 DR
DP
F*'$/7%2%:(: /G ,$%-.*'/(+ !5'$5('(: =@@>
!
neopterin Enhanced
DQ
phagocytosis
TGF-!,
FGF CD68
IL-10
Enhanced
TNF-", Fc chemotaxis
IL-1 receptor
A. Activated rheumatoid synovial macrophage

93(2(&*3 @..-2/3/71
1. Synovial macrophage 2. Giant cell 3. Stellate
B. Activated cells of the rheumatoid synovial membrane synovial cell

1. IgM rheumatoid factor

C. Rheumatoid factors (anti-globulins)

2. IgG rheumatoid factor
( also IgA and IgE
rheumatoid factor ) "
Allo- or auto- Synovial membrane Intra-articular space
antigen?
+ APC
Polyclonal
B-cell
activation
Auto- Immune
antibodies complexes
(RF)

Complement
activation C3a,b

Cytokines +

!
Vasculitis C5a inflammatory
mediators
Tissue
and cartilage Cartilage
destruction
D. Impaired B-cell regulation
CDH

"
! B9&)9$+&C0$0*%$ 5'&0%&0&

!" #$%&&'(')%*'+,
!"#$# %$# &#'#$%( )*$+& *) ,-'#./(# 0"$*./0 %$1
2"$/2/& 345678 !"# )/$&2 /& !"#$%&'()*#%& +,-9 % &#$1
%.? %.2/1.-0(#%$ %.2/=*?/#&E 2"# X;O %.2/:#. /&
-&-%((> A$#&#.28

5" :%8$/;<,&0* <$'=+%8*>8'*'&

*.#:%2/'# 3;<1.#:%2/'#7 )*$+ 2"%2 =#:/.& /.
#%$(> 0"/(?"**?8 !"#$# %$# &/:./)/0%.2 ?/))#$1
#.0#& =#2@##. A*(>%$2/0-(%$ 456 %.? 2"# %?-(2
)*$+9 @"/0" *00-$& (%2#$ %.? /& ;<1A*&/2/'#8 .#(/
0"%&'()*#%& +,- /& ?/'/?#? /.2* #%$(>1*.&#2 A%-1
0/%$2/0-(%$ %$2"$/2/& 3BCD6E 2>A# F7 %.? (%2#1*.1
&#2 A%-0/%$2/0-(%$ %$2"$/2/& 3GCD6E 2>A# FF78 !"#
#%$(> *.&#2 )*$+ /& 0"%$%02#$/H#? => 2"# A$#1
&#.0# *) %.2/1.-0(#%$ %.2/=*?/#&9 @"#$#%& 2"#
A$#&#.0# *) "/&2*0*+A%2/=/(/2> %.2/:#. IG61
JKL /& 2>A/0%( *) 2"# (%2#1*.&#2 )*$+8 F. %??/2/*.
2* 2"#&# )*$+&9 2"#$# /& %(&* 1$1'23() 4*526(#2
#$',')%$ D119,+$+=/
!"/& ?/&#%&# -&-%((> %))#02& /.)%.2&8 6$2"$/2/&9
/2&#()9 -&-%((> /& .*2 2"# A$/+%$> A$*=(#+ %&
2"# ?/&#%&# 2#.?& 2* $-. % +/(? 0*-$&#8 5"$*./0
/$/?*0>0(/2/&9 @"/0" /& %&&*0/%2#? @/2" 2"# $/&Q *)
=(/.?.#&&9 /& % &#$/*-& 0*+A(/0%2/*.8 !"/& )*$+
*) /$/?*0>0(/2/& /& %&&*0/%2#? @/2" %.2/1.-0(#%$
%.2/=*?/#& %.? A$#?*+/.%.2(> %))#02& :/$(&8
:" 29?0,'$0 .@+,A/$+%8*>8+@%*>/
G/Q# 2"# ;<1A*&/2/'# A*(>%$2/0-(%$ ?/&#%&#&9

,-'#./(# &A*.?>(*%$2"$*A%2"/#& %$# 2"# 0"/(?1

)7&"6() %&'7&('(1 3M2/((N& ?/&#%&#79 @"/0" /& 0"%$1
%02#$/H#? => &#'#$# *$:%. +%./)#&2%2/*.&8
-" ./&*01') 2#! 3.*'$$4& 5'&0%&06
M2/((N& ?/&#%&# A$#&#.2& % ?$%+%2/0 0(/./0%( A/01
2-$# @/2" .-+#$*-& +%./)#&2%2/*.&8 F2 /& 0"%$1
%02#$/H#? => $%&"#& 2"%2 %$# *)2#. 2$%.&/#.29
"/:" )#'#$ 3-A 2* OP !579 A*(>&#$*&/2/& @/2"
A(#-$%( %.? A#$/0%$?/%( #))-&/*.& %.?9 /. +%.>
0%&#&9 "#A%2*&A(#.*+#:%(>8 !"# ?/&#%&# +%>
"**? )*$+& *) %?-(2 &A*.?>(*%$2"$*A%2"/#&8
M#$*.#:%2/'# &A*.?>(%$2"$/2/?#& -&-%((> +%./1
)#&2 @/2" &%0$*/(//2/& %.? /.'*('#+#.2 *) 2"#
"/A ,*/.2 *$ *) *2"#$ (%$:# ,*/.2&8 4-'#./(# &A*.1
?>(*%$2"$*A%2"/#& -&-%((> %))#02 =*>&8 !"#> %$#
0"%$%02#$/&2/0%((> %&&*0/%2#? @/2" 2"# A$#&#.0#
*) IG61JKL %.? 2"# %=&#.0# *) $"#-+%2*/?
)%02*$& %.? %.2/1.-0(#%$ %.2/=*?/#&8 !"# A$*:1
.*&/& /& -.0#$2%/.8 !"# ?/&#%&# +%> #/2"#$
0*+A(#2#(> ?/&%AA#%$ %)2#$ A-=#$2> *$ A$*:$#&&

" /./2/%((> =# +/&2%Q#. )*$ (#-Q#+/% /) 2"# (%=*$%1

2*$> @*$Q1-A $#'#%(& &#'#$# (#-Q*0>2*&/& @/2"
(#)2 &"/)2/.: /. A%2/#.2& @/2" )$#R-#.2 (>+A"%1
?#.*A%2"/#&8 M2/((N& ?/&#%&# -&-%((> *00-$& %& %
&>++#2$/0%( %.? A#$/A"#$%( )*$+ *) A*(>%$2"$/1
2/& @/2" &#'#$# &@#((/.: %.? /+A%/$#? ,*/.2 +*1
2* % 2>A/0%( 0(/./0%( A/02-$# *) %.Q>(*&/.: &A*.1
?>(/2/&8

=/(/2>8

#" 7+$/%8*')9$%8 2#!

82&"620%'(52 !"#$%&'()*#%& +,- -&-%((> &2%$2& =#1
2@##. 2"# %:#& *) K %.? S >#%$&8 !"# 2>A/0%( A%1
2/#.2 "%& +%.?/=-(%$ ,*/.2 /.'*('#+#.2 3*)2#.
@/2" +/0$*:.%2"/%7 %.? % &>++#2$/0%( A%22#$.
*) A*(>%$2"$/2/&8 BA/A">&#%( :$*@2" ?/&*$?#$&
@/2" (/+= (#.:2" ?/))#$#.0#& %$# A*&&/=(# 0*+1
A(/0%2/*.&8 T/$(& %$# A$#?*+/.%.2(> %))#02#?8
!"# (%=*$%2*$> 2#&2& %$# '%:-#E %.2/1.-0(#%$
%.2/=*?/#& %$# *00%&/*.%((> ?#2#02#?8 F. +%.>
0%&#&9 A*(>%$2/0-(%$ 456 +%> 0*+A(#2#(> $#&*('#
%)2#$ A-=#$2>8
82&"!"1('(52 !"#$%&'()*#%& +,-9 @"/0" /& %(&*
$#)#$$#? 2* %& U#%$(>1*.&#2 $"#-+%2*/? %$2"$/1

!
2/&9V -&-%((> =#:/.& /. 0"/(?$#. *'#$ PW >#%$&
*) %:#8 !"# ;<1A*&/2/'# ,-'#./(# )*$+ /& /.?/&2/.1
:-/&"%=(# )$*+ &#$*A*&/2/'# %?-(2 $"#-+%2*/?
%$2"$/2/&8 F. +*&2 0%&#&9 2"#$# /& % &#'#$# 0*-$&#
*) ?/&#%&# @/2" &>++#2$/0%( %$2"$/2/0 ?#&2$-01
EFG 2/*.8 G%=*$%2*$> 2#&2& $#'#%( $"#-+%2*/? )%02*$&
 Juvenile chronic arthritis (JCA)
29?0,'$0 #>8+,') !8*>8'*'&
!
Polyarticular Systemic Oligoarticular
40% 10% 50%
( Still’s disease)

RF-negative Early onset

(early onset) ANA+ type I
(EOPA)

RF-positive Late onset

(late onset) HLA-B27+ type II
(LOPA)
A. Subtypes

#$',')%$ D119,+$+=/
Fever Seronegative Seropositive
(up to 41°C)
Age of onset Age of onset
Exanthema 2–5 years >10 years
Lymphadeno-
pathy
Mandibular
Polyserositis involvement Symmetric
(micrognathia) destructive
Organ f:m arthritis
enlargement 4:1
f:m Symmetric
2:3

"
polyarthritis
(epiphysial
Exanthema growth
defect)
Arthritis
(polyarticular) Lab. findings:
ESR , CRP Lab. findings:
Lab. findings:
leukocytes RF+
unspecific
(shift to the left) ANA+ 75%
(ANA+ 25%)
anemia DR4+

B. Systemic form ( Still’s disease) C. Polyarticular forms

Chronic Arthritis Uveitis

iridocyclitis (few joints)

f:m Sacroiliitis f:m

9:1 1:9

Lab. findings: Lab. findings:

Iridocyclitis
D. Early childhood oligoarthritis
ANA+ 50%
RF neg.
HLA-, B27+
ANA-, RF neg.

E. Juvenile spondyloarthropathy
!
EFH

"
! D,.',$2.E*$*+($ F%.*(.*.

!"#$# %&$'(%#($ ")*# +(#), $&-&.)(&,&#$/ 01 2)(3

,&45.)(6 ,"#7 )(# .&18#% 97 )$$'4&),&'1 :&," ;<=3
>?@6 ,"# 2(#$5-#% &--51# 2),"'+#1#,&4 A)43
,"# -'$, 4'--'1 2('9.#- &$ %)4,7.&,&$6 ,"# ()3
%&). &1A.)--),&'1 'A ).. L'&1,$ 'A ) A&1+#( '( ,'#/

,'(6 )1% ,72&4). 4.&1&4). -)1&A#$,),&'1$/ !"# /" 0(+123*&*.%.

1)-# B$2'1%7.')(,"('2),"7C &-2.&#$ &1*'.*#3
-#1, 'A ,"# )D&). $8#.#,'1/ !"&$ +('52 'A %&$'(3
%#($ &$ 4.)$$&A&#% )44'(%&1+ ,' ,"# 4(&,#(&) 'A ,"#
E5('2#)1 F2'1%7.')(,"('2),"7 F,5%7 G('52
HEFFGI $## ,)9.#J/
!" #$%&%'($ )*(+,-*.
!"&$ +('52 'A %&$#)$#$ &14.5%#$ )187.'$&1+
$2'1%7.&,&$ HF2=J6 (#)4,&*# )(,"(&,&%#$ H(#=J6 )(3
,"(&,&%#$ )$$'4&),#% :&," 4"('1&4 &1A.)--),'(7
9':#. %&$#)$# H0>KJ6 )1% 2$'(&),&4 )(,"(&,&$/
#$%&%'($ GAA,&2$23@
F2'1%7.')(,"('2),"&#$ )(# 'A,#1 )$$'4&),#%
:&," &1A.)--),'(7 9':#. %&$#)$#$ )1%['( 5(#3
,"(). '( 4#(*&4). &1A.)--),&'1$/ !"# A)4, ,"),
.)(+# \5)1,&,&#$ 'A )1,&+#1&4 -),#(&). 4)1 #1,#(
&1,' ,"# 4&(45.),&'1 $##-$ ,' 2.)7 ) 2)(,&45.)(.7
&-2'(,)1, ('.# &1 2),&#1,$ :&," &1A.)--),'(7
-54'$). 4")1+#$/ 0A ) +#1#,&4 2(#%&$2'$&,&'1
).$' #D&$,$6 ,"# )(,"(&,&%#$ ,#1% ,' '445( ), )
,&-# :"#1 ,"# ,(&++#(&1+ %&$#)$# &$ 1' .'1+#(
2(#$#1,/ !"# 2('-',#( (#+&'1$ 'A 2('&1A.)--)3
,'(7 47,'8&1# +#1#$ H+#1#,&4 -'%&A&#($J )1% ,"#

=187.'$&1+ $2'1%7.&,&$ &$ ) $7$,#-&4 &1A.)-3
-),'(7 %&$#)$# ,"), -)&1.7 )AA#4,$ ,"# )D&).
$8#.#,'1 )1% L'&1,$6 95, $'-#,&-#$ ,"# &1,#(1).
'(+)1$/ 0, 2(#%'-&1)1,.7 )AA#4,$ -).#$ )1%
5$5)..7 $,)(,$ 9#,:##1 ,"# )+#$ 'A MN )1% OP
7#)($/ =2)(, A('- ,"# L'&1,$6 ,"# %&$#)$# ).$' )A3
A#4,$ A&9('4)(,&.)+&1'5$ $,(54,5(#$6 $54" )$ ,"#
$714"'1%('$#$ )1% &1,#(*#(,#9(). %&$8$/ Q),"'3
.'+&4). 4")1+#$ )(# #$2#4&)..7 4'--'1 ), ,"#
$&,#$ 'A &1$#(,&'1 'A ,#1%'1$ )1% .&+)-#1,$/
,72#$ 'A ,(#),-#1, )AA#4, ,"# A5(,"#( 4'5($# 'A
%&$#)$#/
#" 0-*4($*&'* 25 67!8/9: !&+%3*&
!"# 2(#*).#14# 'A ;<=3>?@ )1,&+#1 &$ 4)/ ]PT
]N R &1 &1%&*&%5).$ :&," )187.'$&1+ $2'1%7.&,&$6
)1% ^TMP R &1 ,"# +#1#(). 2'25.),&'16 %#2#1%3
&1+ '1 ,"# #,"1&4 4'-2'$&,&'1/ F'-# $,5%&#$
")*# 4'14.5%#% ,"), 52 ,' ?P R 'A ).. ;<=3
>?@32'$&,&*# &1%&*&%5).$ :&.. %#*#.'2 )187.'$3

"
!"# 4'5($# &$ 4"('1&4 )1% 2('+(#$$&*#6 )1%
&1+ $2'1%7.&,&$ '( 51%&AA#(#1,&),#% $2'1%7.')(3
,"# $2&1# )1% $)4('&.&)4 L'&1,$ )(# ).:)7$ )A3
,"('2),"&#$ %5(&1+ ,"#&( .&A#,&-#/
A#4,#%/ =%%&,&'1). &1*'.*#-#1, 'A ,"# 2#(&2"3
#(). L'&1,$ '445($ &1 ?N R 'A 4)$#$/ !"# %&$#)$#
-)7 ).$' ")*# #D,()3)(,&45.)( -)1&A#$,),&'1$6
;<<= #$(..%5%'(+%2& 25 <>2&?@$2(-+1-2>(8
,"# -'$, 4'--'1 'A :"&4" )(# )1,#(&'( 5*#&,&$
+1%*.
H&(&,&$J )1% 5(#,"(&,&$I 2('$,),&,&$ &$ 4'--'1 &1
,"# -).# 2),&#1,$/
!"#$%&'" #(%)(&%&*"+ )(# 'A,#1 )$$'4&),#% :&," !"#$%&&%'()* +,-"%$ ,%-"
) 2(&'( 9':#. &1A#4,&'1 '( 5(#,"(&,&$/ S.&+'3 !"
)(,"(&,&$ &1*'.*&1+ ?TU .)(+# '( $-).. L'&1,$ .*"(/-'-+
5$5)..7 '445($ )A,#( ) .),#147 'A MP ,' 1' %+*&&0')-1 ()
-'(# ,")1 OP %)7$/ !"# L'&1,$ 'A ,"# .':#( #D3 ,)02(&-"%"'$* -" '30 $(40) $-&5+
,(#-&,&#$ )(# ).-'$, ).:)7$ )AA#4,#%6 )1% ,"#(# (&? 2&* 2- A2-* 25 +1* 52$$2B%&3C
&$ 2(#A#(#1,&). &1*'.*#-#1, 'A ,"# 81## )1% 6(+-'-/0 #%&-$* 3-+'()*
)18.# L'&1,$/ 01 )%%&,&'1 ,' 45,)1#'5$ -)1&3 6+()-%+-+
A#$,),&'1$ H8#(),'%#(-) 9.#1'((")+&45-I $## !"#$%&&%'()* 5(40$ 2-+0%+0+
2"','+()2"J6 4'1L514,&*&,&$ )1% &(&%'474.&,&$ 7)0'3)-'-+8 10)/-1-'-+8 () %19'0 2-%))30% 4-'3-"
)(# ).$' 4'--'1 HV#&,#(W$ ,(&)%X )(,"(&,&$6 5(#3 : &("'3 50#()0 %)'3)-'-+
,"(&,&$6 4'1L514,&*&,&$J/ ;9''(1< ,%-" %$'0)"%'-"= 50'400" )-=3' %"2
,+-(&#%&$ #(%)(&%&+ -)7 )(&$# A('- -'1')(3 $0#' =$9'0%$ %)0%+
,"(&,&$6 '.&+')(,"(&,&$6 '( 2'.7)(,"(&,&$/ Y)17 2)3 >"'30+(,%'3*
,&#1,$ :&," ) .'1+ "&$,'(7 'A ,"# %&$#)$# -)7 .%1)(-$--'-+

!
")*# 2'.7)(,&45.)( -)1&A#$,),&'1$ :&," 4")()43
,#(&$,&4 &1*'.*#-#1, 'A ,"# %&$,). &1,#(2").)13
+#). L'&1,$ HK0ZJ 'A ,"# A&1+#($ )1% ,'#$6 ,"# &13
,#(2").)1+#). L'&1,$ 'A ,"# ,"5-9$/ !"#
$)4('&.&)4 L'&1,$ )1% *#(,#9(). L'&1,$ -)7 ).$'
H:I 9# )AA#4,#%/ 01 2#(&2"#(). L'&1, &1*'.*#-#1,6
 #$%&%'($ )*(+,-*. 25 <>2&?@$(-+1-%+%.
!
Axial and
peripheral
arthritis

Ankylosis

#$%&%'($ GAA,&2$23@
Enteritis/
Balanitis/ diarrhea
urethritis

Enthesio- Keratoderma

"
pathy blenorrhagicum

A. Clinical manifestations of spondyloarthropathies

Genetic Environmental Ankylosing

- HLA spondylitis 95%
- gender Infections
- ethnic
Reiter’s syndrome
- factors
(classic form) 80%

Undifferentiated
spondyloarthropathy 70%
Disease

Arthritis with IBD 25%

Cytokine genes Genetic Psoriatic arthritis 25%

modifier

Reactive arthritis 20–80%

Treatment

Clinical
outcome

B. Pathogenesis of spondyloarthropathy
Normal population

C. Frequency of HLA-B27 antigen

8–10%
!
H::

"
! #(6'(%$6C&%&;)% <+6&)6&6

!"# $"%## &'(#)* (#*+%,-#( -#)'. /%# 0*#( $'

#12)/,3 $"# 40#*$,'3 '5 "'. $"# 6789:;< /3$,9
=#3 ,* ,3>')>#( ,3 $"# 2/$"'=#3#*,* '5 *2'3(?9
.,$" "0&/3 6789:;< +'&-,3#( .,$" !;9&,9
+%'=)'-0),3 /3( ,&2)/3$#( ,3 *"/& 2%#=3/3$
%/$*@ !"# $%/3*=#3,+ 2%'=#3? #1",-,$#( &/3,5#*9
)'/%$"%'2/$",#*@ $/$,'3* *,&,)/% $' $"'*# '5 6789:;<9/**'+,/$#(
*2'3(?)'/%$"%'2/$",#* ,3 "0&/3*@ G3 /((,$,'3
!" #$%&'(%)* #+,+'*- $' *#)59=#3# 2%'(0+$*A $"#? /)*' (#&'3*$%/$#(
$"# 2%#*#3+# '5 "0&/3 6789:;< /3$,=#3 /3(
!",* "?2'$"#*,*A ),B# $"# C$')#%/3+#D $"#'%?A /*9
*0&#* $"#%# ,* =%#/$ *$%0+$0%/) *,&,)/%,$? -#9 !;9&,+%'=)'-0),3@ !"# /3,&/)* (#>#)'2#( /%9
$"%,$,*A 2*'%,/*,*A 3/,) +"/3=#*A /3( +'),$,*@ G3$#%9
$.##3 $"# 2')?&'%2",+ %#=,'3* '5 $"# 6789
#*$,3=)?A $"# (,*#/*# (,( 3'$ (#>#)'2 ,3 /3,&/)*
:;< /3$,=#3 /3( -/+$#%,/) 2/$"'=#3*@ E"#3 ,39
%/,*#( ,3 / =#%&95%## #3>,%'3&#3$@ !",* ,&9
5#+$,'3* '++0%A $"# -/+$#%,/) /3$,=#3* /%# %#+'=9
2%#**,>#)? 03(#%),3#* $"# %')# '5 ,35#+$,'3* ,3
3,F#( /* 5'%#,=3A /3( /(#40/$# !9+#))9&#(,/$#(
/3( "0&'%/) %#*2'3*#* '++0%@ :#+/0*# '5 $"# $"# 2/$"'=#3#*,* '5 *2'3(?)'/%$"%'2/$",#*@
*$%0+$0%/) *,&,)/%,$? .,$" 6789:;<A $"# /3$,=#3
,* &,*$/B#3)? ,(#3$,5,#( /* 5'%#,=3@ 8* / %#*0)$A
3%+1+')% =,,(1$%$A-

$"# ,&&03# *?*$#& -#=,3* $' /$$/+B #3('=#39

'0* $,**0#A .",+" $%,==#%* / *$,)) 03B3'.3 +/*9
+/(# $"/$ )#/(* $' $"# &/3,5#*$/$,'3* '5 *2'3(?9
)'/%$"%'2/$"?@

." /0$%&*)1'&2
!"# $')#%/3+# &'(#) ,* -/*#( '3 *,&,)/% /*9
*0&2$,'3*@ G3 $",* +/*#A "'.#>#%A $"# *$%0+$0%/)
*,&,)/%,$? -#$.##3 6789:;< /3( $"# &,+%'-,/)
/3$,=#3* ('#* 3'$ )#/( $' /3 /0$'/==%#**,>#

" 2%'+#**A -0$ $' ,3+'%%#+$ $')#%/3+# '5 $"# -/+$#%9

,/) /3$,=#3*@ 8* / %#*0)$A $"# 2/$"'=#3* 2#%*,*$ ,3
$"# /55#+$#( H',3$A /3( $"#? /%# 3'$ #55#+$,>#)?
#),&,3/$#( -? $"# ,&&03# *?*$#&@ !"# +'39
5%'3$/$,'3 .,$" $"# 2/$"'=#3 )#/(* $' $"# (#9
>#)'2&#3$ '5 ,35)/&&/$'%? 2%'+#**#* $"/$ $%,=9
=#% /%$"%,$,*@

3" 04& /5*$,+6'($(62 .78 9-:$;4&6+6

8++'%(,3= $' $",* %#+#3$)? (#>#)'2#( &'(#)A
6789:;< /3$,=#3 ,* 3'$ (,%#+$)? ,3>')>#( ,3
$"# /3$,=#3 %#+'=3,$,'3 '5 /3 /%$"%,$'=#3,+
2#2$,(#A -0$ /+$* /* /3 /0$'/3$,=#3 $"/$ ,3(,%9
#+$)? *#$* '55 $"# ,35)/&&/$'%? +/*+/(# >,/
IJK9&#(,/$#( &#+"/3,*&*@ 8++'%(,3=)?A $"#
6789:;< &')#+0)# ,* -%'B#3 ('.3 ,3$' $,3?
5%/=&#3$* L2#2$,(#*M ,3*,(# $"# +#))*@ !"# 5%/=9
&#3$* #3$#% $"# 2#2$,(#9-,3(,3= *,$# '5 $"#
6789JN /3$,=#3 /3( /%# $"#3 2%#*#3$#( $'
$"# /+$0/) /%$"%,$'=#3,+ IJKO ! +#))*@ !"#*#
!9"#)2#% +#))* *#$ $"# 2%'+#** '5 /%$"%,$,* ,3
&'$,'3@

!
D8E
<" =1>(';+$1 $? @:$1>-%$)*;4*$:);4- +1
0*)16A&1+' B);6
!"# (,%#+$ ,&2/+$ '5 $"# 6789:;< /3$,=#3 ./*
(#&'3*$%/$#( ,3 /3,&/) #12#%,&#3$* .,$"
$%/3=#3,+ %/$*@ N/$ ''+?$#* .#%# $%/3*5#+$#(
 5);4$A&1&6+6 $? @:$1>-%)*;4*+;+6
!
Cross-reactive Persistence of
antibodies pathogenic
or T cells bacteria

Antigen Antigen
determinant determinant

HLA-B27 HLA-B27

Microbe Microbe

3%+1+')% =,,(1$%$A-
"2-micro- "2-micro-
!-chain !-chain
globulin globulin

A. Molecular mimicry

CD8+
T cell
B. “Tolerance”

Injection of
genes encoding for
the heavy chain
"
and the "2-
microglobulin
HLA-B27 in a rat egg cell

Arthritis
Implantation
of transfected
egg in syngenic
rats

HLA-DR
Transgenic
offsprings

Own Arthritis
CD4+

C. Promiscuous B27 hypothesis

T cell gene product
Human
HLA-B27
D. Induction of spondyloarthropathy
D. in transgenic rats
Psoriasis

Colitis
!
D8F

"
! 8%1+%)$193)3&:) ;013:131

!" #$%&
!"#$%"& '()* "+,)-*, ."($ */+ %00)$)-%*#(1
%12 2+3(,#*#(1 (. )"#0 %0#2 2)+ *( % '+1+*#0 3"+4
2#,3(,#*#(1 #1 %,,(0#%*#(1 5#*/ /#'/ -+6+-, (.
3)"#1+ #1 */+ 2#+*7 8()*& 0"&,*%-, 9$(1(,(2#)$
)"%*+: %00)$)-%*+ $%#1-& #1 */+ ;(#1*,< =)* %-,(
#1 */+ 0%"*#-%'+ %12 0(11+0*#6+ *#,,)+ =& ,&,4
*+$#0 ,3"+%2#1'7
! 8()* 3%*#+1*, /%6+ %1 #1/+"#*+2 2+.+0* #1
)"%*+ +>0"+*#(17 ?/+ 0(12#*#(1 "+$%#1,
%,&$3*($%*#0 %* 1("$%- )"%*+ 0(10+1*"%4
*#(1,7 @(5+6+"< % 3)"#1+4"#0/ 2#+* -+%2, *(
*/+ %00)$)-%*#(1 (. )"%*+ 9/&3+")"#0+$#%A
!B $'C2-: %12< )-*#$%*+-&< *( */+ 3"+0#3#*%*#(1
(. )"%*+ ,%-*,7 D+0(12%"& '()* #, 0%),+2 =& #14
2)0-0+:) <77%-$)$=*
'" ($)*+,$-./0&01
!(-&0/(12"#*#, #, %1 #1.-%$$%*#(1 (. )1E1(51
+*#(-('& */%* %..+0*, 6%"#(), 0%"*#-%'#1(), ,*")04
*)"+,< +,3+0#%--& */+ +%",< 1(,+< %12 *"%0/+%7 H*
(.*+1 (00)", #1 %,,(0#%*#(1 5#*/ ,&,*+$#0 6%,0)4
-#*#,7 ?/+ 2#,+%,+ $(,* 0($$(1-& =+'#1, =+4
*5++1 */+ %'+, (. JK %12 LK &+%", %12 /%,
%1 #1*+"$#**+1* 0()",+7 H1.-%$$%*#(1 %12 ,5+-4
-#1' (. */+ 0%"*#-%'#1(), ,*")0*)"+, -+%2, *( */+
2+6+-(3$+1* (. 2+.("$#*#+,< ,)0/ %, ,%22-+
1(,+ %12 0%)-#.-(5+" +%"7 D(.*+1#1' (. */+ *"%4
0/+%- 0%"*#-%'+ 0%1 -+%2 *( #1,3#"%*("& ,*"#2("
%12 *"%0/+%- 5%-- 0(--%3,+7 ?/+ %"*#0)-%" 0%"*#4
-%'+ #, %..+0*+2 #1 % 3%**+"1 ,#$#-%" *( 1(1+"(4
,#6+ 3(-&%"*/"#*#,7 M&+ #16(-6+$+1* */%* $%1#4

0"+%,+2 ,+")$ )"%*+ -+6+-, 2)+ *( #10"+%,+2
0+--)-%" 0%*%=(-#,$ 9+7'7< #1 3(-&0&*/+$#%
6+"%< 6%"#(), -+)E+$#%,< 0&*(,*%*#0 */+"%3&<
%12 "%2#(*/+"%3&: (" 2+0"+%,+2 +>0"+*#(1
9+7'7< *)=)-%" 2+.+0*, (" 0($3+*#*#(1 ."($
-%0*%*+< E+*(1+,< (" 2#)"+*#0, %* */+ *)=)-+,:7
" ?/+ 3"+0#3#*%*#(1 (. '()*& 0"&,*%-, $(,*
0($$(1-& (00)", #1 */+ ;(#1*, (. */+ -(5+"
+>*"+$#*#+,< 5/+"+ #* *"#''+", %1 #1.-%$$%4
*("& "+,3(1,+7 F '()*& %**%0E $%& #16(-6+
.+,*, %, +3#,0-+"#*#,< #"#*#,< %12 )6+#*#, #,
0($$(17 N%,0)-#*#, (. */+ $%;(" =-((2 6+,,+-,
0%1 "+,)-* #1 %("*#*#, %12 %("*#0 #1,)..#0#+10&7
I-((2 *+,*, "+6+%- #10"+%,+, #1 */+ 3%"%$+*+",
(. #1.-%$$%*#(1< =)* */+"+ #, %1 %=,+10+ (. 1)4
0-+%" %)*(%1*#=(2#+,7 F0)*+ +3#,(2+, %"+ $%1%4
'+2 =& 3"+21#,(-(1+ */+"%3&O ,+6+"+ %**%0E,
),)%--& "+P)#"+ %G%*/#(3"#1+< 0&0-(3/(,3/%4
$#2+< (" 0&0-(,3("#1 F7

"
*/+ .#",* $+*%*%",(3/%-%1'+%- ;(#1* (. */+ 2" '3,+43&51 6*-./$73
=#' *(+ 93(2%'"%: (" */+ E1++ ;(#1* 9'(1%'"%:7
I+/0Q+*R, ,&12"($+ #, % ,&,*+$#0 #1.-%$$%*#(1
8"%1)-(0&*+, $#'"%*+ #1*( */+ ;(#1* %12 3/%4 (. */+ ,$%-- 6+,,+-, 0/%"%0*+"#G+2 =& % *"#%2 (.
'(0&*(,+ */+ 0"&,*%-, =)* 0%11(* 0%*%-&G+
,&$3*($,< #10-)2#1' %3/*/(), )-0+"%*#(1 (.
*/+$ =& -&,(,($%- $+0/%1#,$,7 ?/+ 0"&,*%-,
*/+ ("%- $)0(), $+$="%1+, %12 '+1#*%-#%
2%$%'+ */+ -&,(,($%- $+$="%1+ (. */+
%12 )6+#*#,7 S%"+ $%1#.+,*%*#(1, #10-)2+ (-#4
'"%1)-(0&*+,< "+,)-*#1' #1 */+ "+-+%,+ (. +14
'(%"*/"#*#, (. */+ -(5+" +>*"+$#*#+,< 6%,0)-#*#,
G&$+, %12 $+2#%*(", (. #1.-%$$%*#(17 ?/+ (. */+ 3)-$(1%"& 6+,,+-,< %12 0+"+="(6%,0)-%"
'()*& %**%0E #, ,+-.43"(3%'%*#1'7 H1 %0)*+
,&$3*($,7 ?/+ +*#(-('& (. I+/0Q+*R, ,&12"($+
'()*& %**%0E,< */+ '(%- (. *"+%*$+1* #,< */+"+4
#, )1E1(517 F1 %,,(0#%*#(1 5#*/ @TF4IUV
.("+< *( 2#,")3* */+ #1.-%$$%*("& "+,3(1,+7
/%, =++1 .()127 ?/+ ("%- %3/*/(), )-0+"%*#(1,
?/+,+ %**%0E, 0%1 =+ +..+0*#6+-& $%1%'+2
$),* =+ 2#..+"+1*#%*+2 ."($ /%=#*)%- ("%-
5#*/ 0(-0/#0#1+< %1 %-E%-(#2 */%* %""+,*, 0+-- %3/*/%+ %12 */(,+ %,,(0#%*+2 5#*/ #$$)1+
2#6#,#(1 #1 $+*%3/%,+ =& 2#,")3*#1' */+ $#4
6%,0)-#*#, %12 W"(/1R, 2#,+%,+7 ?/+ 3%*#+1*,
*(*#0 ,3#12-+7 ?/+ 2")' %-,( =#12, *( */+ 0(14
%"+ ),)%--& *"+%*+2 5#*/ -(0%- ,*+"(#2 */+"%3&
*"%0*#-+ +-+$+1*, (. '"%1)-(0&*+,< */+"+=&
(" ,&,*+$#0 2")',< ,)0/ %, 0&0-(,3("#1 F %12
3"+6+1*#1' */+$ ."($ $#'"%*#1' *( */+ ,#*+,
0&0-(3/(,3/%$#2+7
(. #1.-%$$%*#(17
!"#$%&' ($)* #, 0/%"%0*+"#G+2 =& */+ 2+3(,#4
*#(1 (. )"%*+ 0"&,*%-, #1 ,(.* *#,,)+, 9()*+" +%"<
/++-:< =(1+ 9+,3+0#%--& 3"(>#$%- *( */+ ;(#1*,:<
%12 E#21+& 9":7 !"(3/&-%0*#0 *"+%*$+1* .(" 3"+4
6+1*#(1 (. '()*& %**%0E, 0(1,#,*, #1 "+2)0#1'

!
>?@
*/+ )"%*+ 0(10+1*"%*#(17 ?/#, 0%1 =+ %0/#+6+2
*/"()'/ 2#+*%"& $+%,)"+, (" 2")' *"+%*$+1*7
F--(3)"#1(- #, % )"#0(,*%*#0 2")' */%* #1/#=#*,
>%1*/#1+ (>#2%,+< */+"+=& "+2)0#1' )"%*+ 3"(4
2)0*#(17 I+1G="($%"(1+ #, % )"#0(,)"#0 2")'
*/%* #10"+%,+, "+1%- )"%*+ +>0"+*#(17
 Diet
#$%&A ($)*+,$-./0&01A :-. '3,+43&51 6*-./$73

Allopurinol
!
Secondary Tophi in
Primary Increased cell decay
Purines derived cartilage
from food Benzbromarone
O H
H N N Decreased
O urate elimination
O N N
7 mg/dl
H H Gout osteo-
Uric acid Urate pool arthropathy
Colchicine Olecranon
bursitis
Renal
Urate damage
crystals Chemotaxis
Soft tissue

2)0-0+:) <77%-$)$=*
IL-1
Macrophage tophi
Inflammatory reactions on hands
Granulocyte
Knee joint
(gonagra)

Piercing Release of First meta-

enzymes
tarso-

"
Phagocytosis and mediators
phalangeal
joint
1. Pathogenesis and therapy 2. Manifestations (podagra)
A. Gout

Uveitis Cauliflower Systemic Association

ear vasculitis with HLA B52
of small vessels
Saddle Meningo-
nose encephalitis
1 Uveitis
Tracheal CNS:
collapse vasculitis
Aortitis Pulmonary
vasculitis

2 Oral
aphthae Pericarditis
Erythema
nodosum,
pyoderma
3 Genital Oligoarthritis,

!
ulcerations esp. lower
limbs
Additional
Ear cartilage lesion Clinical triad findings

B. Polychondritis C. Behçet’s disease

>?>

"
! !#$%&'$()%*(-/

!" !#$%&'$()%*+ ,&$$-.'/

!"#$%&' %($)%'$&*)+&", $-%$ .#)+(/" /"#$%&'
.%$$"#', &' &'+&#"/$ &00(')12()#",/"'/" ,$(3
#-"(0%$&/ +&,"%,",A %'+ >%*2" M @B&?'&1&/%'/"
)1 %($)%'$&*)+&", &' $-" +&%?'),&, )1 %($)&03
0('" +&,"%,",A &' $-" %.."'+&N ,"/$&)'5
+&", 4,"" .5 67!8 $-%$ %#" /-%#%/$"#&,$&/ )1 ,9,3
$"0&/ %($)&00(').%$-&",5 :' 0%'9 /%,",;
$-"," %($)%'$&*)+&", %22)< % .#"2&0&'%#9 /2%,3
,&1&/%$&)' )1 ,."/&1&/&$9 %'+ )1 $-" +&,"%,", %,,)3
/&%$"+ <&$- $-"05 !)''"/$&=" $&,,(" +&,"%,",
%#" %,,)/&%$"+ <&$- /-%#%/$"#&,$&/ %($)%'$&*)3
+&",5 >-"9 <"#" )#&?&'%229 /%22"+ @/)22%?"' =%,3
/(2%# +&,"%,",A *"/%(," &$ <%, %,,(0"+ $-%$ $-"
/)22%?"'3/)'$%&'&'? /)''"/$&=" $&,,(" <%, $-"
$%#?"$ )1 %($)&00('&$95 >-&, ?#)(. )1 +&,"%,",
&'/2(+", ,9,$"0&/ 2(.(, "#9$-"0%$),(, 4BCD8;
BE)F?#"'G, ,9'+#)0"; ,/2"#)+"#0%; .)2909),&3
;=('(3&= D66#'%=%1+

$&,H+"#0%$)09),&$&,; %'+ ?"'"$&/ /)''"/$&="

$&,,(" +&,"%," 4I!>J85 >-" 2%#?" 0%E)#&$9 )1
$-" $%#?"$ %($)%'$&?"', %#" /)',$&$("'$, )1
$-" /"22 '(/2"(, %'+ /9$).2%,0 $-%$ .2%9 %
#)2" &' $-" .#)/",,&'? )1 ?"'"$&/ &'1)#0%$&)'5
>-" .%$$"#', %'+ +&,"%," %,,)/&%$&)', %#" +"3
,/#&*"+ &' >%*2" K @L'$&3'(/2"%# %'$&*)+&", &'

" 0(1'(2(3&'3- %2 !#$%&'$()%*(-/ (' $4- 5(&1'%/(/ %2 !#$%(66#'- 5(/-&/-/

!#$%7
&'$()%*+
089 :;<5 03=-.%7
*-.6&
:+%7
/($(/
!//%3(&$-* *(/-&/-
0>%
?1.-'@/
/+'*.%6
A4-#6&7
$%(*
&.$4.($(/
,.(6&.+
B&/3#=($(/
!'$(7
C4%/C4%7
=(C(*
/+'*.%6-
!"! ### ### ### # ### # # #
$%&"! ### ' ' ' ' ' ' '
() ## ' ' ' ' ' ' '
*+',"- # ### # # ' ' ' '
,./0%0123 - ## ' ' ' ' ' ' '
-4"! # ' ' ' ' ' ' '
,0 ## # # ' ### # ' '
52 ## # # ' ### # ' '
,!66 ## ## ' ' # ## ' '
(7389 ' ' ### ' ' ' ' '
4:;<=01:=: ' ' ### ' ' ' ' '

!
>0'+ ' ' ## ' ' ' '
-)'(73 ' ' # # ' ' ' '
42=$.03.?.; ### # # ' # # ' ###
!"4! ' ' ' ' ' ' ### '
EFG ,@:A12<0.$ B27<0= ## # # # ### ### # '
 !#$%&'$()%*+ ,&$$-.'/
!

1. Rim pattern 2. Homogenous pattern 3. Nucleolar pattern

(150x magnif; anti-DNA) (435x enlarged; anti-DNA) (e.g. fibrillarin)

;=('(3&= D66#'%=%1+
4. Coarse-speckled pattern 5. Fine-speckled pattern 6. Anti-centromere antibody
(U1RNP/Sm) (Ro/La) pattern

"
7. PM-Scl pattern 8. Anti-spindle-apparatus 9. Anti-coilin antibody
antibody pattern pattern

10. Anti-PCNA antibody

pattern
A. Autoantibody patterns
11. Anti-mitochondrial
antibody pattern
12. Anti-Jo-1 antibody
pattern !
EFH

"
! #/&&*'+%5* 6%..,* 7%.*(.* (&8 9(.',$%+%.

!"#$%&'( )*+*# %,"$-%&.$/#*# 0!123 '# . (-,/4'(5

'4$%,&'$$%4$ .*$/'&&*4% '46).&&.$/," 7'#%.#%
$-.$ .66%($# &*)$'+)% /,8.4 #"#$%&# .47 '# (-.,9
*#% /6 &/4/()/4.) .4$';/7'%#5 %<8<5 .4$'9DUX5
'&&*4% .7#/,+$'/4 $%(-4'V*%#5 .47 .*$/)/9
8/*# #$%& (%)) $,.4#+).4$.$'/4 0#%% +< ?AY!3
.($%,':%7 ;" $-% +,%#%4(% /6 .4$'94*()%., .4$'9 .,% (*,,%4$)" '4 $-% ()'4'(.)Z%F+%,'&%4$.) $%#$9
;/7'%#< =-% 7'#%.#% .66%($# >/&%4 ?@ $'&%# '48 +-.#%<
&/,% /6$%4 $-.4 &%4< =-% .8% /6 /4#%$ '#
6,/& ?A $/ B@ "%.,#< C# 6/, &/#$ /$-%, '46).&9
&.$/," ,-%*&.$/'7 7'#%.#%#5 $-% C&%,'(.4
!#4 #-%+*-%( 0/- #$(..%0%'(+%/& /0 123
D/))%8% /6 E-%*&.$/)/8" 0CDE3 -.# %#$.;)'#-%7
. (.$.)/8 /6 (,'$%,'. 6/, ().##'6'(.$'/4 /6 !12 0#%%
!"#"$ $"%&
=.;)% A /6 $-% C++%47'F3<
'(%)*(+ $"%&
!" #$%&%'($ )*(+,-*. /0 123
=-% ()'4'(.) +'($*,% /6 !12 G.,'%# 8,%.$)" 7%9 ,&*-*%./%(-(0(-1
+%47'48 /4 $-% $"+% /6 /,8.4 '4G/)G%&%4$<
#$%&%'($ :;;,&/$/<=

!H'4 &.4'6%#$.$'/4# .,% . (/&&/4 '4'$'.) 6%.9 2$"# 3#).$%

$*,% '4 I@ J /6 $-%#% +.$'%4$#< K$-%, (/&&/4
6%.$*,%# '4()*7% $-% (-.,.($%,'#$'( L;*$$%,6)" 4$-&$(-(%
,.#-5M >-'(- /((*,# '4 .,/*47 A@ J /6 +.$'%4$#5
.47 7'#(/'7 #H'4 '4G/)G%&%4$5 >-'(- /((*,# '4 5.$*%(-(%
N@ J /6 +.$'%4$#O G.#(*)'$'( )%#'/4# .,% .)#/
(/&&/4< =-% &.P/,'$" /6 !12 +.$'%4$# #*66%, 6./"# +(%*$+.$
6,/& P/'4$ +.'45 ;*$ /4)" . 6%> 7%G%)/+ #%G%,%
7.3$*#*8()"# +(%*$+.$
P/'4$ 7%6/,&'$'%# 0Q.((/*7R# .,$-,'$'#5 #%% +-/$/9
8,.+-3< =-'# $"+% /6 7%6/,&'48 .,$-,'$'# '#
9.:"-*#*8()"# +(%*$+.$

"
*#*.))" .##/('.$%7 >'$- %F$%4#'G% #*;)*F.$'/4
'4 $-% .;#%4(% /6 ;/4% 7%#$,*($'/4< E%4.) '49 ;::3/*#*8()"# +(%*$+.$
G/)G%&%4$ 0)*+*# 4%+-,'$'#35 DS! '4G/)G%&%4$
0%+')%+#" /, #$,/H% .((/&+.4'%7 ;" #%(/47.," 4/-(/3)#."$ "/-(<*+(.%
.4$'9+-/#+-/)'+'7 #"47,/&%3 .47 +)%*,/+%,'9
(.,7'$'# .,% )'6%9$-,%.$%4'48 (/&+)'(.$'/4# /6 !"# $%&'()*+#,'$ ,- $#-%*( .#)#/)%,+ ,0 1 ,-
!12< T%4%,.) #"&+$/&#5 #*(- .# 6%G%, .47 6.9 &,-# ,0 )"#$# 22 /-%)#-%* %+ * 3*)%#+) .'-%+4
$'8*%5 .,% /;#%,G%7 '4 $-% .($'G% +-.#%# /6 * 4%5#+ ,6$#-5*)%,+ 3#-%,. %$ /(*$$%0%#. *$
$-% 7'#%.#%< .%*4+,$)%/ ,0 789:
!""#$%&%'()*& +(*'$%,(,- =-% 7%&/4#$,.$'/4
/6 .4$'94*()%., .4$';/7'%# 0CSC3 '# '&+/,$.4$
;%(.*#% /6 $-%', .##/('.$'/4 >'$- /,8.4 &.4'9
6%#$.$'/4#< =-% +,%#%4(% /6 .4$';/7'%# .8.'4#$
7/*;)%9#$,.47%7 USC '# . +.$-/84/&'( 6'47'48<
=,%.$&%4$ '# #%)%($%7 '4 .((/,7.4(% >'$- $-%
#%G%,'$" /6 7'#%.#% .47 $-% $"+% .47 #%G%,'$" /6
/,8.4 &.4'6%#$.$'/4#< 1/>97/#% 8)*(/(/,$'9
(/'7# .47 .4$'&.).,'.) .8%4$# &." #*66'(% '4
&')7 6/,&# /6 $-% 7'#%.#%< =-%#% 7,*8# .,% +.,9
$'(*).,)" %66%($'G% 6/, #H'4 &.4'6%#$.$'/4#5 .47
$-%" ,%7*(% $-% 6,%V*%4(" /6 .$$.(H#< C(*$% .$9
$.(H# ,%V*',% -'8-97/#% #$%,/'7 ;/)*# $-%,.+"<
W4$,.G%4/*# ("()/+-/#+-.&'7% '# '47'(.$%7

!
6/, $,%.$&%4$ /6 #%G%,% /,8.4 &.4'6%#$.$'/4#5
#*(- .# 7'66*#% 8)/&%,*)/4%+-,'$'# .47 4%*,/9
+#"(-'.$,'( )*+*#< C:.$-'/+,'4% '# '47'(.$%7 6/,
$,%.$&%4$ /6 &/7%,.$% /,8.4 &.4'6%#$.$'/4# /,
#*;#%V*%4$ $/ . ("()/+-/#+-.&'7% $,%.$&%4$
>?@ +-.#%< =,%.$&%4$ &/7.)'$'%# '4G/)G'48 $-%
 #$%&%'($ )*(+,-*. /0 123
!
30%
CNS
involvement

50%
butterfly erythema

20%
discoid

#$%&%'($ :;;,&/$/<=
skin involvement

50%
pleuropericarditis

90%
arthralgia,
arthritis
"
50%
renal involvement

80%

!
common symptoms
(fever, fatigue) 70%
vasculitis/
skin involvement

A. Clinical manifestations of systemic lupus erythematosus (SLE)

>?A

"
! 7'**)1%,8) 9,++3) :,+)$+) $*; <$+13=,%,+

!"# $"#%&'#( %) $"# *+$"%,#)#('( %- ./0 1+&2

+( 3'4#52 +( $"# 65')'6+5 7+)'-#($+$'%)( %- $"#
4'(#+(#8 9:7#&%:( +:$%+)$';%42 *"#)%7#)+
,'+5? (:;#)4%$"#5'+5? (:;#*'$"#5'+5E '( &#(*%)('=
;5# -%& $"# 4#1#5%*7#)$ %- 4'--#&#)$ $2*#( %- 5:=
*:( )#*"&'$'( C(## +5(% *8 NNN --8E8
6+:(#4 ;2 7+<%& :)4#&52'), 6#55:5+& +:$%'77:=
)'$2 4'($:&;+)6#( +&# *&#4%7')+)$ 65')'6+5 -#+=
$:&#(8

!" #$%&'()*)+,+ '- ./+%)0,1 2343+

56/%&)0$%'+3+
!"# 4'(#+(#=')4:6'), 7#6"+)'(7( ')'$'+552
7+)'-#($ +( $'((:# 5#('%)(8 >'&+5 ')-#6$'%)(
"+1# ;##) '7*5'6+$#4 +( + 6+:(#? ;:$ @> &+4'+=
$'%) 6+) +5(% $&',,#& $"# 4'(#+(#8 A2$%B')#( C#8,8?
!9D=!E &#5#+(#4 4:&'), $"# 4#1#5%*7#)$ %-
$'((:# 5#('%)( 5#+4 $% $"# +;#&&+)$ #F*&#(('%)
7=,*,1$= >003*'='(/

%- +:$%+)$',#)( %) $"# 6#55 (:&-+6#8 9:65#+&

+)$',#)( C#8,8? G% +)$',#)E $"#&#;2 &#+6" $"#
(:&-+6# %- 6#55(? (:6" +( B#&+$')%62$#(8 H*%*$%$'6
6#55( $"+$ 3#&# #F*%(#4 $% 6#&$+') )%F+# &#5#+(#
+*%*$%$'6 ;5#;(? 3"'6" %-$#) 6%)$+') +)$',#)(
-&%7 $"# ):65#:( +)4 62$%*5+(78 D&%7 $"#)
%)? $"# 6#)$&+5 7#6"+)'(7 '( $"# *&#(#)$+$'%)
%- +:$%+)$',#)( $% !="#5*#& 6#55(8 I7*+'&7#)$ %-
&#,:5+$%&2 7#6"+)'(7( +)4 $"# &#(:5$'), 5%((
%- *#&'*"#&+5 $%5#&+)6# *&#(:7+;52 *5+2( +)

"
'7*%&$+)$ &%5# ') $"# *&%6#((8 J=6#55 "#5* %6=
6:&(? $"#&#;2 +55%3'), $"# J 6#55( $% *&#(#)$
+)$',#)( $% +:$%&#+6$'1# ! 6#55(8 0F$#)('%) %-
$"# +:$%'77:)# &#(*%)(# $"#&#-%&# %66:&( +(
K#*'$%*# (*&#+4'),8L
H:$%+)$';%4'#( +,+')($ 6#55( %- $"# "#7+$%=
*%'#$'6 (2($#7 +&# *&%4:6#4 4:&'), $"# 6%:&(#
%- *%5265%)+5 J=6#55 +6$'1+$'%)8 !"# 7%($ '7*%&=
$+)$ 65')'6+5 6%)(#M:#)6#( %- $"#(# #1#)$( +&#
5#:B%*#)'+ +)4 $"&%7;%*#)'+8 H:$%+)$';%4'#(
+,+')($ *"%(*"%5'*'4( +)4 " N=,526%*&%$#')=O
4#1#5%* +( ') (#6%)4+&2 +)$'=*"%(*"%5'*'4 (2)=
4&%7#8 !"'( 6+) &#(:5$ ') 6%7*5'6+$'%)(? (:6" +(
$"&%7;%('(? +;%&$'%)? +)4 6#&#;&+5 ($&%B#8
!"# 4#1#5%*7#)$ %- '77:)# 6%7*5#F#( ;2
(:;6#55:5+& +)$',#)(? #(*#6'+552 )+$'1# 4%:;5#=
($&+)4#4 P9H +)4 +)$'=P9H +)$';%4'#( '( +)=
%$"#& '7*%&$+)$ *+$"%,#)#$'6 7#6"+)'(78 I)
$"'( 6+(#? $"# ):7;#& %- '77:)# 6%7*5#F#(
*&%4:6#4 '( $%% 5+&,# $% ;# +4#M:+$#52 *"+,%=
62$%(#4 +)4 #5'7')+$#4 ;2 $"# 7%)%):65#+&
*"+,%62$'6 (2($#7 CQR.E8
!"# '77:)# 6%7*5#F#( +66:7:5+$# ') 1#(=

!
?@A
(#5 3+55( +)4 #1#)$:+552 6+:(# 1+(6:5'$'(8 I) 6%)=
<:)6$'%) 3'$" 6%7*5#7#)$ +6$'1+$'%)? *5+$#5#$
+,,&#,+$'%)? +)4 5#:B%62$# +6$'1+$'%)? $"'( 5#+4(
$% 1#((#5 %665:('%) +)4 (:;(#M:#)$ %&,+) 4+=
7+,#8 !"# +66:7:5+$'%) %- '77:)# 6%7*5#F#(
') 4'--#&#)$ &#,'%)( %- $"# ,5%7#&:5:( C7#(+)=
 Tissue lesion Histones Sm-antigen
#$%&'()*)+,+ '- .25

Autoantibodies
!
against
Cytokines Noxae: DNA nRNP
phospholipids
TNF-! viruses, UV light Nucleolus La (SS-B) Thrombosis, Blood
miscarriages, vessel
Ro (SS-A) cerebral infarctions

Nuclear antigens
Antibodies against cells

Apoptosis Cytoskeleton Ro (SS-A)

Aberrant filament
expression of Thrombo-
auto- Apoptotic Cell membrane penia Leuko-
antigens blebs protein Anemia penia
Polyclonal

7=,*,1$= >003*'='(/
Nucleosomes Cytoplasmic antigens B-cell activation

Impaired
regulation

B-cell help
B-cells

Epitope
spreading
Genetic

APC

Tissue lesion:
release of
autoantigens
susceptibility

Phagocytosis

Antibodies against subcellular antigens

(DNA, RNP etc.)
"
Immune complexes
Overloading of the Deposition in
MPS the kidney

Enzyme release Granulocyte Deposition of Glomerular

Complement small basal membrane
cleavage products immune
(anaphylatoxins) complexes
Large
immune
complexes
Complement

!
receptor
Immune Fc-receptor
complex Platelet aggregation Endothelial cells Epithelial cell

Vasculitis Immune complexes and glomerulonephritis

A. Pathogenesis of systemic lupus erythematosus
?@B

"
! 0(11&$2.3& 4.556& 7.5&+5& +1) 8+5$6%.2.5

!" #$%&'()&'*+
!"#$%&'$%()* &% +%&,%$--./$ -0-1$(." -"#$%&-.-
23!!4* .- "5)%)"1$%.6$' 70 8.7%&-.- &8 15$ "&99$":
)9' 1$#)9,.$"1)-.) 2?4> Q91.:"$91%&($%$ )91.:
7&'.$- )%$ ) 10+.")# 8.9'.9, &7-$%/$' .9 PM N
&8 )## +)1.$91- <.15 AHO!? -09'%&($> ?5$
"&9'.1.&9 .- &81$9 )--&".)1$' <.15 +%.()%0
1./$ 1.--;$ <.15 +%$8$%$91.)# .9/&#/$($91 &8 15$
7.#.)%0 ".%%5&-.- 23TA4>
-=.9* /$--$#-* #;9,-* +#$;%)* (0&")%'.;(* +$%.:
D9 )''.1.&9 1& .((;9&-;++%$--./$ 15$%)+0
")%'.;(* $-&+5),;-* )9' -()## .91$-1.9$> ?5$
<.15 -1$%&.'- &% 7)-." 15$%)+$;1." +%$+)%)1.&9-*
");-$ &8 15.- (;#1.-0-1$( '.-$)-$ .- ;9=9&<9>
1%$)1($91 .- )#-& -0(+1&()1."> A)#".;( )9:
! ?5$ )88$"1$' 1.--;$- $@5.7.1 )9 )7;9')9"$ &8
1),&9.-1- )%$ ;-$' 1& 1%$)1 15$ ".%";#)1&%0 '.-&%:
)"1./)1$' ABC! ? "$##-* <5."5 1%.,,$% "&##),$9
'$%- )--&".)1$' <.15 H)09);'I- -09'%&($U
-0915$-.- .9 8.7%&7#)-1- 70 <)0 &8 DE:F )9'
+%&-1),#)9'.9 .98;-.&9- )%$ ;-$' 8&% -=.9 ;#:
DE:G> D9"%$)-$' "&##),$9 '$+&-.1.&9 .9 15$
"$%)1.&9-> 3%&-1)"0"#.9- 5)/$ +%&/$' 1& 7$ $88$":
$@1%)"$##;#)% -+)"$ #$)'- 1& -"#$%&-.- &8 15$
1./$ 8&% )9,.&+)150>
"&99$"1./$ 1.--;$> D9 /$--$#-* 15$ "&##),$9
'$+&-.1- ");-$ $9'&15$#.)# ')(),$ )9' &": ," -./&) 0(11&$2.3& 4.556& 7.5&+5&
"#;-.&9 ';$ 1& .91.()# +%&#.8$%)1.&9> ?5.- ;#:
0%.1.$+% 9**61(%(:;

1.()1$#0 %$-;#1- .9 15."=$9.9, )9' .9';%)1.&9
&8 15$ -=.9* '0-8;9"1.&9 &8 15$ )88$"1$' .91$%:
9)# &%,)9-* )9' .98)%"1.&9- %$-;#1.9, 8%&(
&7#.1$%)1.&9 &8 15$ /$--$#->
" H)09);'I- -09'%&($* ) ".%";#)1&%0 '.-&%'$%
)88$"1.9, 15$ '.-1)# +)%1- &8 15$ $@1%$(.1.$-*
.- )9 $)%#0 -0(+1&( &8 -"#$%&'$%()> D1
()0 +%$"$'$ 15$ &15$% -0(+1&(- 70 -$/$%)#
0$)%-> D9 15$ #)1$% "&;%-$ &8 '.-$)-$* .9.1.)##0
+).9#$-- $'$()- 8&%( .9 15$ 5)9'- 2-);-),$:
J.@$' "&99$"1./$ 1.--;$ '.-$)-$ 2JA?B4* &%
&/$%#)+ -09'%&($* .- "5)%)"1$%.6$' 70 15$ &/$%:
#)++.9, &8 -0(+1&(- &8 '.88$%$91 "&99$"1./$
1.--;$ '.-$)-$- 2!EO* -"#$%&'$%()* %5$;()1&.'
)%15%.1.-* +&#0(0&-.1.-* '$%()1&(0&-.1.-* !V&W,:
%$9I- -09'%&($4> H)09);'I- +5$9&($9&9 .-
;-;)##0 15$ 8.%-1 $)%#0 -0(+1&( &8 15$ '.-$)-$>
X15$% 8$)1;%$-* .9 '$"%$)-.9, &%'$% &8 8%$:
Y;$9"0* )%$ -"#$%&')"10#0 )9' -<$##.9, &8 15$
5)9'-* +&#0)%15%)#,.)* +;#(&9)%0 -0(+1&(-*

"
#.=$ 8.9,$%-4 )9' $/$91;)##0 +%&,%$-- 1& -"#$%: .(+).%$' $-&+5),$)# (&1.#.10* (0&-.1.-* )9'
&')"10#0 2J)'&99) 8.9,$%-4 <.15 )"%&:&-1$&: -=.9 ()9.8$-1)1.&9-> Z.,5 1.1$%- &8 );1&)91.7&:
#0-.-> KH)1:7.1$ 9$"%&-.-L &8 15$ 8.9,$%1.+- '.$- ),).9-1 %.7&9;"#$)-$ 3 2[F:HR34 )%$ ) 10:
()0 '$/$#&+ ';$ 1& .(+).%$' ".%";#)1.&9> +.")# 8.9'.9,-> Q91.:9;"#$)% )91.7&'.$- )9'
?5$ "5)%)"1$%.-1." 8$)1;%$- &8 -"#$%&'$%() %5$;()1&.' 8)"1&%- ")9 )#-& 7$ '$1$"1$'> Q;1&:
+)1.$91- <.15 8)".)# -"#$%&-.- )%$ ) -()## )91.7&'.$- ),).9-1 '-BRQ* !"#:PM* !(* H&* E)*
(&;15 2(."%&-1&(.)4 )9' +&.91$' 9&-$> ?$#: )9' 3J )%$ .98%$Y;$91#0 '$1$"1$'> ?5$ 1%$)1:
)9,.$"1)-.)- &8 15$ -=.9 )9' (;"&-)$ )%$ )#-& ($91 &8 JA?B .- -.(.#)% 1& 15)1 &8 -"#$%&'$%()
"&((&9> J0&")%'.)# 8.7%&-.- )9' 7.#)1$%)# &% !EO> ?5$ )"1;)# %$,.($9 /)%.$- .9 )""&%')9"$
7)-)# +;#(&9)%0 8.7%&-.- &"";% .9 CM N &8 <.15 15$ 10+$ )9' -$/$%.10 &8 15$ +%$'&(.9)91
)## +)1.$91- <.15 -"#$%&'$%()> ?5$%$ ()0 -0(+1&(->
7$ $#$/)1.&9 &8 1<& +)%)($1$%- &8 .98#)(():
1.&9* A:%$)"1./$ +%&1$.9 2AH34 )9' 15$ $%0:
15%&"01$ -$'.($91)1.&9 %)1$ 2O!H4* .9 )''.:
1.&9 1& 15$ '$1$"1.&9 &8 10+.")#
);1&)91.7&'.$- .9 15$ +)1.$91I- -$%;(> ?5$
'$(&9-1%)1.&9 &8 )91.:"$91%&($%$ )91.7&:
'.$- &% )91.7&'.$- ),).9-1 1&+&.-&($%)-$ D
2)91.:!"#:PM )91.7&'.$-4 .- ) +%.()%0 .((;:
9&#&,.")# 8$)1;%$> Q91.:9;"#$)% )91.7&'.$- &8
'.88$%$91 -+$".8.".1.$- ")9 )#-& 7$ 8&;9'*
<5$%$)- )91.:'-BRQ )9' !( )91.7&'.$-
)%$ )7-$91>

!
<==
# AHO!? -09'%&($ .- )9 &#'$% '$-.,9)1.&9 &8 )
#.(.1$' 8&%( &8 -"#$%&'$%()> ?5$ )"%&90( .-
()'$ ;+ &8 15$ 8.%-1 #$11$%- &8 15$ "5)%)"1$%:
.-1." -0(+1&(- &8 15$ -09'%&($S ")#".9&-.-
2A4* H)09);'I- -09'%&($ 2H4* $-&+5),$)#
(&1.#.10 '.-1;%7)9"$ 2O4* -"#$%&')"10#0 2!4*
CD4+
T cell
#$%&'()&'*+ +1) -./&) 0(11&$2.3& 4.556& 7.5&+5&

Sclerosis of
!
connective
IL-1 tissue

IL-2
Proliferation
Activation Fibroblast Collagen of vascular
activation synthesis intima
1. Pathogenesis

Systemic Occlusion
sclerosis of of blood
connective tissue vessels

0%.1.$+% 9**61(%(:;
Microstomia Shortened
tongue frenulum
Myocardial Interstitial
fibrosis lung fibrosis
Esophageal
hypomotility

"
Malabsorption, Pitting scars Coronary Renal
impaired motility Sclerodactyly on fingertips angiopathy infarction

Auto- Centromere (CREST) Scleroderma

ANA SLE
Ab Topoisomerase I
MCTD
2. Symptoms Poly- Sjögren’s
myositis syndrome/RA

Dermato-
myositis
Raynaud’s Pulmonary
Sclerodactyly Calcinosis
syndrome involvement

Impaired
Raynaud’s Esophageal Hand esophageal
phenomenon hypomotility swelling, motility
sclero-
Skin
Telangiectasias dactyly
symptoms
Polyarthralgia
polyarthritis

Anti-
centromere Ab

3. CREST syndrome
A. Scleroderma
Association
with PBC
Anti-U1-RNP-Ab ANA
highly positive

B. Mixed connective tissue disease (MCTD)

!
<=>

"
! #2&&*'+%7* 8%..,* 4%.*(.* (&9 :(.',$%+%.

!" #$%&%'($ )*(+,-*.

!"#$"%&$"'%# ()* +(,* -*$.**% /)"+()0 (%,
#*&'%,()0 12'34)*%5# #0%,)'+*6 78* /)"+()0
9')+ "# (% (:$'"++:%* ,"#*(#* '9 $8* *;'&)"%*
4<(%,# ."$8 *;$)(4<(%,:<() #0#$*+"& "%='<=*>
+*%$? .8*)*(# $8* #*&'%,()0 9')+ "# (<#' (##'>
&"($*, ."$8 '$8*) (:$'"++:%* ,"#*(#*#? #:&8 (#
)8*:+($'", ()$8)"$"# @ABCDBE '9 &(#*#F? &'%%*&>
$"=* $"##:* ,"#*(#*# @1GH? #&<*)',*)+(? /'<0>
+0'#"$"#F? =(#&:<"$"# @/'<0()$*)"$"# %','#(F
(%,I') /)"+()0 -"<"()0 &"))8'#"# @AB E '9 &(#*#F?
J(#8"+'$'5# (:$'"++:%* $80)'","$"#? (%,
&8)'%"& (&$"=* 8*/($"$"#6 1*&'%, '%<0 $' )8*:>
+($'", ()$8)"$"#? 12'34)*%5# #0%,)'+* "# '%* '9
$8* +'#$ &'++'% "%9<(++($')0 )8*:+($"&
#$%&%'($ ;66,&2$23<
@11>UF (%, G( (%$"4*% @11>TF6 1"%&* $8*#* (:$'>
(%$"-',"*# (<#' '&&:) "% '$8*) (:$'"++:%* ,"#>
*(#*#? $8*") ,"99*)*%$"(< ,"(4%'#$"& =(<:* "# <"+>
"$*,6 78* (44)*##"=* /'<0&<'%(< (&$"=($"'% '9 T
&*<<# :<$"+($*<0 /)'4)*##*# $' %'%>J',4S"%5#
<0+/8'+( "% XBCXA E '9 &(#*#6
#" 4%(3&2.%.
M% (,,"$"'% $' $8*#* 8*+($'<'4"&(< 9*($:)*#? &*)>
$("% /($8'<'4"&(< &8(%4*# ()* (<#' '9 ,"(4%'#$"&
"+/')$(%&*? 9') *;(+/<*? !"#$%&'%() *')* '9 $*()
#*&)*$"'% @,*4)** '9 .*$$"%4 '9 ( #$)"/ '9 /(/*)
/<(&*, '% $8* <'.*) *0*<",F? !+,-.() *')* '9 #(<"=(
/)',:&$"'% @$8* /($"*%$ +:#$ &8*. '% ( &'+>
/)*##F? )$+/-0%+1#2? )+/$3+%2 0/+.4 )"$.*$0%+1#2

,"#*(#*#6 K'+*% ()* (99*&$*, %"%* $"+*#
+')* '9$*% $8(% +*%6 78* '%#*$ "# :#:(<<0 (9$*)
LB 0*()# '9 (4*6 !)0%*## '9 $8* *0*# @;*)>
'/8$8(<+"(F (%, ,)0 +':$8 @;*)'#$'+"(F ()*
$8* +'#$ &'++'% #0+/$'+# '9 12'34)*%5# #0%>
,)'+*6 M%9<(++($"'% '9 $8* #(<"=()0 (%, <(&)">
+(< 4<(%,# 9'<<'.*, -0 <0+/8'&0$"& "%9"<$)($"'%
(%, ,*#$):&$"'% '9 $8* 4<(%,:<() $"##:* "# $8*
:%,*)<0"%4 -(#"# '9 $8*#* N#"&&(O #0+/$'+#6
P'<0()$8)(<4"( @%'%*)'#"=* ()$8)"$"#F? +0(<4"(?
9') ="#:(<"[($"'% '9 $8* ,:&$# @)()*9(&$"'% (%,
<:+"%(< %())'."%4F? (%, /+5$+/ 5$-1)2 9') 8"#$'>
<'4"&(< ,"(4%'#"# @*646? '9 /*)",:&$(< <0+/8'&0>
$"& "%9"<$)($"'%F6 1"&&(<"S* #0%,)'+*#? #:&8 (#
(+0<'",'#"# (%, UM!1? (%, $8* *99*&$# '9 &*)$("%
,):4# @*646? (%$",*/)*##(%$#F +:#$ -* &'%#",>
*)*, "% $8* ,"99*)*%$"(< ,"(4%'#"#6
5(&(3*6*&+
7)*($+*%$ "# "%"$"(<<0 #0+/$'+($"& (%, "# <"+>

"
Q(0%(:,5# #0%,)'+*? (%, <0+/8(,*%'/($80 "$*, $' $8* <'&(< (//<"&($"'% '9 ()$"9"&"(< $*()#
()* *;$)(4<(%,:<() +(%"9*#$($"'%# '9 12'34)*%5# @+*$80<&*<<:<'#*F (%, ()$"9"&"(< #(<"=()0 9<:",6
#0%,)'+*6 R'+/<"&($"'%# "% $8* <:%4# @"%$*)#$"> Z'%#$*)'",(< (%$">"%9<(++($')0 ,):4# (%, &')>
$"(< /%*:+'%"(F? S",%*0# @"%$*)#$"$"(< %*/8)"$"#? $"#'%* ()* :#*, $' $)*($ +"<, 2'"%$ "%='<=*+*%$6
$:-:<() (&",'#"#F? (%, <"=*) @"% PTRF ()* )()* 1*=*)* *;$)(4<(%,:<() +(%"9*#$($"'%# )*\:")*
+(%"9*#$($"'%#6 $8* :#* '9 ([($8"'/)"%*6
/" 0(+123*&*.%.
U %:+-*) '9 9(&$')# /<(0 ( )'<* "% $8* ,*=*<'/>
+*%$ '9 12'34)*%5# #0%,)'+*? .8"&8 "# (##'>
&"($*, ."$8 JGU !QV? !WX? (%, !WY (%$"4*%#6
78* /)*=(<*%&* '9 12'34)*%5# #0%,)'+* "%
.'+*% #:44*#$# $8($ *#$)'4*%# /<(0 ($ <*(#$ (
#://')$"%4 )'<* "% "$# /($8'4*%*#"#6 78* (&$:(<
$)"44*) '9 4<(%,:<() ,0#9:%&$"'% "# (##:+*, $'
-* ( =")(< "%9*&$"'%6 H/"$8*<"(< &*<<# "% $8* "%>
9*&$*, 4<(%, /)*#*%$ =")(< (%$"4*%#6 78"# ($$)(&$#
7 &*<<#? .8"&8 "%9"<$)($* $8* 4<(%,:<() $"##:* (%,
&(:#* ( <'&(< "%9<(++($')0 )*(&$"'%? )*#:<$"%4
"% ,(+(4* $' $8* 4<(%,:<() $"##:*6 78* 7 &*<<#
(&$"=($* $8* 4<(%,:<() */"$8*<":+ (%,? +'#$ "+>
/')$(%$<0? T &*<<#6 78"# )*#:<$# "% *;&*##"=*? :%>

!
&'%$)'<<*, T>&*<< /)'<"9*)($"'%? .8"&8 "%"$"(<<0
+(%"9*#$# "% $8* /*)"/8*)(< -<'', (# 80/*)4(+>
+(4<'-:<"%*+"( "% (##'&"($"'% ."$8 $8* /)*>
#*%&* '9 "++:%* &'+/<*;*#6 M%&)*(#*# "% $8*
H1Q (%, RQP <*=*<# &(% -* ,*$*&$*, "% (,,"$"'%
=>? $' (%$">%:&<*() (%$"-',"*# @UZUF? )8*:+($'",
9(&$')#? (%, (:$'(%$"-',"*# (4("%#$ Q' (%$"4*%
 Glandular Extraglandular
@A2
B3-*&C. @<&9-26*
!
Xerophthalmia
Xerostomia Rheumatoid Collagenosis
Nonerosive
arthritis arthritis (SLE,
scleroderma)
Interstitial
pneumonia Secondary
Primary biliary Sjörgen’s
Liver cirrhosis (PBC) syndrome
involvement
Vasculitis
Interstitial (PAN)
nephritis

Autoimmune
Chronic
thyroiditis
Raynaud’s active hepatitis

#$%&%'($ ;66,&2$23<
1. Symptoms phenomenon
A. Clinical findings 2. Secondary Sjögren’s syndrome

Viral
Endogenous factors Exogenous factors
infection?
HLA DR3, DQ1/DQ2 Viruses (herpes, retroviruses)
Hormones (estrogens)
Gland
duct IL-1

Gland

"
Epithelial cell activation IL-6
lobe
IL-1 IFN-!

Gland tissue
Viral antigens IL-2 Polyclonal
B-cell activation
T cells Sicca Extraglandular
symptoms manifestations ?
2. Possible pathomechanisms Autoantibodies

Polyclonal B-cell Poly-, oligo-, monoclonal Monoclonal

Polyclonal activation in B-cell activation in B-cell activation
Lymphocyte B-cell exocrine glands systemic manifestation
Lymphoma
infiltration activation 3. Lymphoma development

!
Luminal
narrowing
Function ANA,
Rarefaction rheumatoid
factors
1. Exocrine glands Sialography Lip biopsy, histology anti-Ro-,
anti-La Ab
B. Pathogenesis C. Diagnosis
=>=

"
! =$11-2*)>- ?)((3- ,)(-/(- /16 @/(23%)*)(

!" #$%&'&$()*)(+ ,-.'/*$'&$()*)(+

012%3()$145$6& 7&$()*)(
!"# $%&'&$(% )&$*+,# -. *"# /(,&-+0 .-,10 -. 12-3
0&*&0 $(' /(,2 4,#(*%25 !"# 6&(4'-0*&$ $,&*#,&( (,#
),#0#'*#6 &' 7!85 9-%212-0&*&0 7"8 &0 $"(,($*#,3
&:#6 ;2 ),-<&1(% 1+0$%# =#(>'#00? #0)#$&(%%2
&' *"# 0"-+%6#,0? +))#, (,10? ('6 *"&4"05 !"#
)(*&#'*0 #<)#,&#'$# 6&..&$+%*&#0 &' 4#**&'4 +)
-+* -. ( $"(&, ('6 $%&1;&'4 0*(&,05 @#,1(*-12-3
0&*&0 7#8 &0 (66&*&-'(%%2 $"(,($*#,&:#6 ;2 *"# -$3
$+,,#'$# -. 0>&' 1('&.#0*(*&-'0? #0)#$&(%%2 -'
(,#(0 -. *"# 0>&' #<)-0#6 *- %&4"*5 A'# -. *"#
1-0* $-11-' 1('&.#0*(*&-'0 &0 *"# 0-3$(%%#6
"#%&-*,-)# ,(0" 7$85 B"(,($*#,&0*&$ )()+%-&6
0>&' $"('4#0 $(%%#6 C-**,-'D0 0&4' 6#/#%-) -'
=%)1)2/% 0''31$%$9&
=" #/*<$9-1-()(
S&># *"#&, "&0*-%-42? *"# )(*"-4#'#0&0 -. )-%23
12-0&*&0 79T8 ('6 6#,1(*-12-0&*&0 7@T8 (%0-
6&..#,05 B%(00 P THB31#6&(*#6 1#$"('&010
)%(2 ( ),#6-1&'('* ,-%# &' )-%212-0&*&05 P'
)-%212-0&*&0? (;#,,('* #<),#00&-' -. $%(00 P
HSE ('*&4#'0 -$$+,0 -' *"# 0+,.($# -. 1+0$%#
$#%%0? ="&$" (,# '-,1(%%2 HSE3'#4(*&/# 7-'%2
( .#= -*"#, $#%%0 &' *"# ;-62 (,# HSE3'#4(*&/#8?
6+# *- ( 4#'#*&$ ),#6&0)-0&*&-' ('6 +'>'-='
7/&,(%U8 .($*-,05 B2*-*-<&$ ! $#%%0 *"#' ,#$-4'&:#
*"# (%*#,#6 12-$2*#0 (0 V.-,#&4'W ('6 6#0*,-2
*"#15 !"&0 &0 *"# "&0*-%-4&$(% ;(0&0 -. *"#
(.-,#1#'*&-'#6 $"(,($*#,&0*&$ ),-$#00#0 -.
$#%% 6#(*" =&*"&' *"# 1+0$%# ;+'6%#5 X&1&%(,

*"# >'+$>%#0 7%85 E $-'$-1&*('* *+1-, &0 -.*#'
),#0#'* &' 1('2 6#,1(*-12-0&*&0 )(*&#'*0 -/#,
FG 2#(,0 -. (4#5 H#'$#? 0#%#$*&/# &'/#0*&4(*&-'0
.-, $(,$&'-1(0 1+0* ;# 1(6#? #0)#$&(%%2 &' *"#
,#4&-' -. *"# ;,#(0*0? %+'40? ('6 4(0*,-&'*#0*&'(%
*,($*5 !"# (+*-('*&;-62 .&'6&'40 (,# 4#'#,(%%2
+'$"(,($*#,&0*&$I %-= *&*#,0 -. ('*&3'+$%#(, ('*&3
;-6&#0 (,# -$$(0&-'(%%2 .-+'65 B-'/#'*&-'(%
;%--6 *#0*0 ,#/#(% "&4" $-'$#'*,(*&-'0 -. $,#(3
*&'# >&'(0# 7BJ8 ('6 12-4%-;+%&'5 !"# ),#0#'$#
)(*"-4#'#*&$ 1#$"('&010 (,# 0+0)#$*#6 &'
&'$%+0&-'3;-62 12-0&*&0 7PYT85 !"# 1#$"('&01
-. 6#/#%-)1#'* -. (12%-&63$-'*(&'&'4 $#%% &'3
$%+0&-'0 &' PYT &0 0*&%% +'$%#(,5
P' 6#,1(*-12-0&*&0? *"# &'.%(11(*&-' (,&0#0
.,-1 *"# )#,&120&(% /#00#%05 H#'$#? ;%--6 /#03
0#% 6(1(4# &0 ( $#'*,(% #%#1#'* &' *"# )(*"-3
4#'#0&0 -. *"# 6&0#(0#5 !"# ,#0+%*&'4 *&00+#
&0$"#1&( %#(60 *- 0#$-'6(,2 6#(*" -. *"# 1+03
$%# $#%%0? $"(,($*#,&0*&$(%%2 =&*" ),-'-+'$#6

"
-. ('*&3),-*#(0-1# ('*&;-6&#0 =(0 (%0- ,#3 )#,&.(0$&$+%(, &'/-%/#1#'*5
$#'*%2 6#1-'0*,(*#65
!"#$%&'"#()#*&) &'"+,-.) 7#8 &0 (' &'6#)#'3
6#'* 6&0#(0# #'*&*2 $"(,($*#,&:#6 ;2 *"# ),#3
0#'$# -. K-3L ('*&;-6&#0? ="&$" (,# 6&,#$*#6
(4(&'0* "&0*&62% 02'*"#*(0#5 !"# *2)&$(% $%&'&$(%
.#(*+,#0 -. *"# 6&0#(0# &'$%+6# &'*#,0*&*&(% %+'4
6&0#(0#? (,*",&*&0? M(2'(+6D0 )"#'-1#'-'? 0>&'
1('&.#0*(*&-'0? .#/#,? ('6 1+0$+%(, =#(>'#005
/"012&$-"%3-+' .'-&$#$& 7&8 &0 ('-*"#, 6&0*&'$*
6&0#(0# #'*&*25 N'%&># *"# (.-,#1#'*&-'#6 6&03
#(0#0? &* "(0 ( ),#6&%#$*&-' .-, 6&0*(% 1+0$%#05
O-, *"# 1-0* )(,*? *"&0 #'*&*2 "(0 '- $"(,($*#,3
&0*&$ %(;-,(*-,2 .#(*+,#05

5" 8)(*$%$9& $: 01:%/''/*$.& 7&$;/*<)-(

!"# "&0*-%-4&$(% )&$*+,#0 -. )-%212-0&*&0 ('6
6#,1(*-12-0&*&0 /(,2 4,#(*%25 P' )-%212-0&*&0?
B@Q! ! $#%%0 6&,#$*%2 &'.&%*,(*# *"# &'6&/&6+(%
1+0$%# $#%%0 =&*"&' *"# 1+0$%# .&;#,0 70## (%0-
'()85 @#,1(*-12-0&*&0? -' *"# -*"#, "('6? &0
$"(,($*#,&:#6 ;2 /(0$+%&*&0 =&*" $-'$-1&*('*

!
)#,&/(0$+%(, &'.%(11(*&-' +'6#, *"# &'.%+#'$#
-. B@R! ! $#%%05 P' *"&0 $(0#? 12-$2*# 6#(*"
-$$+,0 (0 ( 0#$-'6(,2 #..#$* -. /#00#% %#0&-'05

ABC
1. Polymyositis/ 2. Anti-synthetase syndrome
7&$()*)2 ,)(-/(-(
!
dermatomyositis
Heliotrope Fever Lab. findings:
positive for
rash Jo-1 Ab
Tumors Interstitial
(derma- lung disease
tomyositis) a) Typical clinical findings
Arthritis b) Increased creatine
Proximal Raynaud’s phenomenon kinase activity
myositis mechanic’s hand
c) Multifunctional
changes in electron
Lab. findings: micrographs
ANA+ 3. Inclusion-body
anti- myositis d) Bioptic proof of myositis

=%)1)2/% 0''31$%$9&
protea-
somes Ab+ Distal myositis e) Myositis-associated
CK , antibodies
myglobin Lab. findings:
not
characteristic 4. Diagnostic criteria

5. Heliotropic exanthema 6. Gottron’s sign 7. Histology of polymyositis

"
A. Polymyositis/dermatomyositis/inclusion body myositis

T cell Muscle Blood

infiltrates cells vessel Genetic susceptibility
(CD8+) and other factors

Muscle
fiber

PM/IBM Perimysium Expression of ?

HLA class I antigens
T cell Occluded Complement-mediated
infiltrates blood vessel microangiopathy
(CD4+)
Cytotoxic T cell

DM
Necrotic perivascular
muscle fibers
B. Histology of myositis
Muscle fiber

1. PM/IBM
C. Pathogenesis
Tissue ischemia

2. Dermatomyositis
!
ABD

"
" #/--'4.*<' ?*226' +*2'%2' %-9 5%246(*.*2

!" #$%&'( )*(( +',*-*.*/- /, 012.'3*4

5%246(*.*2
!"#$%& '(&& )%*(+(,(-+ -* ./0,%1(2 3#024&(,(0

5%246(*.*2 *-</(<*-: (%8:' <'22'(2

!"# $%&"'(')*+%( ,#-*.*&*'. '- /%0+1(*&*0 *0 2%0#,
'. &"# *.-(%33%&'45 *.-*(&4%&*'. %., .#+4'0*0 '-
&"# 6%((0 '- 2('', /#00#(07 !"# +(*.*+%( 053$8
! 5(#+, 2%&& 6,%1$-7#&8 #7,%7(,(0
&'30 /%45 )4#%&(5 *. %++'4,%.+# 6*&" &"# #9&#.&
! 9#:#/#04;0 #7,%7(,(0
%., ('+%&*'. '- &"# %--#+&#, /#00#( 0#)3#.&07 :0
% 4#01(&; ,*%).'0*0 '- /%0+1(*&*0 *0 /#45 +'3$(#97
5%246(*.*2 *-</(<*-: 3'9*63=2*>'9 <'22'(2
: .132#4 '- +(%00*-*+%&*'.0 #9*0&; 21& &"# +(%08
0*-*+%&*'. 2%0#, '. &"# 0*<# '- &"# %--#+&#, /#08 !
<-&/#7,%7(,(0 +-=-0#
0#( "%0 $4'/#, &' 2# 10#-1( *. +(*.*+%( %$$(*+%8
&*'.07 !"*0 +(%00*-*+%&*'. *0 +%((#, &"# ="%$#( !
>#?#0#:(;0 =(0%#0%
>*(( ,#-*.*&*'. %-&#4 &"# $(%+# 6"#4# &"# +'.8
0#.010 +'.-#4#.+# 6%0 "#(, ?0## !%2(# @ '- 5%246(*.*2 *-</(<*-: 23%(( <'22'(2
&"# :$$#.,*9A7
#(*-*4%( @336-/(/:1

! @%A%+%7;0 A7#+4&-1#,-0(0
7" #(%22*,*4%.*/- /, 5%246(*.*2 !44/89*-:
./ ;'4$%-*23 /, +'<'(/&3'-. ! !"47AB.,7#400 0/+=7-1%
:. %(&#4.%&*/# 050&#3 +(%00*-*#0 &"# /%0+1(*8 ! C(27-02-$(2 $-&/#+A((,(0
&*,#0 %++'4,*.) &' &"#*4 3#+"%.*03 '- ,#/#('$8
3#.&; &"#4#25 -'+10*.) '. /#00#( (#0*'.0 ,*8 ! .2"-
D+&%(+B'%+-2" $47$47#
4#+&(5 %&&4*21&%2(# &' %1&'%.&*2',*#0 ?:B=:8
%., :C=:8%00'+*%&#, /%0+1(*&*0D 0## $7 EFGA7 !
E00%+,(#& 27/-A&-F4&(+%1(2 G#024&(,(0
!"# -'43%&*'. '- +*4+1(%&*.) *331.# +'38

#
$(#9#0 $(%50 % H#5 4'(# *. &"# $%&"')#.#0*0 '- !
!4,#+%-40 &%4:-2/,-2&#0,(2 #+A((,(0
3%.5 /%0+1(*&*,#07 I#$#.,*.) '. &"#*4 +'3$'8
0*&*'.; &"%& *0; &"# &5$# %., 0*<# '- &"# -'4#*).
%.&*)#. '4 %1&'%.&*)#. %., '- *./'(/#, %.&*8
2',*#0; &"#0# *331.# +'3$(#9#0 3#,*%&# &"#
%+&*/%&*'. '- *.-(%33%&'45 #--#+&'4 3#+"%.8
*030 ?#7)7; %+&*/%&*'. '- +'3$(#3#.&; 3'.'8
+5&#0; (53$"'+5&#0; %., &"4'32'+5&#0D $4',1+8
&*'. '- +5&'H*.#0D +"#3'&%9*0 '- )4%.1('+5&#0A
'. &"# #.,'&"#(*137 !"*0 4#01(&0 *. "*0&'(')*8
+%((5 ,#3'.0&4%2(# *.&4%/%0+1(%4 %., $#4*/%08
+1(%4 *.-*(&4%&*'. %., -*24*.'*, .#+4'0*0 '- &"#
/#00#( 6%((7
!"# 053$&'30 '- /%0+1(*&*0 +%. '++14 *. 2%8
0*+%((5 %.5 *.-#+&*'. %., %4# +'33'. *. *.-#+8
&*'.0 25 &"# -'(('6*.) $%&"')#.0J !"#$%"&'&''();
!*+,&-$++*; ./'&0*'"$#1(,; !%1#&'2*$"*+$); "#8
$%&*&*0 K /*410; >LM; C$0&#*.NK%44 /*410; 3)%$#4
51++(); 6$1)2,*-1*; %., 71+*#1*7 L. 3%(*).%.& ,*08
#%0#0 ?#7)7; >',)H*.O0 ,*0#%0# %., "%*45 +#((
(#1H#3*%A; &"# $4*3%45 $%&"')#.0 %4# &"'0#
&"%& %--#+& &"# (53$"'4#&*+1(%4 050&#37 : "*08
&'45 '- &"# 10# '- 3#,*+%&*'.0; 01+" %0 %.&*2*'8

"
&*+0; *0'.*%<*,; )'(,; I 8$#.*+*((%3*.#; $'&%00*13
*',*,#; %., 2101(-%. 310& 2# +'.0*,#4#, %0 %
$'&#.&*%( +%10#7

ABC
 D'-'8%( #(%22*,*4%.*/- /, 5%246(*.*2
"
Capillary

Arteriole Venule
Small
Large to medium- artery Vein
Cutaneous
sized artery leukocytoclastic
angitis

Aorta Schönlein-Henoch purpura and essential cryoglobulinemia

Microscopic polyangitis
Wegener’s granulomatosis and Churg-Strauss syndrome

#(*-*4%( @336-/(/:1
Panarteritis nodosa and Kawasaki’s disease

Temporal arteritis and Takayasu’s arteritis

A. Chapel Hill definition of systemic vasculitis

Immune vasculitis:
pauci-immune vasculitis,
autoantibody- associated

ANCA: Wegener’s granulomatosis,

microscopic polyangitis
AECA: Kawasaki’s disease

Immune complex vasculitis:

autoantigen induced: SLE
#
Infection related:
hepatitis B (classic PAN)
hepatits C

Granulomatous vasculitis:
giant cell arteritis
– Takayasu’s arteritis
– temporal arteritis

Infection-related vasculitis:
– virus-associated: CMV
– rickettsia
– spirochaeta

"
Tumor-associated vasculitis:
cryoglobulinemia
lymphomatoid granulomatosis
hairy cell leukemia

B. Subtypes of vasculitis according to mechanism of development

ABE

#
! =&00%4*6,% #6335% +63%23% 208 12345-6*63

!" #$%&'( &) *$% +%,%-&./%0* &)

12345-6*63 723%8 &0 9%:%0%';3
<'205-&/2*&363
!"#$%&'()% * +!,*-. $/% $("0%$ ('$&0%' #1 ('$&2
'%3$"#4/&5 67$#45()8&6 ('$&9#:&%) +62;<=;-.
&) ( 6%'$"(5 8%:&($#" &' $/% 4($/#0%'%)&) #1
$/&) >()635&$&6 :&)%()%? !,* &) '#$ (66%))&95% $#
$/% ('$&9#:&%) &' $/% 4"%)%'6% #1 "%)$&'0 4#572
8#"4/#'365%(" '%3$"#4/&5 0"('35#67$%) +!@<-
&' $/% (A3"#4/&5&6 0"('35%) +!-? !"&#" (6$&>($&#'
97 4"#&'15(88($#"7 67$#B&'%) 5%(:) $# $/% :%2
>%5#48%'$ #1 (:/%)&#' 8#5%635%) #' !@< (':
%':#$/%5&(5 6%55) +C=- (': $# $/% $"(')5#6($&#' #1
&'$"(67$#45()8&6 !,* #' $/% 6%55 8%89"('% +"-?
D/% !@< $/%' (:/%"% $# $/% %':#$/%5&(5 6%55)
=-60642- B//50&-&:(
$#"7 #1 (55%"0&6 "/&'&$&). 9"#'6/&(5 ()$/8(.
6/"#'&6 )&'3)&$&). #" :"30 (55%"0&%)-? D"(')&%'$
%#)&'#4/&5&6 4358#'("7 &'1&5$"($%) ("% #1$%' :%2
$%6$%: ($ $/% #')%$ #1 $/% :&)%()%? ;) $/% :&)%()%
4"#0"%))%). #"0(' 8('&1%)$($&#') )&8&5(" $#
$/#)% #9)%">%: &' 4#57("$%"&$&) '#:#)( +!;<-
:%>%5#4 I&$/ )784$#8) #1 ("$/"(50&(. 4(54(95%
43"43"(. 0()$"#&'$%)$&'(5 4(&'. (': /74%"$%'2
)&#'? ,%'(5 &'>#5>%8%'$ &) 3'6#88#'? D/%
8(&' 6(3)% #1 :%($/ &' $/%)% 4($&%'$) &) 6(":&(6
1(&53"% :3% $# 6(":&#87#4($/7? M5##: $%)$) "%2
>%(5 '#')4%6&1&6 )&0') #1 &'15(88($&#' (':
8())&>% %#)&'#4/&5&( I&$/ 6#3'$) #1 #>%"
NOPPQ88* +34 $# RPS &' $/% :&11%"%'$&(5 6#3'$-.
/&0/ 5%>%5) #1 $#$(5 E0C. (': )#8%$&8%) "/%38(2

+#-? D/% !@< ("% $/%' (6$&>($%: (': )$("$ $#
:%0"('35($% :3% $# $/% 9&':&'0 #1 ;<=; $#
8%89"('%29#3': !,*? E' $/% >&6&'&$7 #1 %'2
:#$/%5&(5 6%55). $/% !@< "%5%()% $#F&6 8%:&($#")
(': 57)#)#8(5 4"#$%&') $/($ ("% '#$ (66%))&95%
$# $/% !24"#$%&'()% &'/&9&$#"? D/&) "%)35$) &'
57)&) #1 $/% %':#$/%5&(5 6%55) (': '%6"#$&A&'0
>()635&$&) +$-?
7" 9%:%0%';3 <'205-&/2*&363
$#&: 1(6$#")?
+" @&-(2'*%'6*63 A&8&32
!#57("$%"&$&) '#:#)( +!;<- &) ( '%6"#$&A&'0 >()2
635&$&6 :&)%()% #1 $/% 8%:&382)&A%: +4"&8("&57
>&)6%"(5- ("$%"&%)? D/% 65&'&6(5 4&6$3"% &) 3)3(557
6/("(6$%"&A%: 97 %F$%')&>% 7%$ '#')4%6&1&6
)784$#8) &'653:&'0 0%'%"(5 8(5(&)%. 1%>%".
I%&0/$ 5#)). (': ("$/"(50&(? !%"&4/%"(5 '%">%
&'>#5>%8%'$ 8(7 8('&1%)$ 97 I(7 #1 8#'#2

"
'%3"&$&) 835$&45%F +4(&'. 4("()$/%)&( #" 4("%)&)
G%0%'%"H) 0"('35#8($#)&) 3)3(557 &'>#5>%) $/% &' $/% &''%">($%: ("%( #1 $/% (11%6$%: '%">%)- &'
344%" (': 5#I%" "%)4&"($#"7 $"(6$ (': $/% B&:2 $/% %("57 )$(0%) :3% $# >()635&$&) #1 $/% >()(
'%7). 93$ (::&$&#'(5 )784$#8) #1 >()635&$&) '%">#"38? =%'$"(5 '%">#3) 8('&1%)$($&#').
8(7 (5)# #663" &' #$/%" #"0(' )7)$%8)? E' )36/ () (4#45%6$&6 &'1("6$&#'). 6#'>35)&#'). #"
8#)$ 6()%). $/% :&)%()% &'&$&(557 8('&1%)$) () 4)76/#)%). ("% 5%)) 6#88#'? T&:'%7 &'>#5>%2
( 6/"#'&6 &'15(88($&#' #1 $/% 344%" "%)4&"($#"7 8%'$ &) >%"7 6#88#'. %)4%6&(557 05#8%"35#'%2
$"(6$ &' 6#'J3'6$&#' I&$/ 836#)(5 356%"($&#'. 4/"&$&) ())#6&($%: I&$/ 4"#$%&'3"&( (': /%8(2
43"35%'$ "/&'&$&). )&'3)&$&) #" &'15(88($&#' #1 $3"&(? D/% 6#':&$&#' 6(' "(4&:57 4"#0"%)) $#
$/% 8&::5% %(". (': 4"#0"%))&>% :%)$"36$&#' "%'(5 1(&53"%? UM) ('$&0%' 6(' 9% :%$%6$%: &'
(': :%1#"8&$7 #1 $/% 6("$&5(0&'#3) 4("$ #1 $/% 34 $# OP S #1 6()%)?
'()(5 )B%5%$#'? !358#'("7 8('&1%)$($&#') &'2
653:% $"(6/%#9"#'6/&(5 %"#)&#'). 4'%38#'&(.
(': 0"('35#8() $/($ 8(7 3':%"0# 6(>%"'#3)
:%0%'%"($&#'? D/% 8(&' 65&'&6(5 1%($3"%) ("%
6#30/&'0 (': /%8#4$7)&). (': $/% )7)$%8&6
1%($3"%) &'653:% 1%>%" (': I%&0/$ 5#))? ,%'(5 &'2
>#5>%8%'$ +4"#$%&'3"&(. /%8($3"&(. 4"#0"%))&>%
"%'(5 1(&53"%-. ("$/"(50&(. 43"43"(. )B&' 356%"(2
$&#'). (': %4&)65%"&$&) ("% 6#88#' 8('&1%)$(2
$&#') &' $/% 0%'%"(5&A($&#' )$(0%? E'>#5>%8%'$
#1 $/% /%("$. 4%"&4/%"(5 '%">%). #" 0()$"#&'$%)$2
&'(5 $"(6$ &) 5%)) 6#88#'? D/% :%$%6$&#' #1 )%"2

!
38 ('$&9#:&%) (0(&')$ !,* +62;<=;- &) ( "%5(2
$&>%57 )4%6&1&6 1&':&'0?

=" =$5':>?*'2533 ?(08'&/%

=/3"0KL$"(3)) )7':"#8% &) ( >()635&$&6 :&)%()%
CDE 65#)%57 ())#6&($%: I&$/ (55%"0&6 :&($/%)&) +/&)2
 ANCA
B//50% 12345-6*68%3 208 @&-(2'*%'6*63 A&8&32

!1-antitrypsin
!
PR3-!1- PR3-ANCA-IC
antitrypsin

PR3

TNF-!

IL-8, IL-1 LFA-1 LFA-1

LFA-1 LFA-1
ICAM-1 ICAM-1 ICAM-1 ICAM-1

=-60642- B//50&-&:(
Endothelial cells (EC)

1. Resting PMN 2. PMN and EC 3. PMN adherent 4. PMN activated

and EC preactivated to EC by ANCA
A. Vasculitis development theory e.g., in Wegener’s granulomatosis

2. C-ANCA 3. Saddle nose 4. Vasculitis of the toes

"
Bulbar protrusion Sinusitis BP diastolic >90
Otitis Allergic Encephalomalacia
Sinusitis rhinitis (juvenile stroke)
Swelling of parotid Pulmonary
gland infiltration Coronary
Pulmonary insufficiency
infiltration Asthma
Ulcers in stomach
CNS granulomas Carditis and intestine
Episcleritis Eosinophilc
Rhinitis, gastroenteritis
Testicular
ulcers pain
Interstitial
Subglottic nephritis
stenosis Livedo
Myalgias reticularis
Tracheal/
bronchial stenosis Arthralgias
Myalgias
Glomerulonephritis Purpura
Myalgias/myositis Arthralgias

!
Poly-
Arthralgias neuropathy Painful cutanous
Leukocytoclastic nodules
IgE Skin nodes
vasculitis
c-ANCA Eosinophilia HBsAg
Polyneuropathy Skin necrosis Polyneuropathy
1. Clinical findings
B. Wegener’s granulomatosis C. Churg-Strauss syndrome D. Polyarteritis nodosa
CDF

"
! (1&&)7'$8) .$,,5) 9$,)%,) %&2 :%,75*$'$,

!"#$# %$# &'( &)*#+ (, -.%/& 0#11 %$&#$.&.+ 234567

!"#"$"%&'% "()*(+)+%8 '".0" %,,#0&+ &"# %($&% %/9
.&+ :$%/0"#+8 %/9 )*,-.("/ "()*(+)+%8 '".0" ./;
<(1<#+ &"# 1%$-# 0$%/.%1 %$&#$.#+= !"# ".+&(1(-.0%1
,#%&>$#+ (, :(&" &)*#+ %$# ?%++.<# &".0@#/./- (,
&"# %$&#$.%1 '%11 ($ ,$%/@ %$&#$.%1 +&#/(+.+ 2!"#6
%/9 &"# *$#+#/0# (, *(1)/>01#%$ -.%/& 0#11+
2!"$6= !"# *%&"(-#/#+.+ (, &"#+# 9.+#%+#+ .+ +&.11
>/01#%$= 3#/#&.0 *$#9.+*(+.&.(/ 2AB5;CDE6 %/9
!;"#1*#$ 0#11;?#9.%&#9 .??>/# ?#0"%/.+?+
1#%9./- &( -$%/>1(?% ,($?%&.(/8 *(++.:1) 9>#
&( +&.11 >/.9#/&.,.#9 ./,#0&.(/+8 %$# &"# ?%./ ");
*(&"#+#+ (/ &"# *%&"(-#/#+.+ (, 345=
!" #$%&' ()** !+')+$'$,- .)/01+%* !+')+$'$,
(*$&$7%* ;//5&1*1<4
:) 9#?(/+&$%&./- &)*.0%1 #0"(-$%*".0 0"%/-#+
:) C(**1#$ +(/(-$%*")= !"# *$(-/(+.+ .+ -((98
:>& +&#$(.9 &$#%&?#/& ?>+& >+>%11) :# %9?./.+;
&#$#9 ,($ (/# &( &'( )#%$+ :#,($# % 1%+&./- $#;
?.++.(/ .+ %0".#<#9=
!"#"$"%&'% "()*(+)+% 2%($&.0 %$0" +)/9$(?#6 .+
% <%+0>1.&.0 9.+#%+# &"%& *$#9(?./%/&1) %,,#0&+
)(>/- '(?#/= !"# <%+0>1.&.+ ./<(1<#+ &"# &"($;
%0.0 %($&% %/9 .&+ :$%/0"#+= !"# *$#9(?./%/&
01./.0%1 ,#%&>$#+ %$# &"#$#,($# $#1%&#9 &( <#++#1
+&#/(+.+8 #=-=8 01%>9.0%&.(/8 *>1+#1#++/#++8 <%+0>;
1%$ ?>$?>$+8 %/9V($ ")*#$&#/+.(/= M#<#$8
'#.-"& 1(++8 ?)%1-.%8 %/9 %$&"$%1-.% ?%) %1+(
:# (:+#$<#9 ./ &"# ./.&.%1 ./,1%??%&($) *"%+#=
A#%9%0"#8 9.WW./#++8 <.+>%1 0(?*1%./&+8 %($&.0

%&2 .%3%4%,56, !+')+$'$, ./+>,,.0.#/0)8 %/9 %/#>$)+? %$# 1#++ 0(??(/=

!"# 1%:($%&($) &#+&+ $#<#%1 #N&#/+.<# 0"%/-#+
!#?*($%1 %$&#$.&.+ 20%11#9 %1+( 0("1+"/ "()*(+)+%
./ /(/+*#0.,.0 *%$%?#&#$+ (, ./,1%??%&.(/= !%;
%/9 2.().1'% "()*(+)+%6 .+ % $#1%&.<#1) 0(??(/
@%)%+>X+ %$&#$.&.+ $#+*(/9+ '#11 &( +&#$(.9+=
9.+#%+# ./ *%&.#/&+ (<#$ FG )#%$+ (, %-#H +##
A('#<#$8 &"# *$(-/(+.+ .+ ?>0" '($+# '"#/
2%6 ,($ 9.%-/(+&.0 0$.&#$.%= D%&.( ./ '(?#/ &(
#N&#/+.<# <#++#1 1#+.(/+ %$# *$#+#/& %& &"#
?#/ .+ I7J= !"#$# .+ *$.?%$) ./<(1<#?#/& (0;
&.?# (, 9.%-/(+.+ 2)6=
0>$+ ./ %$&#$.#+ (, &"# "#%9 $#-.(/ 2#=-=8 &"# &#?;
*($%1 %$&#$)8 $#&./%1 %$&#$)8 %/9 0#$#:$%1 %$;
&#$.#+6 :>& (&"#$ <#++#1 $#-.(/+ ?%) %1+( :#
%,,#0&#9= 5*%$& ,$(? -#/#$%1 +)?*&(?+ 1.@# ,#;

"
<#$8 1%++.&>9#8 %/9 '#.-"& 1(++8 (&"#$ 0(??(/
+)?*&(?+ ./01>9# "#%9%0"#8 ")*#$#+&"#+.% ./
&"# "#%9 $#-.(/8 %/9 *%1*%:1# ./9>$%&.(/ (,
&"# &#?*($%1 %$&#$) 2&6= !"# ?(+& ,#%$#9 0(?;
*1.0%&.(/ .+ +>99#/ :1./9/#++ 9># &( $#&./%1
%$&#$) (001>+.(/= K)?*&(?+ +>0" %+ <.+>%1 .?;
*%.$?#/&8 #)# %0"#+8 ($ 1.-"& +#/+.&.<.&) $#L>.$#
./&#/+.<# ./<#+&.-%&.(/ %/9 $%*.9 &"#$%*#>&.0
./&#$<#/&.(/= M>/9(+0(*) $#<#%1+ (001>+.(/ (,
$#&./%1 %$&#$) :$%/0"#+ ($ *%*.11%$) #9#?%=
K0%1* >10#$%&.(/ 9># &( % 1%0@ (, 0.$0>1%&.(/ .+
% $%$# 0(?*1.0%&.(/ 2'6=
5**$(N.?%&#1) IGOPG Q (, *%&.#/&+ '.&"
&#?*($%1 %$&#$.&.+ "%<# 0(/0(?.&%/& +)?*&(?+
(, *(1)?)%1-.% $"#>?%&.0%H +## 2(6 ,($ 9.%-/(+;
&.0 0$.&#$.%= !"# *$#9(?./%/& ,#%&>$#+ %$# *%./
./ &"# *$(N.?%1 +"(>19#$ %/9 &".-" ?>+01#+=
!"#$# %$# %1+( -#/#$%1 +)?*&(?+8 +>0" %+ 1%++.;
&>9#8 ,%&.->#8 9#*$#++.(/8 %/9 1(';-$%9# ,#<#$8
'".0" %$# >+>%11) #N&#/+.<#=
5 *$(?./#/& 1%:($%&($) ,#%&>$# (, :(&" 9.+;
#%+#+ .+ % ?%$@#9 ./0$#%+# ./ &"# #$)&"$(0)&#
+#9.?#/&%&.(/ $%&# 2RKD6 '.&" <%1>#+ (,&#/ ./

!
=>?
#N0#++ (, JGG ?? ./ J "(>$= S.19 %/#?.% %/9
1#>@(0)&(+.+ ?%) %1+( :# 9#&#0&#9= T.1%&#$%1
:.(*+) (, % 1(/-#$ +#-?#/& (, &"# &#?*($%1 %$;
&#$) '.&" +#$.%1;+#0&.(/ ".+&(1(-) .+ $#L>.$#9 &(
#+&%:1.+" &"# 9.%-/(+.+ (, &#?*($%1 %$&#$.&.+= U/
0#$&%./ 0%+#+8 &"# 9.%-/(+.+ 0%/ :# #+&%:1.+"#9
 Headache
#$%&' ()** !+')+$'$,
!
Aching shoulders and/ or bilateral stiffness
Temporal arteritis
Scalp skin necrosis Disease onset within 2 weeks

Jaw claudication Initial ESR increase of >40 mm in 1 hour

Pulmonary Morning stiffness >1 hour

vasculitis
(rare) Age over 65 years
Coronary
insufficiency Depression and/or weight loss
(rare)
Bilateral tenderness on palpation of upper arm
Cerebral infarction
via extracranial

(*$&$7%* ;//5&1*1<4
2. Diagnostic criteria of polymyalgia rheumatica
vessels
(rare)
Ocular findings Patient over 50 years at first manifestation
Newly occurrent headache
– Loss of vision
– Eye muscle-paresis Clinical findings in temporal arteries:

Polymyalgia tenderness on palpation, pulselessness

of pelvis/ highly increased ESR

"
ESR shoulder
CRP (bilateral) positive arterial biopsy

1. Clinical findings in temporal arteritis/ 3. Diagnostic criteria of temporal arteritis

polymyalgia rheumatica

4. Histology of Takayasu’s arteritis 5. Branch stenosis in

Takayasu’s arteritis

6. Histology of occluded
temporal artery
7. Temporal arteritis 8. Head skin ulcer

A. Clinical features of giant cell arteritis: Takayasu’s and temporal arteritis

!
=>>

"
! 67,* 4,+)$+)+

!"#$%&"$& !" # $!"%#"% #""&'!#(%$ )!(* )*%#+"

)!(* ,#"(- ")%++!./ #.$0 !. 1#.- '#"%"0 "%2%3%
!('*!./4 5*% "6!. %37,(!&." #3% (3#."!%.( #.$
# !"#$%&"$&+ 5&*%,+$#$* !" '*#3#'(%3!=%$ @- *-<
,%3,!/1%.(%$ )%#+" (*#( ,%3"!"( 8&3 1&3%
(*#. AB *&73"4 5*% @#"!" &8 (*!" $!"%#"% !"
8#$% )!(*&7( "'#33!./4 # (-,% DDD *-,%3"%."!(!2!(- 3%#'(!&. #.$ #""&<
'!#(%$ 8&31#(!&. &8 !117.% '&1,+%I%" #.$
!" #$%&'()*)+,+ '&1,+%1%.( '&."71,(!&.4 5*% 2#"'7+!(!"
+%#$" (& 73(!'#3!# $7% (& (*% 3%+%#"% &8 2#<
97(#.%&7" 1#"( '%++" ,+#- # 6%- 3&+% !. (*%
"&#'(!2% 1%$!#(&3"4
,#(*&/%.%"!" &8 73(!'#3!#4 :8(%3 # ,3%'!,!(#(!./
' !"#$%&"$& '$210.#-*& ;1#"(&'-(&"!"> (%.$" (&
"(!17+7"0 (*% 1#"( '%++" 3%+%#"% ,3%8&31%$ ;*!"<
@% # '*!+$*&&$ $!"%#"% #""&'!#(%$ )!(* $!"<
(#1!.%0 *%,#3!.0 %.=-1%"> #.$ .%)+- 8&31%$
"%1!.#(%$0 3%$$!"*<@3&). ",&(" (*#( 8&31
1%$!#(&3" &8 !.8+#11#(!&. ;,3&"(#/+#.$!."0
73(!'#3!#+ +%"!&." )*%. 37@@%$4 5*% 7.$%3+-<
+%76&(3!%.%"> (*#( !.$7'% $%31#+ %$%1#4
!./ 1#"(&'-(&1#" 7"7#++- $!"#,,%#3 ",&.(#<
?$%1#" &8 (*% "6!. /%.%3#++- "7@"!$% )!(*!.
.%&7"+-4
AB *&73" #.$ #3% #''&1,#.!%$ @- !('*!./ #.$
%3-(*%1#4 5*% ,%3"!"(%.'% &8 # "!./+% %88+&3%"<
38,*,9$8 :55;*'8'(1

3" 4,$(*'+,+ $*0 ./)$%5)*%

'%.'% 8&3 1&3% (*#. AB *&73" "7//%"(" (*% ,3%<
"%.'% &8 73(!'#3!#+ 2#"'7+!(!" ;"%% !"#>0 # "!/. &8
#7(&!117.% $!"%#"%4 :8(%3 #'(!2#(!&. #.$
/3#.7+#(!&.0 (*% 1#"( '%++" 3%1#!. 3%83#'(&3-
8&3 # 8%) *&73" (& $#-"4 C3(!'#3!# (*%3%8&3% '#.<
.&( @% !.$7'%$ #( (*% "#1% "!(% 7.(!+ #8(%3 # '%3<
(#!. +#(%.'- ,%3!&$4
-" ./,(()/+ $*0 .12)+
C3(!'#3!# '#. @% '#7"%$ @- 1#.- $!88%3%.( "(!<
5*% '#"% *!"(&3- 7"7#++- ,&!.(" (& (*% ,3%'!,!<
(#(!./ 8#'(&3"4 J&""!@+% 1%'*#.!'#+ '#7"%"
;!"$> #.$ $37/ (3!//%3" "*&7+$ #+"& @% "&7/*(4
K#2!./ (*% ,#(!%.( 6%%, # $!#3- '#. @% *%+,87+4
5*% ,&""!@!+!(- &8 #. !.8%'(!&7" &3 #7(&!117.%
,3!1#3- $!"%#"% 17"( @% '&."!$%3%$ !. ,#(!%.("
)!(* '*3&.!' 73(!'#3!#4 D. #$$!(!&. (& #2&!$!./
(*% (3!//%3"0 # '&1@!.#(!&. &8 KL #.$ KA #.<
(#/&.!"(" '#. @% ,3%"'3!@%$ (& @+&'6 (*% +&'#+

"
%88%'(" &8 *!"(#1!.%4
17+!0 #++ &8 )*!'* +%#$ (& # "!1!+#3 '+!.!'#+ ,!'<
(73%4 5*% '#7"%" 1#- @% ,*-"!'#+0 !117.&+&/!<
'#+0 &3 ,"%7$&#++%3/!' !. .#(73%4 5*% !.$7'(!&.
&8 73(!'#3!# *#" #+"& @%%. &@"%32%$ !. !.8%'(!&."
;*%,#(!(!" &3 ,#3#"!(!' !.8%'(!&.">4
$ D. '()*$%&+ ,"#$%&"$&0 # ,*-"!'#+ "(!17+7"
+%#$" (& %$%1# 8&31#(!&. &3 1#"( '%++ $%/3#<
.7+#(!&. !. ,#(!%.(" )!(* # *-,%3"%."!(!2%
2#"'7+#3 .%32&7" "-"(%14 5*% 3%#'(!&. '#.
@% (3!//%3%$ @- ,3%""73%0 *%#(0 '&+$0 3%)#31<
!./0 +!/*(0 3#$!#(!&.0 '*&+!.%3/!' "(!17+!
;")%#(!./>0 #$3%.%3/!' "(!17+! ;"(3%"">0 #.$
#E7#/%.!' "(!17+!4 D. %-.#&%# ,"#$%&"$&0 %$%<
1# 8&31#(!&. !" +!1!(%$ (& (*% "!(% &8 '&.(#'(
)!(* (*% "(!17+7" ;%4/40 ,&!"&. !2-0 !."%'( @!(%0
F%++-8!"*>4
% /%,#0 $11,.-+-2$%&+ ,"#$%&"$& !" #. #++%3/!'
D/?<$%,%.$%.( (-,% D 3%#'(!&. (*#( '#. !.<
$7'% #.#,*-+#'(!' "*&'6 )!(*!. # 1#((%3 &8
1!.7(%"4 G3&.'*&",#"10 /+&((!' %$%1#0
#.$ '!3'7+#(&3- "-1,(&1" #3% (-,!'#+ 8%#<
(73%"4 H37/"0 "7'* #" #.(!@!&(!' #.$ *-,.&<
(!'"0 #.$ '%3(#!. 8&&$" #3% ,&(%.(!#+ (3!//%3"4

!
<==
& 5*%"% 3%#'(!&." #3% $!"(!./7!"*%$ 83&1 '*0,3
4-&++0"2$% "0&%#$-.* (& '%3(#!. "7@"(#.'%" ;#"<
,!3!.0 ,3%"%32#(!2%"0 3#$!&/3#,*!' '&.(3#"(
1%$!#> (*#( ;1#-> +%#$ (& 73(!'#3!#+ #.$ #.#<
,*-+#'(&!$ 3%#'(!&." )!(*&7( # ",%'!8!' !1<
17.&+&/!'#+ 3%#'(!&.4
 >/%,9$/,$
!
Histamine Neutral
proteases
Histamine,
neutral proteases,
prostaglandin D2,
leukotriene C4

Mast cell
Edema

Blood

38,*,9$8 :55;*'8'(1
vessel

Vasodilatation Permeability Skin

lesion
A. Pathogenesis

Aspirin
kg

"
Dermo-
Bridging Preservatives
graphism Pressure Cold Heat
of IgE molecules
Light Drugs
X-ray contrast
agents
IgE
Aquagenic
X-ray
Sensi- Hypersensitivity,
Adrenergic Cholinergic tization, histamine
stress sweating Min. degranu-
Food lation
1. Physical urticaria 2. Immunological urticaria 3. Pseudoallergic urticaria

Rubbing Edematous swelling

Urticaria >24h

Hyper- Healing with residual

Mediators pigmentation pigmentation

C1q

Vasculitis Immune
complexes C3
4. Urticarial vasculitis

B. Triggers and manifestations

Complement
factors
Mastocytoma

5. Urticaria pigmentosa
Spontaneous
regression in 90%

!
<=?

"
! 34', 5'&.%&.&

!"#$%&$ '()*%$+$+, +, %# +#-.%**%$+"# "- $/(

,0+# &%1,(' 23 '+)(&$ &"#$%&$ 4+$/ %# +#51)+"1,
%6(#$ 7#"8%9:
H/( 2%,+, -") $/( "1$2)(%0 "- %..()6+& &"#$%&$
'()*%$+$+, +, )((8<",1)( $" $/( %..()6(#+& ,$+=
*1.1, %-$() ,(#,+$+C%$+"# 7"9: K()%$+#"&3$(='(=
)+A(' &3$"0+#(,> (,<(&+%..3 HLM=!> DE=N> %#' &/(=
!" #$%&&'(')%*'+, *"0+#(,> +#+$+%$( $/( +#-.%**%$")3 )(,<"#,( +#
$/( (<+'()*+,: H/( ,(#,+$+C(' H &(.., %#' *%&)"=
;&1$( $"8+& '()*%$+$+, +, % -")* "- '()*%$+$+,
</%6(, *+6)%$( -)"* '()*%. 2.""' A(,,(., 4+$/
$/%$ "&&1), %-$() <)+") #"8%=+#'1&(' ,0+# '%=
(#'"$/(.+% $/%$ (8<)(,, %'/(,+"# *".(&1.(,
*%6(> -") (8%*<.(> '1( $" ,1#21)#: ?(<(%$('
'1( $" $/( +#'1&$+"# "- &3$"0+#(,: E%#6()/%#,
(8<",1)( $" 4(%0 +))+$%#$, 7(:6:> 23 )(<(%$('.3
&(.., 2(%)+#6 (,<(&+%..3 .%)6( #1*2(), "- ,1)=
4%,/+#6 %#'@") '+,+#-(&$+#6 $/( /%#',9 &%#
-%&( <(<$+'(IFO! &"*<.(8(, ,(#,+$+C( %''+=
.(%' $" &1*1.%$+A( ,0+# '%*%6( 7&1*1.%$+A(
$+"#%. H &(.., 4/+&/> +# $1)#> )(.(%,( &3$"0+#(,>
$"8+& '()*%$+$+,9:
$/()(23 .(%'+#6 $" $/( %&&1*1.%$+"# "- +#-.%*=
B#.+0( $/(,( $4" -")*, "- '()*%$+$+,> %..()6+&
*%$")3 &(.., +# $/( (<+'()*+,: H/( %..()6+& &"#=
&"#$%&$ '()*%$+$+, +, #"$ &%1,(' 23 #"8%( 21$
$%&$ '()*%$+$+, $/(# 2(&"*(, &.+#+&%..3 *%#+=
<)+*%)+.3 23 #"#$"8+& ,12,$%#&(, $/%$ <)"'1&(
#$',')%$ 6778,+$+09

-(,$: H/( *",$ (--(&$+A( $)(%$*(#$ +, $/( $"$%.

+**1#"."6+&%. )(%&$+"#, +# $/( %--(&$(' %)(%,
%A"+'%#&( "- $/( %..()6(#+& ,$+*1.1,: O3<",(#=
"- $/( ,0+#> )(,1.$+#6 +# +#-.%**%$+"#: ;..()6+&
,+$+C%$+"# +, #"$ (--(&$+A(:
&"#$%&$ (&C(*% 7%..()6+& &"#$%&$ '()*%$+$+,9
4+.. 2( '(,&)+2(' +# $/( -".."4+#6:

-" #+,*%)* !$$./0.,&

!/)"*%$( +# .(%$/() %#' #+&0(. +# &."$/+#6 %#'
5(4(.)3 %)( &"**"# $)+66(), "- %..()6+& &"#$%&$
'()*%$+$+,: D#$)%(<+'()*%. ('(*%, -")* %$ $/(
%--(&$(' ,+$(, '1( $" $/( 2)(%0'"4# "- +#$()&(.=

" .1.%) 2)+'6(,: E3*</"&3$(, %.," *+6)%$( $" $/(

(<+'()*+,: F('+%$"), "- +#-.%**%$+"# .(%' $"
A%,"'+.%$%$+"# +# $/( '()*+, 4+$/ ,12,(G1(#$
('(*% -")*%$+"#:
H/( *".(&1.(, $/%$ <)"A"0( $/( (&C(*% %)(
1,1%..3 ,*%.. %#' $/()(-")( 2(/%A( %, /%<$(#,:
H/(3 &%##"$ $)+66() %# +**1#( )(,<"#,( 4+$/=
"1$ /(.<: H/(3 *1,$ -")* &"A%.(#$ 2"#', 4+$/
(<+'()*%. <)"$(+#, ") 2( +#$(6)%$(' +#$" $/( &(..
*(*2)%#( $" '(A(."< &"*<.($( %#$+6(# (--+=
&%&3 4/(# <)(,(#$ +# /%<$(#I<)"$(+# &"*=
<.(8(,: H/( *".(&1.(, *%3 %.," 2( <)(,(#$ %,
<)"/%<$(#, +# $/( (<+'()*+,> 4/()( $/(3 %)(
$)%#,-")*(' +#$" %&$+A( /%<$(#, 1<"# (8<",1)(
$" .+6/$ 7!"#$#%&&'()*+ +#,$%+$ -'(.%$*$*/9:

#" 1%*2+0.,.&'&
E%#6()/%#, &(.., +# $/( (<+'()*+, <.%3 % 0(3
)".( +# $/( ,(#,+$+C%$+"# <)"&(,, 7!9: ;#+*%. (8=
<()+*(#$, /%A( ,/"4# $/%$> 4/(# $/( &(.., %)(
)(*"A(' -)"* $/( ,0+#> ,(#,+$+C%$+"# '"(, #"$
"&&1) %#' $".()%#&( $" $/( %..()6(# '(A(."<,:

!
E%#6()/%#, &(.., $/%$ %&$ %, %#$+6(#=<)(,(#$+#6
&(.., 7;J!9 <+&0 1<> <)"&(,,> %#' <)(,(#$ $/( %.=
.()6(# $" H &(.., +# $/( .3*</ #"'(,: H/( ,(#,+=
$+C(' H &(.., %)( %$$)%&$(' 23 &3$"0+#(, -)"*
E%#6()/%#, &(.., %#' 0()%$+#"&3$(, %#' +#-+.=
:;: $)%$( $/( %--(&$(' ,0+# )(6+"#:
 Toxic event Toxic event
#+,*%)* !$$./0'.&

Allergen
!
Acute toxic dermatitis Cumulative toxic Allergic contact
dermatitis dermatitis
– strong event – weak event – non-toxic event
– only once – repeatedly – sensibilization causes
– e. g., sunburn – e. g., frequent hand washing type IV allergy
or desinfection – e. g., nickel

#$',')%$ 6778,+$+09
A. Causes of dermatitis

Nickel

Lymphocyte Vasodilation
infiltration and dermal
Leather, edema
chromate
Intra-

"
Hair dyes with epidermal
p-phenylene edema
diamine

Rubber
com-
pounds

Antibiotics,
neomycin

B. Contact allergens

Epidermis T cell Edema Inflammatory Endothelium:

infiltrate adhesion
Light molecules
Sensitization Extravasation

Langerhans
cell Migration Repeated
Lymph antigen
nodes exposure

Allergen TNF-!
IL-1

Keratinocytes

a) Sensitization
C. Pathogenesis
b) Induction of eczema
IL-1
TNF-!

!
:;<

"
! 51&6 (&-),-)-

!" !#$%&' ()*+,#&#&-

!"#$%& '()*+"%"%, -.(/)#'()*+"%"%,0 %, + &1)#.%&
$)/)%"%& (&2(*+"#/, '%,(+,( "1+" %, #3"(. +&4
"1( ?(,,(7,9 B" &+. 5( (=")(*(76 '%33%&/7" #) %*4
$#,,%57( "# %'(."%36 "1( +."%8(. )(,$#.,%57( 3#)
3#)*+"%#. #3 %**/.( &#*$7(=(,9 :1()(3#)(<
$#"(."%+7 /.'()76%.8 '%,(+,(, -%.3(&"%#., '%,4
&#*$+.%(' 56 +77()8%& +,"1*+ +.' +77()8%& )1%4
(+,(,< "/*#)< +/"#%**/.( '%,(+,(,< +.' $+)"%4
.%"%,9 :1( '%,(+,( #&&/), %. %."()*%""(." +""+&;,
&/7+)76 '%,(+,(, #3 "1( &#77+8(. ?+,&/7+) "6$(0
+.' *+%.76 &+/,(, ,;%. 7(,%#., #. "1( 3+&(<
,1#/7' 5( ,#/81"9
.(&;< +.' 37(=/)+7 ,/)3+&(,9 :1( %.37+*(' +)(+,
#3 "1( ,;%. "(.' "# 5(&#*( %.3(&"('9 :1( *#,"
&#**#. &+/,(, +)( ,")($"#&#&&+7 %.3(&"%#.<
!"#$%"&'&''()4%.'/&(' $6#'()*+< +.' (&2(*+
1()$("%&/* '/( "# %.3(&"%#. >%"1 "1( 1()$(,
,%*$7(= ?%)/,9 @(.("%& +.' (.?%)#.*(."+7 3+&4
"#), -3##' +77()8(.,< ,;%. %))%"+"%#.< $,6&1#7#8%4
&+7 3+&"#),0 $7+6 + )#7( %. "1( +$$(+)+.&( #3 "1(
()/$"%#.,9 :1( %**/.( $+"1#8(.(,%, #3 +"#$%&
73&6&',3 8++06$3$92

'()*+"%"%, %, /.&7(+)9 A%81 7(?(7, #3 B8C +.' %*4

*/.( &#*$7(=(, &#."+%.%.8 B8C +)( #3"(.
3#/.' -!09 B.&)(+,(' (=$)(,,%#. #3 "1( )(&($"#),
3#) B8C +.' D&!EB +.' BB #. *#.#&6"(, +.' F+.4
8()1+., &(77, &+. 5( #5,()?('9 :1()( %, *+%.76 +
:AG )(,$#.,(9 BF4H +&"%?+"(, B8C $)#'/&"%#. +.'
"1( :AI )(,$#.,( %, $+)"%+776 ,/$$)(,,('< >1%&1
)(,/7", %. +. %.&)(+,(' "(.'(.&6 "# %.3(&"%#.9
:1()( %, ,"%77 .# &+/,+7 ")(+"*(." 3#) +"#$%&
(&2(*+9 :1( $+"%(.", +)( ")(+"(' ,6*$"#4

"
*+"%&+776 >%"1 "#$%&+7 &#)"%,#.( +.' "+) $)(4
$+)+"%#., "# $)(?(." %.37+**+"%#. +.' )('/&(
%"&1%.89

." /)01$'2#$'3,-#&' 4,-'03&#&-

F(/;#&6"#&7+,"%& ?+,&/7%"%, -&+77(' +7,# *++$#,-'
.*)'(+-"-) +.' !'/&01+$-123$1&'/ %(#%(#*0 %, +.
%.37+**+"#)6 '%,(+,( #3 "1( ,*+77 +.' *('4
%/*4,%2(' &/"+.(#/, ?(,,(7,9 :1( 7(,%#., -1(4
*#))1+8(,< .(&)#"%& 7(,%#.,< /)"%&+)%+7 +.' $+4
$/7#%' &1+.8(,0 +)( ,6**(")%&+776 '%,")%5/"('
+.' #&&/) *+%.76 #. "1( 7#>() (=")(*%"%(,9 B*4
*/.( &#*$7(=(, $7+6 + &)%"%&+7 )#7( %. "1(
$+"1#8(.(,%, #3 "1( '%,(+,(9 :1( +&&/*/7+"%#.
#3 "1( %**/.( &#*$7(=(, %. ?(,,(7 >+77, +7#.8
>%"1 "1( ,/5,(J/(." +&"%?+"%#. #3 &#*$7(*(."
/7"%*+"(76 7(+', "# "1( %.37+**+"#)6 )(,$#.,(9
D(?()< K#%." &#*$7+%.",< +.' 8+,")#%."(,"%.+7
&#*$7+%.", +)( &#**#. 8(.()+7 )(+&"%#.,L
B8! .($1)#$+"16 %, +. #&&+,%#.+7 &#*$7%&+"%#.9
:1( '%+8.#,%, %, (,"+57%,1(' 56 1%,"#$+"1#7#869
M%7' &+,(, )(,$#.' "# $16,%&+7 *(+,/)(,< 5/"

!
$+"%(.", >%"1 ,6,"(*%& %.?#7?(*(." )(J/%)( %*4
*/.#,/$$)(,,+.",9
:1( '%+8.#,%, #3 7(/;#&6"#&7+,"%& ?+,&/7%"%, %,
(,"+57%,1(' 3)#* "1( 3%.'%.8, #3 &7%.%&+7 +.'
1%,"#7#8%&+7 "(,",9 B**/.#37/#)(,&(.&( *%&)#4
:;< ,&#$%& "(&1.%J/(, &+. +7,# 5( /,(' "# '(*#.4
,")+"( "1( '($#,%"%#. #3 %**/.( &#*$7(=(, %.
Genetic factors
!#$%&' ()*+,#&#&- ,6= /)01$'2#$'3,-#&' 4,-'03&#&-
!
Fc!RII
Metabolic disorders IgE- on
Immunological disorders immune mono-
IgE complexes cytes

Allergic rhinitis
IgE
Allergic
asthma
Eczema on flexor surfaces
TH2 IL-4 B cell

Environmental factors
Fc!R

73&6&',3 8++06$3$92
Food Mast cells,
Frequent basophil
Skin irritations infections granulocytes,
Psychological factors TH1 releasability

1. Trigger factors 2. Pathogenesis

A. Atopic dermatitis (neurodermatitis)

"
Systemic manifestation

Complement
Deposition
of
immune
complexes
in vessel
IgA
nephropathy
Petechias
Urticaria
Papules

!
Hemorrhage
Necrosis
Blood vessel changes Symmetric
manifestation
B. Leukocytoclastic vasculitis
:;>

"
! ,-'. /'$0($0$

!" #$%&'($'$
!"#$%&"%" '("#$%&"%" )*+,&$%"- %" & ./$/0%1&$2 0/$3
4&1#"%" 5.&$&51/$%6/0 72 1./ ($/"/85/ #9 :/++3
2/11#/" *,-*)%.#%3 %" 4&%8+2 & 0%"/&"/ #9 1./
/+0/$+2< N1 %" 5.&$&51/$%6/0 72 1./ ($/"/85/ #9
+&$,/; 1/8"/ 7+%"1/$" 5#81&%8%8, 5+/&$ #$ 7+##03
"1&%8/0 9+*%0< H./ "(+%1 %8 1./ 7&"/4/81 4/43
0/9%8/0; *"*&++2 5%$5*4"5$%7/0 9#5% #9 %89+&43
7$&8/ #55*$" %8 1./ "*7/(%0/$4&+ $/,%#8< H./
4&1%#8 5#)/$/0 72 "%+)/$2 "5&+/"< !"#$%&"%"
&*1#&81%7#0%/" 1.&1 5&*"/ 7*++#*" (/4(.%,#%0
.&" &8 %85$/&"/0 9&4%+%&+ %85%0/85/ &80 %" &""#3
'E!- &$/ 0%$/51/0 &,&%8"1 7&"/4/81 4/47$&8/
5%&1/0 :%1. =>?3@AB; =>?3C:D; &80 =>?3EFG<
&81%,/8" '7*++#*" (/4(.%,#%0 ?,; E!3N; E!3NN-
! H./ 12(/" #9 ("#$%&"%" &$/ 0%"1%8,*%"./0 &53
+#5&1/0 %8 1./ ./4%0/"4#"#4/" &80 +&4%8& +*3
5#$0%8, 1# 1./%$ (&1.#,/8/1%5 5&*"/"; %</<;
5%0& #9 1./ 7&"/4/81 4/47$&8/< H./ 9#$4&1%#8
.#$8%9%5&1%#8 0%"#$0/$" '.2(/$I/$&1#"%";
#9 7+%"1/$" %" %80*5/0 72 5#4(+/4/81 &51%)&1%#8
(&$&I/$&1#"%"- &80 %44*8#+#,%5&+ 4/5.&83
&80 1./ $/+/&"/ #9 /8624/" 9$#4 ,$&8*+#521/"<
%"4"< H 5/++" &80 ,$&8*+#521/" 4%,$&1/ %81#
4*%3,$-#15"%" 6/11#"& &+7/%"%(& %" & 8#8%83
1./ ("#$%&1%5 +/"%#8"< H./ 0%"/&"/ 5&8 7/ 1$%,3
9+&44&1#$2 0/$4&1#"%" 1.&1 #55*$" %8 &0*+13
,/$/0 72 & 8*47/$ #9 /J#,/8#*" 9&51#$" '%83
.##0 &80 %" 5.&$&51/$%6/0 72 "*7/(%0/$4&+
K*$2; LM $&0%&1%#8; 5#+0- &80 /80#,/8#*" 9&53
1+'.'2(+ 344*.%+%56

7+%"1/$ 9#$4&1%#8< H./ 7+%"1/$" #55*$ #8 "I%8

1#$" '%89/51%#8; =NM; 4/0%5&1%#8"; &+5#.#+;
#)/$ 1./ K#%81" &80 &$/ %80*5/0 72 1$%)%&+ 1$&*3
.2(#5&+5/4%&; "1$/""-< H./ 0*$&1%#8 #9 &8 &13
4&"< H./ 0%"/&"/ %" 5.$#8%5< H./ 7+%"1/$" *"*&++2
1&5I #$ 1./ 5.$#8%9%5&1%#8 #9 1./ 0%"/&"/ 0/3
#55*$ #8 1./ .&80"; 9//1; &80 1./ /J1/8"#$ "*$3
(/80" #8 & :%0/ )&$%/12 #9 /(%0/$4&+ &80
9&5/ #9 1./ +#:/$ +/,; &80 1./2 +/&)/ 02"1$#(.%5
%44*8#+#,%5&+ 9&51#$"<
"5&$" &80 4%+%& &91/$ 1./2 ./&+< H./ &*1#&81%3
" O%1/" #9 ($/0%+/51%#8 9#$ ("#$%&1%5 +/"%#8" &$/
7#0%/" &$/ 0%$/51/0 &,&%8"1 1./ 12(/ MNN 5#++&,/8
1./ /J1/8"#$ "*$9&5/" #9 1./ +%47"; 1./ %+%#"&3
#9 1./ +&4%8& 0/8"& #9 1./ 7&"/4/81 4/43
5$&+ $/,%#8; &80 .&%$2 &$/&" #9 1./ "5&+(<
7$&8/<
O5$&15.%8, 1./ ("#$%&1%5 +/"%#8" ,%)/" 1./
8,$-&(%(%" ),$*,(%9#$-%" '8/)$%:.;" 3%",&",-
"5&+/" & 12(%5&+ (./8#4/8#8 #9 :&J2 "1&%8"
%" & 5.$#8%5; $/+&("%8, "I%8 0%"/&"/ 1.&1 %" /J3

"
5.&$&51/$%6/0 72 & "*(/$9%5%&+; :&J2 "5&+/ '#-;
1$/4/+2 ($*$%1%5< N1 %" 5.&$&51/$%6/0 72 1./
#$ 4&I/" 1./4 /J.%7%1 & P+&"13(/++%5+/Q (./3
0/)/+#(4/81 #9 (&(*+/" &80 )/"%5+/" &80 %"
8#4/8#8 5.&$&51/$%6/0 72 1./ &((/&$&85/
5+#"/+2 &""#5%&1/0 :%1. ,+*1/83"/8"%1%)/ /81/$#3
#9 & "%+)/$2 (/++%5+/ #85/ &++ "5&+/" .&)/
(&1.2< T1./$ 5.&$&51/$%"1%5 9/&1*$/" %85+*0/ 1./
7//8 $/4#)/0 '$-; #$ & 1&(/$%8, (&11/$8
($/"/85/ #9 ,$&8*+&$ N,? 0/(#"%1" %8 1./ 0/$4&+
5.&$&51/$%6/0 72 (*851%9#$4 7+//0%8, &91/$
(&(%++&/ &80 "*7/(%0/$4&+ 7+%"1/$%8,< H./$/ %" &
$/4#)&+ #9 1./ +&"1 (/++%5+/ '%-< !"#$%&"%" &$'
5+#"/ &""#5%&1%#8 :%1. =>?3EU; =>?3@AG; &80
()$#*&()%+& '("#$%&1%5 &$1.$%1%"- %" & 0%"1%851
&*1#&81%7#0%/" 1# $/1%5*+%8 &80 /80#42"%*4<
/81%12 &""#5%&1/0 :%1. 4#8#&$1.$%1%" #$ (#+23
&$1.$%1%"< H./ K#%81" #9 1./ 9%8,/$" &80 1#/" &$/
4#"1 5#44#8+2 &99/51/0<

)" )*++%*$ ,-'. /'$0($0$

!,-*)%./" 0/1.&$%" %" & 7+%"1/$%8, "I%8 0%"/&"/
1$%,,/$/0 72 &*1#&81%7#0%/" 0%$/51/0 &,&%8"1
0/"4#,+/%8; & 0/"4#"#4&+ &0./"%#8 4#+/5*+/
#9 1./ 5&0./$%8 ,$#*(< @/"4#,+/%8" &$/ ,+25#3
($#1/%8" 1.&1 8#$4&++2 ($#)%0/ 5/++R5/++ 5#81&51
1# 1./ 0/"4#"#4/ 72 .#4#12(%5 7%80%8,< ?81%3
7#0234/0%&1/0 &51%)&1%#8 #9 /J1$&5/++*+&$ ($#3
1/&"/" 0/"1$#2" 1.%" 5#81&51< H./ %81/$5/++*+&$
5/4/81 #9 1./ "1$&1*4 "(%8#"*4 7$/&I"

!
0#:8; &80 1./ %80%)%0*&+ I/$&1%8#521/" 7/5#4/
$#*80/0 '&5&81.#+2"%"-< H.%" $/"*+1" %8 %81$&/(%3
0/$4&+ "(+%11%8, &80 "*7"/S*/81 7+&"1 9#$4&3
1%#8 &80 /$#"%#8< H./ $/"*+1%8, +#"" #9 9+*%0";
($#1/%8"; &80 /+/51$#+21/" 5&8 S*%5I+2 1&I/ #8
789 +%9/31.$/&1/8%8, ($#(#$1%#8"<
 Genetic
#$%&'($'$ (.: )*++%*$ ,-'. /'$0($0$

Sites of
!
predisposition predilection
HLA-DR7,
-Cw6, -B13 Psoriatic
Impaired Immune
keratinization dysregulation arthritis
IL-8, LTB4, IgA , ANA
EGF, TGF-!
keratinocytes IL-8

Latent
psoriasis a
Exogenous Endogenous b
c
HIV
Provocation

1+'.'2(+ 344*.%+%56
UV Skin scaling
Ca2+ C2H5OH
Manifest
psoriasis

Epidermal
hyper- Auto- Inflammatory
activation reaction
regeneration
1. Pathogenesis
A. Psoriasis 2. Symptoms

Desmoplakin Cell membrane

"
Auto-
anti-
bodies
Cytoskeleton Desmoglein
Normal skin Acantholysis
1. Pemphigus Desmosome

Tonofilaments Basal cell

Auto-
anti- Hemi-
bodies desmosomes
Laminin
Basement membrane

Bullous pemphigoid
BP-I, -II Lamina
Collagen IV lucida
Epidermolysis
bullosa acquisita Collagen VII

!
Lamina
Herpetiform dermatitis densa
Reticulin
Dermal
2. Subepidermal connective tissue
blister formation
B. Bullous skin diseases
78;

"
" ,-.*%&('*2.*('-6 8(.2-.2.

!" #$%&'() !*%&+$() ,-.*%(*(. /01+2 !3

!"#$%&' ()#$*"&' +(,)#&)&, -).*/ 01 &, (% (2)$&34
32%/ 5&,/(,/ (,,$'&()/5 6&)" (2)$(%)&7$5&/,
(+(&%,) '"&/8 '/99,: *(#&/)(9 '/99,: (%5 &%)#&%,&'
8(')$#; <% ).*/ 0 +(,)#&)&,: )"/ 3(&% '"(%+/, $'4
'2# &% )"/ 82%52, (%5 7$5. $8 )"/ ,)$3('":
'(2,&%+ +9(%529(# ()#$*". 6&)" ,27,/=2/%)
('"9$#".5#&( (%5 #/52'/5 &%)#&%,&' 8(')$# *#$4
52')&$%; >.*/ 0 +(,)#&)&, *#$52'/, #/9()&?/9.
8/6 ,.3*)$3,; <) 3(%&8/,), 9()/ 6&)" ,&+%, $8
&%5&+/,)&$% (%5 '"#$%&' ?&)(3&% @AB 5/8&'&/%'.
-*/#%&'&$2, (%/3&(1; >"/ "/3()$9$+&'(9 8&%54
&%+, &%'925/ ".*/#'"#$3&' 3('#$'.)&' (%/3&(
(%5 ".*/#,/+3/%)/5 +#(%29$'.)/,; C/2#$9$+&4
'(9 8/()2#/, &%'925/ ,&+%, $8 82%&'29(# 3./9$,&,:
#6('()-6 =>>9'&6&?1
#" ,69*2':.2'.(*(;2 <'*2%&+-*$1
S92)/%4,/%,&)&?/ /%)/#$*()". -,*#2/1 &, '"(4
#(')/#&T/5 7. (% (99/#+&' #/(')&$% )$ +9&(5&%: (
,27,)(%'/ '$%)(&%/5 &% '/#/(9 *#$)/&%,: &% &%5&4
?&52(9, 6&)" ( +/%/)&' *#/5&,*$,&)&$%; >"/ 5&,4
/(,/ &, (,,$'&()/5 6&)" KM04PQN (%5 4@Z (%)&4
+/%,; I*#2/ &, '"(#(')/#&T/5 7. (2)$(++#/,,&?/
&%89(33()&$% 5&#/')/5 (+(&%,) )"/ 3.$/*&)"/4
9&(9 (%'"$#(+/ 8&7#&9, $8 )"/ &%)/,)&%/; >"/ &34
32%$9$+&'(9 8/()2#/, &%'925/ (2)$(%)&7$5&/,
(+(&%,) /%5$3.,&23 (%5 #/)&'29&% (%5 (%)&4
+9&(5&% (%)&7$5&/,; >"/ ,U&% $8 )"/ ,3(99 &%)/,4
)&%/ 7/'$3/, ()#$*"&' -32'$,(9 89())/%&%+1 (%5
9.3*"$/*&)"/9&(9 &%8&9)#()/, 8$#3; >"/ '9&%&'(9
,.3*)$3, &3*#$?/ 2%5/# ( +92)/%48#// 5&/);

,2'" (, #/52'/5 ?&7#()$#. */#'/*)&$% (%5 ()(D4
&( 52/ )$ &3*(&#3/%) $8 )"/ *$,)/#&$# 82%&'292,
$8 )"/ ,*&%(9 '$923%E ,*(,)&' *(#(*(#/,&, $8 )"/
9/+, 3(. $''2# &% )"/ 9()/ ,)(+/, $8 5&,/(,/ 52/
)$ 5/+/%/#()&$% $8 )"/ *.#(3&5(9 )#('); 0'"9$#4
".5#&( 9/(5, )$ 8(,)&%+ ".*/#+(,)#&%/3&(: (%5
)"/ */%)(+(,)#&% )/,) &, ,)#$%+9. *$,&)&?/;
>"/ (2)$(%)&7$5&/, (+(&%,) '"&/8 '/99, '(% 7/
5&?&5/5 &%)$ )"/ 8$99$6&%+ +#$2*,F
!
0%)&7$5&/, (+(&%,) ( 3&'#$,$3(9 (%)&+/%
09$%+ 6&)" 3(9(7,$#*)&$% (%5 ,)/()$##"/(:
(2)$(%)&7$5&/, 3(. '(2,/ 5/#3()&)&, "/#*/)&4
8$#3&,; >"/,/ *()&/%), (#/ (9,$ () &%'#/(,/5
#&,U $8 3(9&+%(%) 9.3*"$3(: 6"&'" '(% 5/4
?/9$* 8#$3 32'$,(4(,,$'&()/5 9.3*"$&5 )&,,2/;
.*/&#0'1'2,23 S9&(5&% '$%,23/5 &% )"/ 5&/)
*/%/)#()/, )"#$2+" +(*, &% )"/ /*&)"/9&( (%5
/%)/#, )"/ 9(3&%( *#$*#&(: 6"/#/ &) &, (7,$#7/5
7. -KM04P[4 $# KM04P[Z4*$,&)&?/1 0G! (%5 >
'/99,; >"/ )&,,2/47$2%5 )#(%,+92)(3&%(,/ 8$#3,

#
-G!H01: 6"&'" (#/ (9,$ (,,$'&()/5 6&)"
).*/ < 5&(7/)/,
!
0%)&7$5&/, (+(&%,) ( ,2#8('/ (%)&+/% -G!I01:
6"&'" (#/ ?&#)2(99. ,*/'&8&' 8$# ).*/ 0 (2)$4
&332%/ +(,)#&)&,
>.*/ 0 +(,)#&)&, $''(,&$%(99. $''2#, &% '$%4
J2%')&$% 6&)" $)"/# (2)$&332%/ /%5$'#&%/
5&,/(,/,: ,2'" (, ".*/#)".#$&5&,3 (%5 K(,"&4
3$)$L, 5&,/(,/; <) &, (,,$'&()/5 6&)" KM040N:
4@O: 4PQB: (%5 4PQR (%)&+/%,; >#/()3/%) $8 */#4
%&'&$2, (%/3&( &, 6&)" *(#/%)/#(9 ?&)(3&% @AB;
'#$,,49&%U(+/, &% +9&(5&% *#$)/&%: 9/(5&%+ )$
)"/ 8$#3()&$% $8 /?/% 3$#/ *$)/%) >4'/99 /*&4
)$*/,; 0 >KA #/,*$%,/ 9/(5, )$ (% &%89(33()$#.
#/(')&$% (%5 ,)#2')2#(9 '"(%+/,: 6"&9/ '.)$4
U&%/, $8 )"/ >KB #/,*$%,/ (')&?()/ @ '/99, )"()
8$#3 (%)&7$5&/, (+(&%,) +9&(5&% (%5 (2)$(%)&4
7$5&/, (+(&%,) )#(%,+92)(3&%(,/ (%5 )"/ +9&(4
5&%X)#(%,+92)(3&%(,/ '$3*9/D; >"/ (2)$(%)&4
7$5&/, '$%)#&72)/ )$ ()#$*". ./) (#/ 5&#/')/5
(+(&%,) )#(%,+92)(3&%(,/ (%5 )"/#/8$#/ &%"&7&)
&), *$)/%)&()&%+ /88/');

4" 5$(++627. 8(.2-.2

>"&, 5&,/(,/ &, ( '"#$%&' &%8/')&$% 7. !"#$
%&'"()* +&,%%'-,: ( S#(34*$,&)&?/ (')&%$4
3.'/)/ )"() ,2#?&?/, &% )"/ *"(+$,$3/, $8
3('#$*"(+/, &% )"/ &%)/,)&%(9 89$#(; >"/ *()"$4
+/% &, "&,)$9$+&'(99. '"(#(')/#&T/5 (, ( G0I4*$4
,&)&?/ &%'92,&$% 7$5.; >"/ 3('#$*"(+/, ,6/99
(%5 79$'U )"/ 9.3*" 5#(&%(+/ '"(%%/9, 7/4
'(2,/ )"/. (''2329()/ &% )"/ 9.3*" ,*('/,
(%5 9.3*" %$5/,; >"&, *#/?/%), )"/ (7,$#*)&$%

"
$8 5&/)(#. 8(),: #/,29)&%+ &% 3(9(7,$#*)&$% (%5
,)/()$##"/(; I.,)/3&' 8/()2#/, &%'925/ (#)"#(94
+&( (%5 7#$6%&," ".*/#*&+3/%)()&$%; >"/ &34
32%/ 5/8/'), (#/ *#$7(79. ())#&72)(79/ )$ )"/
/88/'), $8 3(9(7,$#*)&$%; V"&**9/L, 5&,/(,/ &,
@AB )#/()/5 6&)" 5#2+, ,2'" (, )/)#('.'9&%/ $?/#
( */#&$5 $8 WXY 3$%)",;
 Vitamin B12 Chief cell
!*%&+$() ,-.*%(*(.C 5$(++627. 8(.2-.2C -'D E+%92

Pepsinogen
"
Auto- Maldigestion/
antibodies malabsorption
HCL Achlorhydria
Intrinsic factor Parietal cells
Intrinsic factor Vit. B12 deficiency
Chief cell
Posterior funiculi Pyra-
midal-
Parietal cell tract

Atrophic Fundus Pernicious anemia:

mucosa

Corpus

#6('()-6 =>>9'&6&?1
Hyperchromic, Hypersegmentarted
macrocytic anemia granulocytes Funicular myelosis

A. Chronic atrophic gastritis type A

Nutritional Macrophages with

fats PAS+ phagosomes Hyper-
pigmen- Fever of
tation unknown
origin

#
Arthritis

Heart
involvement

Intestinal Intestinal Lymph Blood

lumen epithelium lymphatic vessel
blockade
Steator- Mal-
rhea absorption Weight loss
Tropheryma whippeli Diarrhea Steatorrhea
B. Whipple’s disease

Gliadin from food

Transglutaminase Cross-linked gliadin

Normal intestinal TH2

IgA
mucosa

Celiac atrophy
C. Gluten-sensitive enteropathy
Fibroblasts
TNF-!

Mucosal transformation
and destruction
TH1 Autoantibodies

"
@AF

#
! 4-)2$%+'2,)2+'-0 *+),-),)

!" #$%&'() *+),-),

!"#$%&' ()'*+'* )' + ,$"#%), -"+%./#0+1#.' )%2
3/+00+1)#% 1$+1 ,+% )%4#/4* 1$* *%1)"* ()-*'2
()+""$*+ 8+''*( ;)1$ 5/##( #" 0.,.' +%(
'.8*"3),)+/ 0.,#'+/ ./,*"+1)#%'6 +%( ,#%1)%.2
#.'/7 '8"*+(' 3"#0 1$* "*,1.0 1# 1$* 0#"*
8"#M)0+/ "*-)#%' #3 1$* 5#;*/9 T/,*"+1)#% /*+('
1)4* 1"+,1 5.16 )% 0#'1 ,+'*'6 )%)1)+//7 8"*'*%1'
1# 3/+11*%)%- #3 1$* )%1*"'1)1)+/ 0.,#'+* 5*2
+' 1*"0)%+/ )/*)1)' #" "*-)#%+/ *%1*"#,#/)1)'9
1;**% 1$* /*')#%' +%( 1# (*8/*1)#% #3 -#5/*1
:$* )%3/+00+1)#% +33*,1' +// /+7*"' #3 1$* )%1*'12
,*//'9 D78*""*-*%*"+1)#% /*+(' 1# 1$* 3#"0+1)#%
)%+/ ;+//6 )' "*'1"),1*( 1# ()'<#)%1*( '*-0*%1' #3
#3 8'*.(#8#/78'9 F#.5/* ,#%1"+'1 *%*0+' #3
1$* 5#;*/ ='>)8 /*')#%'?6 +%( 1*%(' 1# 8"#(.,*
1$* ,#/#% "*4*+/ + /#'' #3 $+.'1"+ +%( +% +178)2
3)'1./+*6 +5',*''*'6 +%( 8*"3#"+1)#%9 :$* "+()2
,+/6 '*""+1*( 8+11*"%9 :$* 0#'1 (+%-*"#.' ,#02
#/#-),+/ +88*+"+%,* #3 1$* ()'*+'* )' ,$+"+,1*"2
8/),+1)#%' +"* 1#M), 0*-+,#/#% +%( ,#/#"*,1+/
)@*( 57 1$),>*%)%-6 '1*%#')'6 +%( 8##" 0#1)/)17
,+",)%#0+9 T/,*"+1)4* ,#/)1)' ,+% +/'# 0+%)3*'1
#3 1$* +33*,1*( 5#;*/ '*-0*%1 =-+"(*%2$#'*
)% *M1"+)%1*'1)%+/ ')1*'U .4*)1)' +%( +"1$")1)'
+88*+"+%,*?9 A%3/+00+1#"7 ,#%-/#0*"+1* 1.2
+"* 1;# #3 1$* 0+)% %#%)%1*'1)%+/ 0+%)3*'1+2
0#"' (*4*/#8 (.* 1# +5',*'' +%( 3)'1./+ 3#"0+2
1)#%'9 T/,*"+1)4* ,#/)1)' )' +/'# +''#,)+1*( ;)1$
1)#% )% +(<+,*%1 '1".,1."*' =5/+((*" #" '>)%?9
#0+'+1-0 5667'%0%89

A-B %*8$")1)'6 +.1#)00.%* $*8+1)1)'6 +%( 8")2

:$* 0#'1 ,#00#% ,#08/),+1)#%' #3 !"#$%&'
0+"7 5)/)+"7 ,)""$#')'9 :$* 0.,#'+ *M$)5)1'
()'*+'* +"* 1$*"*3#"* '1*%#')' +%( 5#;*/ #52
$)-$ /*4*/' #3 AE2J6 ;$),$ '.--*'1' )%,"*+'*(
'1".,1)#%6 0+/+5'#"81)#%6 +%( 3)'1./)@+1)#%9 B%
:DN +,1)4)179 A-R '.5,/+'' +%+/7'*' "*4*+/ $)-$
)%,"*+'*( 3"*C.*%,7 #3 ,#/#"*,1+/ ,+",)%#0+
/*4*/' #3 A-RH +%( A-RV9 :$* +(()1)#%+/ 8"*'*%,*
+%( +07/#)(#')' $+' +/'# 5**% #5'*"4*(9
#3 +%1)2%*.1"#8$)/ ,71#8/+'0), +%1)5#()*'
!"#$%&' ()'*+'* )' +''#,)+1*( ;)1$ DEB2FGH
=BQ!B? +%( 1$* +''#,)+1)#% ;)1$ ,*"1+)% +.1#2
+%( 2FI;J +%1)-*%'9 K+%7 #3 1$* 8+1)*%1'
)00.%* ()'*+'*' '.--*'1' 1$+1 ./,*"+1)4* ,#/)2
$+4* + $)'1#"7 #3 '0#>)%-6 + "*(.,*( %."')%-
1)' )' 8"#5+5/7 +% +.1#)00.%* ()'*+'* =!?9
8*")#(6 +%(L#" + $)-$ ()*1+"7 )%1+>* #3 "*3)%*(
B,.1* +11+,>' +"* 1"*+1*( ;)1$ './3+'+/+@)%*
,+"5#$7("+1*'9
+%( J2+0)%#'+/),7/+1* (".-'9 :$*'* (".-' )%2

"
:$* 0.,#'+/ /)%)%- #3 1$* )%1*'1)%* *M$)5)1'
$)5)1 1$* '7%1$*')' #3 8"#'1+-/+%()% +%( /*.>#2
$)-$ /*4*/' #3 AE2HN9 O$*% '1)0./+1*( 57 5+,2
1")*%*6 5.1 +' )% !"#$%&' ()'*+'*6 1$*7 )%1*"4*%*
1*")+6 AE2HN +//#;' %+)4* : ,*//' 1# ()33*"*%1)+1*
/+1* )% 1$* )%3/+00+1#"7 ,+',+(*9 S."-),+/ 0+%2
)%1# :DH ,*//'9 B,,#"()%-/76 1$* :DH +,1)4)17 )%
+-*0*%1 ,+% 5* +,$)*4*( ;)1$ 8"#,1#,#/*,12
1$* 0.,#'+ #3 1$*'* 8+1)*%1' )' $)-$6 +' (*1*"2
#079
0)%*( 5+'*( #% 1$* ,#%,*%1"+1)#% #3 APQ2!6
:QP2"6 +%( AE2N9 A-R '.5,/+'' +%+/7'*' "*4*+/
$)-$ /*4*/' #3 A-RN6 +% )00.%#-/#5./)% 1$+1
)' 8+"1),./+"/7 *33*,1)4* )% "*,#-%)@)%- 5+,1*")+/
,+"5#$7("+1* +%1)-*%'9 :$* 8+1$#-*%*1), 5+')'
3#" !"#$%&' ()'*+'* )' 1$*"*3#"* +''.0*( 1# 5*
+ $*)-$1*%*( )00.%* "*'8#%'* 1# *M#-*%#.'
+%1)-*%'6 '.,$ +' 3*,+/ +%1)-*%' =!?9
B,.1* +11+,>' +"* .'.+//7 1"*+1*( ;)1$ './3+'+2
/+@)%*6 J2+0)%#'+/),7/+1* (".-'6 +%(L#" '1*"#)('9
F.")%- "*0)'')#%'6 8+1)*%1' 0+7 "*,*)4* + 1")8/*
(".- ,#05)%+1)#% ,#%')'1)%- #3 +@+1$)#8")%*6
0*1$#1"*M+1*6 +%( ,7,/#'8#")% B9 A% "*3"+,1#"7
,+'*'6 :QP +%1+-#%)'1' +"* .'*(6 '.,$ +' )%3/)M)2
0+59 :# 8"*4*%1 ()'*+'* "*,.""*%,*6 1$* (".-'
'$#./( 5* ,#%1)%.*( )% /#;2(#'* "*-)0*%'9
S."-),+/ 0+%+-*0*%1 )' ,#%')(*"*( #%/7 )3 )1 )'
1# 5* 8*"3#"0*( +' 0)%)0+//7 )%4+')4* '."-*"7

!
:;<
3#" 1"*+10*%1 #3 ,#08/),+1)#%' #" )% ,+'*' "*2
3"+,1#"7 1# (".- 1$*"+879

." /01,$-2+3, #%0+2+)

T/,*"+1)4* ,#/)1)' =T!? )' + ,$"#%),6 "*/+8')%- +%(
"*0)11)%- ()'*+'* #3 1$* ,#/#%9 A1 8"*'*%1' ;)1$
 HLA-DR1 Shorter breast
#&$%'+1 5'=0-66-2%$9 .%>,0 *+),-),)

HLA-DR2 Primary
!
feeding period sclerosing
-DQw5 cholangitis
Assoc. with Refined Associated with Autoimmune
smoking carbohydrate IgA-nephritis hepatitis

Segmental Discontinuous continuous Ulcers

Transmural superficial

Fissural
Bladder fistula Diarrhea Pseudo-polyps Bloody
Inflammatory conglomerate tumor Flattening of mucosa mucous

#0+'+1-0 5667'%0%89
diarrhea
Typical sites of Typical Typical sites Typical
manifestation pattern of manifestation pattern
A. Crohn’s disease B. Ulcerative colitis

IgA switch IgG Chemotaxis

Activation of
complement
cascade

C3a

Chemotaxis
adhesion
C5a Granulocytes Eosinophils

Eicosanoids
Macrophages

Degranulation
"
molecules Sulfasalazine,
5-ASA, steroids

Leukotriene PGE2, PGF2, Histamine, serotonin, bradykinin

LTB4 thromboxane lysomal enzymes, O2 radicals

Vasodilation Lipid peroxidation

edema DNA damage
pain protease inhibitors

Invasion of foreign antigens Invasion of foreign antigens

Tissue damage
into intestinal lumen into intestinal lumen
C. inflammatory reactions in the intestinal wall

IL-12 T H1 IL-5 TH2

B
IgG2

D. Pathological mechanisms
IFN-!
IL-2
TNF-"

Crohn’s disease
IgG1

IgG3
ANCA

Ulcerative colitis
!
:;;

"
! :,-$0%&($)-$&(,2 ;&-),-)-

!" !#$%&''#() *)+,$&$&-

!"# #$%&'&() &* +,$&%--,.# "#/+$%$%0 %0 ,.1
2.&3.4 5#.6#7 + .,-8#9 &* 69%$#9%+ +9# 9#1
6',;# J+,.;%6#7 %$6"%.(7 02%. /%(-#.$+$%&.7
+.; "#/+$&8%'%+9) %.;%(#0$%&.4 !"# /9#0#.6#
&* #Y$9+"#/+$%6 -+.%*#0$+$%&.0 6"+9+6$#9%U#0
SOD +0 + -,'$%0)0$#- ;%0#+0#4 C. 0&-# 6+0#07
:,%9#; *&9 $"# ;%+(.&0%04 !"# ;%0#+0# &66,90
$"# #Y&69%.# /+.69#+07 '+69%-+' ('+.;07 +.; 0+'%1
/9#;&-%.+.$') %. 3&-#. +.; %0 +00&6%+$#;
B+9) ('+.;0 +9# +'0& +**#6$#; M;9) ('+.; ;%01
3%$" 5<=1>?@ +.; 1>?A +.$%(#.04 !"# "%0$&1
#+0#N4 S9%-+9) 8%'%+9) 6%99"&0%0 %0 +00&6%+$#;
'&(%6+' /%6$,9# %0 $"+$ &* 6"9&.%6 "#/+$%$%07 +.;
3%$" IJ&K(9#.E0 0).;9&-# %. FG H &* 6+0#07 +.;
0#9&'&(%6+' $#0$0 9#B#+' ")/#9(+--+('&8,'%.#1
%0 +'0& +00&6%+$#; 3%$" &$"#9 +,$&%--,.# ;%01
-%+4 C--,.&0,//9#00%B# $"#9+/) '#+;0 $& %-1
#+0#04 =.$%1-%$&6"&.;9%+' +.$%8&;%#0 M=Q=N
/9&B#-#.$ &* $"# 0)-/$&-04 =,$&%--,.#
6+. 8# ;#$#6$#; %. $"# 0#9,-4 =Q= +9# /9%-+91
"#/+$%$%0 %0 &*$#. +00&6%+$#; 3%$" &$"#9 +,$&%-1
%') ;%9#6$#; +(+%.0$ $"# X[ 0,8,.%$ &* /)9,B+$#
-,.# ;%0#+0#07 0,6" +0 9"#,-+$&%; +9$"9%$%07
;#");9&(#.+0# 6&-/'#Y#04 !"#%9 9&'# %. $"#
('&-#9,'&.#/"9%$%07 ,'6#9+$%B# 6&'%$%07 D9&".E0
/+$"&(#.#0%0 &* SOD %0 ,.6'#+94 Z.# ")/&$"#0%0
;%0#+0#7 +.; 5+0"%-&$&E0 ;%0#+0#4 C. FGH &*
0,((#0$0 8+6$#9%+' %.;,6$%&.4 =$$#-/$0 +$ %-1
6+0#07 $"#9# +9# 6'%.%6+' 0%(.0 &* B+06,'%$%07 69)&1
32&(&8,2 <''#(%2%91

-,.&0,//9#00%B# $"#9+/) +9# ,0,+'') 3%$"&,$

('&8,'%.#-%+7 +.; IJ&K(9#.E0 0).;9&-#4 L#.#9+'
0%(.0 &* '%B#9 ;+-+(#7 0,6" +0 J+,.;%6#7 %$6"%.(7
.+,0#+7 ;%+99"#+7 *#B#97 +.; "#/+$&0/'#.&-#1
(+')7 6+. +'0& 8# &80#9B#;4 !9+.0+-%.+0# '#B#'0
M=I! +.; =<!N +9# %.69#+0#;7 +.; 0%(.0 &* 6"&1
'#0$+0%0 6+. 8# &80#9B#;4
O) %--,.&'&(%6+' ;#*%.%$%&.7 $"%0 ;%0#+0#
9#/9#0#.$0 +. +,$&%--,.# 9#0/&.0# $& '%B#9
$%00,# 0$9,6$,9#04 !"# /+$"&(#.#$%6 9&'# &* $"#
+,$&+.$%8&;%#0 %.B&'B#; %. $"# /9&6#00 %0 0$%''
0,66#004
3" /0&',01 782)0%-&(9 34%2,(9&$&- 5/736
S9%-+9) 06'#9&0%.( 6"&'+.(%$%0 %0 + 6"9&.%6 *%1
89&$%6 %.*'+--+$%&. &* $"# %.$9+"#/+$%6 +.;
#Y$9+"#/+$%6 8%'# ;,6$04 W+'' $"%62#.%.( +.;
0$#.&0%0 ,'$%-+$#') '#+; $& 6"&'#0$+0%04 SID %0
-&9# 6&--&. %. -#. +.; %0 +00&6%+$#; 3%$"
5<=1O\ +.; 1>?@ +.$%(#.04 D&.6&-%$+.$ ,'1

"
,.6'#+94 !"# +.$%8&;%#0 ;%9#6$#; +(+%.0$ 0$9,61 6#9+$%B# 6&'%$%0 %0 /9#0#.$ %. FG H &* $"# /+$%#.$04
$,9+' /9&$#%.0 +9# 6+''#; '%B#912%;.#) -%69&1 !"# ;%+(.&0%0 %0 #0$+8'%0"#; 8) ;#-&.0$9+$%.(
0&-+' +.$%8&;%#0 M<PQN4 <PQ1R $+9(#$0 6)$&1 $"# /9#0#.6# &* =]D= +.; 8%'# ;,6$ 6"+.(#04
6"9&-# SAFGCC>T7 +. #.U)-# $"+$ -#$+8&'%U#0 =0 %. /9%-+9) 8%'%+9) 6%99"&0%07 $9#+$-#.$ %0
6#9$+%. ;9,(0 M#4(47 8#$+18'&62#907 +.$%+99")$"-%6 0)-/$&-+$%64
;9,(07 +.; +.$%;#/9#00+.$0N4 <PQ1R &*$#. &66,90
%. +00&6%+$%&. 3%$" 5DV+.$%8&;%#04 !"%0 0,((#0$0
$"+$ +,$&%--,.# "#/+$%$%0 %0 + ;%0#+0# &9%(%.+'')
%.;,6#; 8) "#/+$&$9&/%6 B%9,0#04
!"# ;%+(.&0%0 6+. 8# #0$+8'%0"#; 8) ;#-&.1
0$9+$%.( $"# /9#0#.6# &* $"# +,$&+.$%8&;%#04 V%91
+' "#/+$%$%07 '%B#9 ;+-+(# ;,# $& &$"#9 6+,0#07
0,6" +0 ;9,(0 +.; +'6&"&'7 &9 (#.#$%6 #.U)-#
;#*#6$0 M#4(47 !R1+.$%$9)/0%. ;#*%6%#.6)7 W%'0&.E0
;%0#+0#N -,0$ +'3+)0 8# 6&.0%;#9#; %. $"# ;%*1
*#9#.$%+' ;%+(.&0%04 5<= $)/%.( 0"&,'; +'3+)0
8# /#9*&9-#;4 C--,.&0,//9#00%B# $9#+$-#.$
6&.0%0$0 &* /9#;.%0&'&.# +'&.# &9 %. 6&-8%.+1
$%&. 3%$" +U+$"%&/9%.#4

." /0&',01 .&2&,01 3&004%-&- 5/.36

S9%-+9) 8%'%+9) 6%99"&0%07 &9 .&./,9,'#.$7 ;#1

!
0$9,6$%B# 6"&'+.(%$%07 %0 +. %.*'+--+$&9) ;%01
#+0# &* $"# -%.&9 %.$9+"#/+$%6 ;,6$0 $"+$
-+%.') +**'%6$0 3&-#. AG )#+90 &* +(# &9 &';#94
C. +;;%$%&. $& 0%(.0 &* 6"&'#0$+0%07 "%(" '#B#'0 &*
0#9,- 6"&'#0$#9&' 6+. +'0& 8# *&,.;4 X'#B+$#;
=>= 6"&'#0$#9&' '#B#'0 6+. /9&B&2# $"# *&9-+$%&.
&* 6,$+.#&,0 Y+.$"&-+4 Z$"#9 0)-/$&-0 %.1
Criteria [ ] :
!#$%&''#() ?&@)0 ;&-),-)-

Periportal field
with
!
HLA-DR3, -DR4 artery,
periportal vein,
Associated with and bile duct
rheumatoid arthritis, Central vein
glomerulonephritis, ulcerative Lymphocyte
colitis, Crohn’s disease infiltration
Hashimoto’s disease Lobe of liver Histology:
chronic
Clinical findings: Lab. findings: hepatitis
Jaundice Fever Hypergamma- Inflammatory infiltrates in
globulinemia periportal field
Sjögren’s
syndrome Vasculitis
Transaminases GOT, GPT

32&(&8,2 <''#(%2%91
cholestase: bilirubin, !-GT, AP
Hepato-
Itching spleno- Autoantibodies
megaly
LKM 1 cytochrome P450 IID6, in autoimmune hepatitis
Nausea LKM 2 cytochrome P450 II C9, in drug-induced hepatitis
Cryo-
globulin- LKM 3 UDP-glucuronyltransferase in chron. hepatitis D
emia
ANA
Diarrhea
Ab asialoglycoprotein receptor, smooth muscles
A. Autoimmune hepatitis

Hepatocytes
Bile duct

Lymphocyte
infiltration
"
> 40 years
Micronodular
cirrhosis
Associated with Symptoms: Cholestase,
Sjögren’s syndrome melanin maldigestion
(50%), scleroderma,
CREST, rheuma- Hyper- Jaundice bilirubin , !-GT , AMA
toid arthritis, pigmen- alkaline (antimito-
Hashimoto’s tation of the phosphatase chondrial
thyroiditis skin autoanti-
Xanthomas serum cholesterol
B. Primary biliary cirrhosis bodies)

Cholestasis, malabsorption
bilirubin , !-GT , AP

> 40 years
Associated with HLA-B8, DR3
ulcerative colitis in 50%

C. Primary sclerosing cholangitis

Thickening
and stenosis of
bile ducts
ANCA
!
=>A

"
! 8$,-'*3&.*9 6',$3,$,

!" #$%$&'( )*$+',-.,'&'.%

!"#$%&'() (*+&,( '* ( %&"#$'% -'*.(*. %&("(%+."/
'0.- 12 '$+.",'++.$+3 '$'+'())2 ".4."*'1). #1/
6(%+#" ?R;W@ (". ".).(*.-: K&. 1"#$%&#%#$*+"'%/
+'4. (*+&,(+'% ".*9#$*. #%%5"* '$ +7# 9&(*.*:
K&. )5$8 65$%+'#$ "(9'-)2 -.%".(*.* 7'+&'$
+&. 6'"*+ JMZPM ,'$5+.* ($- 8"(-5())2 ".%#4."*
*+"5%+'#$ #6 +&. ('"7(2*3 '$6)(,,(+#"2 %&($8.*3
-5"'$8 +&. $.>+ +7# &#5"*: K&'* <.(")2 "./
($- 1"#$%&'() &29."".*9#$*'4.$.**: ;* #9/
*9#$*.= '$4#)4.* &'*+(,'$.3 9"#*+(8)($-'$/TP
9#*.- +# <'$+"'$*'%= #" $#$())."8'% (*+&,(3 <.>/
?R[TP@3 %2*+.'$2)/).5Q#+"'.$.* ?EKSF3 EKTF3 EKBF@3
+"'$*'%= ())."8'% ?(+#9'%@ (*+&,( '* %&("(%+."'0.-
($- R;W: K&. %2*+.'$2)/).5%#+"'.$.* '$-5%. "./
12 .).4(+.- *."5, A8B %#$%.$+"(+'#$* ($- (**#/
).(*. #6 9"#+.(*.*\ +"29+(*. %).(4.* TI( ($-
%'(+'#$ 7'+& #+&." ())."8'% ,($'6.*+(+'#$* '$ +&.
1"(-2Q'$'$ 6"#, 9"#+.'$ 9".%5"*#" ,#).%5).*3
9(+'.$+ ($- '$ +&. 9(+'.$+C* 6(,')2: D#7.4."3 +&.
7&'%& ).(-* +# 1"#$%&'() ,5*%). %.)) %#$+"(%/
-'66.".$+'(+'#$ 1.+7..$ +&. +7# '* *%&.,(+'%3 (*
+'#$ ($- '$%".(*.- 4(*%5)(" 9.",.(1')'+2: S&2/
*#,. #6 +&. %)'$'%() ($- 9(+&#8.$.+'% 6.(+5".*
,(*.3 #$ +&. #+&." &($-3 9"#,#+.* ,5%5* *./
#6 +&. .$+'+'.* #4.")(9:
%".+'#$: K&. '$-5%+'#$ #6 1"#$%&#%#$*+"'%+'#$
!"#$%&'() &29."".*9#$*'4.$.** ($- +&. +.$/
7'+& ,5%#*() .-.,( ($- ,5%5* *.%".+'#$ "./
-.$%2 +# '$%".(*.- AE/F/-.9.$-.$+ A8B 9"#-5%/
47'%'(37 :;;<%.7.19

*5)+* '$ %#58&'$83 7&..0'$83 ($- 1".(+&).**/

+'#$ (". %#,,#$)2 '$&."'+.- +&"#58& 8.$.* #$
%&"#,#*#,. GHIJ/HII: K&. '$%'-.$%. '* %(: G L
'$ (-5)+* ($- %(: JM L '$ %&')-".$: ;+#9'% (*+&,(
'* 12 6(" +&. ,#*+ %#,,#$ 6#",:
/" 0*'11$* 23(&.*,
;+#9'% ?.>+"'$*'%@ (*+&,( %($ 1. '$-5%.- 12 ($/
',() &('"3 -5*+ ,'+.*3 6.(+&."*3 9#)).$3 ($- ,#)-:
A$ '$+"'$*'% (*+&,(3 #$ +&. #+&." &($-3 +&.
1"#$%&'() &29."".(%+'4'+2 '* %(5*.- 12 +&. '$&(/
$.**: K&. <)(+. ".(%+'#$= ?#@ 1.8'$* FZ] &#5"*
)(+.": EK!F ($- R;W (++"(%+ .#*'$#9&')*: K&.23
'$ +5"$3 (++"(%+ ,(^#" 1(*'% 9"#+.'$ ?_!R@ ($-
.#*'$#9&') %(+'#$'% 9"#+.'$ ?BSR@3 7&'%& &(4.
( +#>'% .66.%+ #$ .9'+&.)'() %.))*: B9'+&.)'() -./
*+"5%+'#$ #%%5"* '$ +&. )(+. *+(8.*: K&'* 5)+'/
,(+.)2 ).(-* +# +&. (%%5,5)(+'#$ #6 ,5%5* '$
+&. 1"#$%&'() )5,.$ -5. +# +&. '$%".(*.- $5,/
1." #6 8#1).+ %.))* ($- &29."+"#9&2 #6 +&.
*51,5%#*() ,5%#5* 8)($-*: D29."+"#9&2 #6

" )(+'#$ #6 %&.,'%()*3 *5%& (* *5)65" -'#>'-. ?NOP@3

#0#$. ?OI@3 ($- %'8(".++. *,#Q. (* 7.)) (* 4'"()
'$6.%+'#$*3 %#)- ('"3 .>."%'*.3 ($- *+".**: ;$()8./
*'%*3 '$%)5-'$8 (*9'"'$3 %($ ()*# %(5*. ($ (*+&,(
(++(%Q:
*,##+& ,5*%). '$ +&. 1(*.,.$+ ,.,1"($.
%($ ()*# 1. #1*."4.-: N'$%. ,($2 #6 +&. .66.%+*
-.*%"'1.- (". '$-5%.- 12 AE/JI 4'( NK;K ]
*'8$()'$83 9&(",(%#)#8'%() 1)#%Q(-. '* 1.'$8
+.*+.- 6#" +&."(9.5+'% 5*.:

4" )3&5.1$%$,', 6" !77$*1'( 85'%'&',

N.$*'+'0(+'#$ +# +&. ())."8.$* ,(2 #%%5" '$ .(")2
%&')-&##- ?!@: ;$+'8.$/9".*.$+'$8 %.))* ?;RS*@
'$ +&. 1"#$%&'() ,5%#*(. %(9+5". +&. '$&().-
())."8.$* ($- 9".*.$+ +&., +# STFU K %.))*3
7&'%& +&.$ -'66.".$+'(+. '$+# K %.))* #6 +&.
KDP 9&.$#+29.: K&.*. %.))* *.%".+. AE/F3 AE/G3
AE/V3 AE/JM3 ($- AE/JI3 7&'%& 9"#,#+. ( *7'+%&
'$ !/)2,9&#%2+. ',,5$#8)#15)'$ *.%".+'#$3
'$-5%'$8 +&., +# 9"#-5%. A8B: A$ (--'+'#$3
AE/JI ()*# '$-5%.* (%+'4(+'#$ #6 .#*'$#9&')'%
($- 1(*#9&')'% 8"($5)#%2+.*3 (* 7.)) (* ".).(*.
#6 %&.,#Q'$.* ($- 9"#+.#)2+'% .$02,.*3 *5%&
(* ,.+())#9"#+.'$(*.*: K&. A8B ,#).%5).* %'"%5/
)(+.3 ($- +&.$ 1'$- +# &'8&/(66'$'+2 ".%.9+#"*
?W%!XA@ #$ ,(*+ %.))* ($- 1(*#9&')* ($- +#
;))."8'% "&'$'+'* '* +"'88.".- 12 %#$+(%+ #6 ())."/
8.$* 7'+& +&. $(*() ,5%#*(: K&'* ".(%+'#$ ()*#
',9)'.* 9"'#" *.$*'+'0(+'#$ 1.%(5*. +&. ())."/
8.$* 1'$- +# *.$*'+'0.- A8B/1.("'$8 ,(*+ %.))*:
N$..0'$8 ($- ,5%5* *.%".+'#$ ?"&'$#""&.(@ %($
#%%5" 7'+&'$ (* )'++). (* IMZ]M *.%#$-* (6+." '$/
&()(+'#$ #6 +&. ())."8.$: T5. +# ( %.$+"() ".6).>3
+&. &29."*.%".+'#$ #%%5"* $#+ #$)2 #$ +&. .>/
9#*.- *'-.3 15+ ()*# '$ +&. %#$+"()(+."() $#*+"'):
K&. ())."8.$* %($ 1. -.+.",'$.- 12 9"'%Q +.*+/
'$83 7&'%& '$4#)4.* '$+"(-.",() '$^.%+'#$ #6 +&.
-'**#)4.- ($+'8.$*: A$ 9#*'+'4. ".(%+'#$*3 7&.()*
6#", 7'+& ".--.$'$8 #6 +&. *5""#5$-'$8 +'**5.
7'+&'$ JGZIM ,'$5+.*:

!
)#7/(66'$'+2 ".%.9+#"* ?W%!XA3 STPI@ #$ .#*'$#/
9&')* ($- ,(%"#9&(8.*: Y&.$ "..>9#*5".
#%%5"* ?"@3 +&. ())."8.$ %($ "(9'-)2 '$+."(%+
7'+& +&. A8B ,#).%5).* +&(+ (". ()".(-2 1#5$-
+# +&. %.)) *5"6(%.: D'*+(,'$.3 9"#+.(*.*3 ).5Q#/
=>? +"'.$.3 9"#*+(8)($-'$*3 ($- 9)(+.).+/(%+'4(+'$8
 Bronchial
/*.%(5'37 !,&5;3 3%+ !77$*1'( 85'%'&',

House mite
!
hyper- Pollen
reactivity
Animal hair
Chromosome 5

Animal dung SO2

Feathers O3
Mold Cold air

Increased Nicotine Stress

IgE- Drugs Physical
R
synthesis Chemicals activity
A. Genetic predisposition B. Trigger factors

APC Reexposure

47'%'(37 :;;<%.7.19
Mucus

T cell
MBP
Proteases ECP
PAF
IL-4 histamine
IL-10 leukotrienes

"
TH2

IL-4 IL-13
IL-6

IgE-
Smooth muscle contraction
synthesis
Glands
Mast cell

1. Sensitization 2. Reexposure, early reaction 3. Late reaction

C. Pathogenesis

Grass
IgE-loaded
Grains basophils

Alder
Hazel
Birch -Sneezing Nasal
-Rhinorrhea allergen
Mold Histamine -Contralateral exposure
-hypersecretion

!
Mites
Animal allergens
Occupational allergens Edema of mucosal epithelium Prick test

D. Allergic rhinitis
=>@

"
! 89*-(%$.'%5 :(*9$*9*
!" #$%&'()'*(*
!"#$%&'%(&( &( " )*+,&(-(,.) '&(."(. $/"#"$,.#0
&1.' 2- ,/. 3#.(.4$. %5 4%4$"(.",&46 6#"4*+%0
)"( &4 )*+,&3+. %#6"4(7 8/. ,#&66.# 5"$,%# &(
3#.(*).' ,% 2. ,/. &4/"+",&%4 %5 " -., *4&'.40
,&5&.' "4,&6.4 9!:7 ;4,&6.403#.(.4,&46 $.++( #.0
+."(. <=0>? <=0>@? <AB0!? "4' 8AB0"7 8/.- #.$#*&,
"$,&C",.' 8D > EFG 8 $.++(? H/&$/ +."'( ,% "4
%+&6%$+%4"+ 80$.++ "+C.%+&,&(7 A*#,/.# #.+."(. %5
)%4%$-,. $/.)%",,#"$,"4, 3#%,.&40> 9IEJ0>:?
)%4%$-,. &45+"))",%#- 3#%,.&4 >" 9I<J0>":?
EKE=>L? "4' <=0>M &4'*$.( )&6#",&%4 %5 )%4%0
$-,.( "4' 80$.++ 3#%+&5.#",&%47 8/. )%4%$-,.(
3#%'*$. 5&2#&4? 5&2#%4.$,&4? 8NA0#? <=0O? <AB0!?
"4' 8BA0" "4' ,/.4 ,#"4(5%#) &4,% .3&,/.+&%&'
;2(4(&$2 ,3314'2'<5
$.++(7 !%). %5 ,/.) $%"+.($. ,% 5%#) )*+,&0
4*$+.",. 6&"4, $.++( "4' 5%#) 4%4$"(.",&46
94%44.$#%,&$: .3&,/.+&%&' $.++ 6#"4*+%)"(7 <=0G
"4' <=0M +."' ,% 3%+-$+%4"+ P $.++ (,&)*+",&%4?
H/&$/ &( #.5+.$,.' "( /-3.#6"))"6+%2*+&4.)&"7
<4 )"4- $"(.(? ,/. '&(."(. &( &4$&'.4,"++-
'&($%C.#.' '*. ,% ,/. 3#.(.4$. %5 2&+",.#"+
.4+"#6.).4, %5 ,/. ).'&"(,&4"+ +-)3/ 4%'.(
92&+",.#"+ /&+"# +-)3/"'.4%3",/-: &4 $/.(,
#"'&%6#")( 9":7 ;4 "$*,. 5%#) %5 ,/. '&(."(.
"
9=%.56#.4Q( (-4'#%).: &( $/"#"$,.#&1.' 2- 2&0
+",.#"+ /&+"# +-)3/"'.4%3",/-? 5.C.#? .#-,/.)"
4%'%(*)? "4' "$*,. "#,/#&,&(? 3"#,&$*+"#+- %5
,/. R4.. "4' ,/. "4R+. 9#:7 P#%4$/%"+C.%+"#
+"C"6. 9P;=: ,-3&$"++- #.C."+( ,/. 3#.(.4$. %5
EFGS 80$.++ "+C.%+&,&( 9$:7 8/. P;= 5+*&' %5,.4
$%4,"&4( *3 ,% >L ,&).( "( )"4- EFGS 8 +-)0
3/%$-,.( "( ,/. 3.#&3/.#"+ 2+%%' 2.$"*(. +-)0
3/%$-,.( "#. #.$#*&,.' 5#%) ,/. 3.#&3/.#"+
2+%%' "4' ,/. (R&4 9"4.#6- ,% (R&4 "4,&6.4(:
&4,% ,/. +*467 <4 4%#)"+ &4'&C&'*"+(? )%#.
,/"4 TL U %5 ,/. $.++( &4 ,/. P;= 5+*&' "#. )"$#%0
3/"6.(? "4' 5.H.# ,/"4 >!>LM +-)3/%$-,.( "#.
#.$%C.#.'V &4 ("#$%&'%(&(? ,.4 %# ,H.4,- ,&).(
)%#. +-)3/%$-,.( "#. ,-3&$"++- #.$%C.#.'7 ;
'.$#."(. &4 ,/. EFGWEFX #",&% &4 3.#&3/.#"+
2+%%' &( "+(% %2(.#C.'7 A.C.# "4' )"+"&(. '.C.+0
%3 '*. ,% &4$#."(.' +.C.+( %5 8BA? <=0>? "4' <=0M
&4 (.#*)7
Y#-,/.)" 4%'%(*)? " 4%46#"4*+%)",%*(
&45+"))",&%4 %5 ,/. (*2$*,"4.%*( ,&((*.? &(
,/. )%(, $%))%4 (R&4 +.(&%47 Y-. &4C%+C.).4,
&( $%))%4 "4' )"- #"46. 5#%) " /"#)+.((
!
=>?
$%4Z*4$,&C"+ 4%'*+. ,% 2+&4'4.(( "( " $%)3+&$"0
,&%4 %5 &4,.#).'&",. "4' 3%(,.#&%# *C.&,&( 9(..
337 [GG? [GM:7 N#"4*+%)",%*( ).4&46&,&( &( "
3%((&2+. )"4&5.(,",&%4 %5 4.*#%("#$%&'%(&(7 <40
$#."(.' &4,.(,&4"+ "2(%#3,&%4 %5 $"+$&*) %$$*#(
2.$"*(. ,/. )"$#%3/"6.( &4 ,/. 6#"4*+%)"(
$%4C.#, [@0/-'#%\-C&,")&4 F ,% >?[@0/-'#%\-0
C&,")&4 F7 ](,.%+-,&$ 2%4. +.(&%4( #"C.+- $%4,#&0
2*,. ,% /-3.#$"+$.)&" "4' /-3.#$"+$&*#&"7 ^.40
,#&$*+"# ,"$/-$"#'&" )"- %$$*# '*. ,% ,/.
3#.(.4$. %5 6#"4*+%)"( &4 )-%$"#'&"+ ,&((*.7
!)"++ 3.#&3%#,"+ 6#"4*+%)"( %# 8 $.++ &45&+,#",.(
.\/&2&,&46 C"#&%*( '.6#..( %5 5&2#%(&( "#. %5,.4
5%*4' &4 ,/. +&C.# 9%:7 8/. '.C.+%3).4, %5
(3+.4&$ 6#"4*+%)"( $"4 $"*(. (3+.4%).6"+-7
8/. $%4$.4,#",&%4 %5 "46&%,.4(&40$%4C.#,&46
.41-). 9;EY: &4 ,/. (.#*) &4$#."(.( '*. ,%
,/. (-4,/.(&( 2- 6#"4*+%)" ,&((*.7
+" ,)('-$./(& 0123'4$%5 6(7%'*(*
J*+)%4"#- 5&2#%(&( )"- %$$*# &4 " 4*)2.# %5
'&(."(.(7 D.4$.? &'&%3",/&$ 3*+)%4"#- 5&2#%(&(
9<JA:? %# $#-3,%6.4&$ 5&2#%(&46 "+C.%+&,&(? &( "
'&"64%(&( %5 .\$+*(&%47 ;$,&C",&%4 %5 ,/. "+C.%+"#
)"$#%3/"6.( 3#.(*)"2+- %$$*#( &4 &4'&C&'*"+(
H&,/ " 6.4.,&$ 3#.'&(3%(&,&%4 "5,.# $%4,"$, H&,/
" -., *4R4%H4 3",/%6.47 ^&#*(.( %# &))*4.
$%)3+.\.( "#. ,/%*6/, ,% 2. #.(3%4(&2+.7
80$.++ $-,%R&4.( )"- "+(% 2. &4C%+C.' &4 ,/.
"$,&C",&%4 3#%$.((7 ;+C.%+"# )"$#%3/"6.( (.0
$#.,. <=0X "4' +.*R%,#&.4.(? H/&$/ #.$#*&, "4'
"$,&C",. 4.*,#%3/&+ 6#"4*+%$-,.(7 N#"4*+%$-,&$
"+C.%+&,&( &( " ,-3&$"+ 5.",*#. %5 &'&%3",/&$ 3*+0
)%4"#- 5&2#%(&(? H/.#."( +-)3/%$-,&$ "+C.%+&0
,&( %$$*#( &4 ("#$%&'%(&(7 8/. "+C.%+"# )"$#%0
3/"6.( "+(% (.$#.,. 5&2#%2+"(, 6#%H,/ 5"$,%#(?
(*$/ "( 8NA0#? &4(*+&4.0+&R. 6#%H,/ 9<NA0>:?
"4' 3+",.+.,0'.#&C.' 6#%H,/ 5"$,%# 9JFNA:7 ]\&0
'",&C. 3#%$.((.( .4"2+. ,/. "+C.%+"# )"$#%0
3/"6.( "4' 4.*,#%3/&+( ,% '.(,#%- ,-3. < 34.*0
)%$-,.(7 8/&( &4'*$.( " $%)3.4(",%#- &4$#."(.
&4 ,/. 4*)2.# %5 ,-3. << 34.*)%$-,.(? H/&$/
3#%'*$. $/.)%,"$,&$ "4' 5&2#%6.4&$ 5"$,%#(7 Y\0
,#"$.++*+"# )",#&\ '.3%(&,&%4 %$$*#(7 8/&( *+,&0
)",.+- +."'( ,% ,/. '.C.+%3).4, %5 5&2#%,&$ $&0
$",#&$&"+ $/"46.(? H/&$/ 3#%'*$. $/"#"$,.#&(,&$
#"'&%+%6&$"+ "4' /&(,%+%6&$"+ 3",,.#4( 9/%4.-0
$%)2 +*46:7 E%#,&$%(,.#%&'( /"C. 2..4 *(.' ,%
,#.", ,/&( '&(."(.? "+,/%*6/ 5#._*.4,+- H&,/ '&(0
"33%&4,&46 #.(*+,(7 <4,.#5.#%40! ,%6.,/.# H&,/
$%#,&$%(,.#%&'( )"- +."' ,% $+&4&$"+ &)3#%C.0
).4,7
 Unknown
#$%&'()'*(* $4) ,)('-$./(& 0123'4$%5 6(7%'*(*
!
pathogen

Monocytes Hematogenic
Mycobacteria? chemotaxis, spread??
Viruses? activation

Alveolus

Inhalation Lymphocytic (CD4) Noncaseating

of pathogens alveolitis granuloma
1. Pathogenic model

Fever, CNS involvement

general Uveitis

;2(4(&$2 ,3314'2'<5
symptoms
Neuropathy
Calcium Parotitis
ACE
neopterin Mediastinal
lymphadenopathy 3. BAL
CD4/CD8 Lung involvement 90%
ratio
"-globulins Cardiac involvement
Liver infiltration Spleen infiltration
Skin lesions
Loefgren’s
syndrome:
fever,
polyarthritis,
erythema
Bone lesions
4. Chest radiograph
"
nodosum,
biliary Arthritis
lymphadeno-
pathy
Erythema
2. Clinical manifestations nodosum
A. Sarcoidosis 5. T-cell infiltrate in the liver

Monocyte Interstitial
chemotaxis and infiltration,
R
activation fibrosis
IGF-1
Inhaled PDGF
noxae TGF-! Type I

Granulo-
cytic Pulmonary fibrosis
Immune alveolitis
Alveolar
complexes
macrophage

!
Type II
pneu-
mocy-
IL-8, tes
T cells leuko- Granulocyte
trienes chemotaxis
B. Idiopathic pulmonary fibrosis Honeycomb lung
=>@

"
! 0,)1'&2%/&3 4'),2),)
!" #$%&'()'* !++,&-'* !+.,/+'%')
! "#$% &#''#( &)*(*&+) $,(-.#'/$0 !"#$%&'
(%) *++,$-%) *+.,/+%#%( 0!1123 /$ 456,$(,&(%#%.'
%#5 6&,78/&%#%(3 %( )*7(,9 :5 (,&(%#%;*#%/&
</++/=,9 :5 (,)/&9*$5 ,"6/(7$, #/ %&4*+,9
*&#%-,&(> ?4, )*7(*#%., *&#%-,&( 8%-$*#, #/'
-,#4,$ =%#4 97(# 6*$#%)+,( %&#/ #4, *+.,/+%3
=4,$, #4,5 #$%--,$ * +/)*+ %887&, $,(6/&(,>
?4, *++,$-,&( 8*5 /$%-%&*#, <$/8 :*)#,$%*3
<7&-%3 )4,8%)*+(3 *&%8*+ 6$/97)#(3 /$ 6+*&#
6$/97)#(> ?4, $,(7+#%&- 456,$(,&(%#%.%#5 $,'
*)#%/& 6$/97),( * 7&%</$8 )+%&%)*+ 6%)#7$,3
$,-*$9+,(( /< =4%)4 #56, /< *&#%-,& )*7(,9
%#> @4,& :*)#,$%* *&9 <7&-% *$, %&./+.,93
#4,5 9/ &/# *)# %&.*(%.,+53 :7# *( *&#%-,&(>
5+'('*2+ 6778(/+/-3
A/$, #4*& BC 9%<<,$,&# /))76*#%/&*+ *&9
,&.%$/&8,&#*+ .*$%,#%,( 4*., :,,& 9,'
()$%:,93 *&9 8*&5 /< #4, &*8,( $,<+,)# #4,
8/9, /< ,"6/(7$,> D*$8,$E( +7&-3 </$ ,"*8'
6+,3 %( )*7(,9 :5 #4,$8/64%+%) *)#%&/85),#,(
</7&9 %& 8/+95 4*5> F/86/(# +7&- %( )*7(,9
:5 <7&-% 0,>->3 !"#$%&'(()"2 #4*# #4$%., %& )/8'
6/(#> 1%$ )/&9%#%/&,$(3 $//8 478%9%<%,$(3
=4%$+6//+(3 *&9 (*7&*( 6$/.%9, %9,*+ -$/=#4
)/&9%#%/&( </$ #4,$8/64%+%) *)#%&/85),#,(3
"
*($+"'$((,3 *8,:*,3 -,./'/,3 *&9 !)%$01
+,"'/')2> G%$9 :$,,9,$E( +7&- %( /:(,$.,9
%& %&9%.%97*+( ,"6/(,9 #/ #4, ,")$,8,&# /<
6%-,/&( *&9 /#4,$ :%$9(> H(/)5*&*#,( *&9
*&459$%9,( *$, #4, 8*%& )4,8%)*+( %&./+.,9
%& #4, 9,.,+/68,&# /< )4,8%)*+ =/$I,$E(
+7&-> ?4,(, )4,8%)*+( *$, 7(,9 #/ 6$/97),
6+*(#%)(3 6*%&#(3 *&9 6/+57$,#4*&, </*8> J,'
(6%#, #4, ,#%/+/-%)*+ .*$%,#53 #4, 7&9,$+5%&-
6*#4/-,&,#%) 8,)4*&%(8 *&9 )+%&%)*+ )/7$(,
/< #4,(, 9%<<,$,&# </$8( /< #4, 9%(,*(, *$,
7&%</$8>
1 2''3(#)#4*&+) 5+%6#4/(/$*$0 ?4, %&4*+,9
6*$#%)+,( )*& %&97), #4, </$8*#%/& /< 6$,)%'
6%#*#%&- H-K *&#%:/9%,(3 =4%)4 </$8 )/86+,'
8,&#'*)#%.*#%&- %887&, )/86+,",(> F/8'
6+,8,&# *)#%.*#%/& )*& *+(/ /))7$ %& #4,
*:(,&), /< *&#%:/9%,( :,)*7(, #4, %&4*+,9
97(# )*& 9%$,)#+5 *)#%.*#, #4, *+#,$&*#%.,
)/86+,8,&# 6*#4=*5> ?4, )/86+,8,&# 6$/'
97)#( 4*., * )4,8/#*)#%) ,<<,)# /& &,7'
#$/64%+ -$*&7+/)5#,(3 =4%)4 *$, #4,$,</$,
$,)$7%#,9 %&#/ #4, *+.,/+%> 1)#%.*#,9 8*)$/'
!
64*-,( *+(/ $,+,*(, .*$%/7( 8/&/I%&,(> H&'
#,$+,7I%&'L3 </$ ,"*86+,3 *86+%<%,( -$*&7+/'
)5#%) )4,8/#*"%(> 1( * $,(7+#3 ,"#,&(%.,
-$*&7+/)5#%) *+.,/+%#%( /))7$( =%#4%& MNOP
4/7$( *<#,$ ,"6/(7$, #/ #4, *&#%-,&> Q#4,$
9:; 8/&/I%&,( $,)$7%# ? ),++( %&#/ #4, *+.,/+*$
(,6#% *&9 %&#,$(#%#%*+ #%((7,( /$ (#%87+*#,
#4, $,+,*(, /< *7#/)$%&, <*)#/$(> 1<#,$
MLNRP 4/7$(3 *99%#%/&*+ ? ),++( 8%-$*#, %&#/
#4, *+.,/+% *&9 )*& :, 9,#,)#,9 :5 :$/&)4%*+
+*.*-,> 1( /66/(,9 #/ (*$)/%9/(%(3 =4%)4
)*7(,( FJM *+.,/+%#%(3 #4,(, ? ),++( *$, 8*%&+5
FJL S> ?4,(, ),++( 9%(6+*5 (766$,((/$ *)#%.%#5
*&9 )*& I%++ TU'(,&(%#%., #*$-,#(V #4,5 ,"'
6$,(( FJBW *&9 FJBR> A*)$/64*-,( *$,
*+(/ <$,X7,&#+5 </7&9 %& #4, G1Y> Z%(#/+/-5
$,.,*+( #4, 6$,(,&), /< 8/&/&7)+,*$ ),++ %&'
<%+#$*#,( %& #4, %&#,$(#%#%*+ #%((7, *&9 #4, ,*$+5
9,.,+/68,&# /< (8*++ -$*&7+/8*(> ?4, 6*#'
#,$& /< *+.,/+%#%( </7&9 %& #4, G1Y <+7%9( )*&
4,+6 %& #4, 9%<<,$,&#%*#%/& /< %&#,$(#%#%*+ +7&-
9%(,*(,( /< 9%<<,$,&# ,#%/+/-5[ =4%+, * 6$,.*'
+,&), /< FJMS ? ),++( %& #4, G1Y %( #56%)*+ /<
(*$)/%9/(%(3 #7:,$)7+/(%(3 *&9 :,$5++%/(%(3 *
FJLS ?'),++ *+.,/+%#%( %( </7&9 %& 456,$(,&(%'
#%.%#5 6&,78/&%#%(3 (%+%)/(%(3 :+*(#/85)/(%(3
*&9 %&#,$(#%#%*+ +7&- 9%(,*(, *((/)%*#,9
=%#4 ZH\3 )/++*-,& .*()7+*$ 9%(,*(, *&9 -$*<#
.,$(7( 4/(# 9%(,*(,>
7 8)*(*&+) &#3.$/0 1)7#, *&9 )4$/&%) </$8( /<
#4, 9%(,*(, *$, 9%(#%&-7%(4,9> 1)7#, !11
8*&%<,(#( (//& *<#,$ *&#%-,& ,"6/(7$,>
]586#/8( /< <,.,$3 )4%++(3 )/7-43 95(6&,*3
*&9 85*+-%* 7(7*++5 9,.,+/6 *<#,$ * +*#,&)5
/< *$/7&9 MNL 4/7$(> ?4, (586#/8( -,&,$'
*++5 6,$(%(# </$ OLNPM 4/7$(3 #4,& (+/=+5 $,'
(%9, %< #4,$, %( &/ <7$#4,$ )/&#*)# =%#4 #4,
*&#%-,&> ?4, (586#/8( #4,& $,/))7$ =%#4
,*)4 $,&,=,9 )/&#*)#> ^*9%/-$*64( 8*5 9,'
8/&(#$*#, &/97+*$ %&#,$(#%#%*+ %&<%+#$*#,( %&
#4, +/=,$ 67+8/&*$5 <%,+9(> H& 8/(# )*(,(3
&/ (6,)%*+ #$,*#8,&# %( &,,9,9> H& (,.,$,
)*(,(3 (#,$/%9( )*& :, *98%&%(#,$,9 #/ *++,'
.%*#, (586#/8(> F4$/&%) ,"6/(7$, #/ #4,
*++,$-,&(3 %>,>3 *# (4/$# %&#,$.*+(3 6$/97),(
(586#/8( #4*# *$, 87)4 8/$, (,.,$,>
@,*I&,((3 *&/$,"%*3 *&9 =,%-4# +/(( 8*5 %&'
%#%*++5 /))7$ %& *:(,&), /< <,.,$> ^,(#$%)#%.,
$,(6%$*#/$5 %86*%$8,&# =%#4 $,(# 95(6&,*
7+#%8*#,+5 9,.,+/6(> H< #4,$, %( +/&-'#,$83
)4$/&%) 9*8*-, #/ #4, 67+8/&*$5 #%((7,3
#4, 9%(,*(, 8*5 7+#%8*#,+5 6$/-$,(( #/ 67+'
8/&*$5 <%:$/(%(3 =4%)4 6$/97),( %&#,$(#%#%*+
<%:$/#%) )4*&-,( /& $*9%/-$*64( 092>
 #$%&'()'* !++,&-'* !+.,/+'%')
!
Hay Farmer’s lung
Actinomycetes

Bird-breeder’s lung
Animals
Animal-derived
proteins
Air-
conditioning Air conditioner lung
Aureobasidium p.
Actinomycetes

5+'('*2+ 6778(/+/-3
Compost lung
Compost Aspergillus

Chemical worker’s
Polyurethane R lung
foam Isocyanates
1. Most common clinical syndromes

Alternative
Early granulocytic alveolitis

IL-8,
chemokines
Lymphocytic alveolitis (CD8+),
interstitial mononuclear
infiltration, granuloma formation
"
4–12 h 48–72 h
complement
activation
C3 C3b pathway
C3a
2. Immunological pathogenesis

4–8 h Therapy 12–24 h

with steroids
Fever,
coughing,
Inhalation dyspnea
a) Acute course

Weakness

!
anorexia
weight Dyspnea Impaired
Chronic exposure while ventilation
loss
b) Chronic course resting

3. Clinical outcomes
A. Extrinsic allergic alveolitis 4. Chest radiograph
9:<

"
! -&+.,'/0*'1 2,+&/+&+
!" #$%&'($)*+,+
! "#$%&'$() #(*)+,#'(- !"#$ %"#& #$%#' ($%)
%"# *+$,-. %+/#'0+*)-(-1($2+0($, 3&0)/401
%#'(4 4'# 5"4,)0&%)-#2 /& 4*6#)*4' 340')1
5"4,#-7 8"# 5"4,)0&%)-(- (- 34($*& '#0#5%)'
3#2(4%#2 9.:7 ;)3# '#0#5%)'- 9#7,7. 8)**1*(<#
'#0#5%)'. 8=>: '#0),$(?# 0#'%4($ -+'@40# 4$%(1
,#$ 54%%#'$- 0)33)$ %) 4** 5')<4'&)$-.
A"#'#4- )%"#'- 4'# -5#0(@(0 @)' 3&0)/40%#'1
(4* 4$%(,#$- 9#7,7. %"# BCDE 3)*#0+*#. A"(0"
(- -5#0(@(0 @)' *(5)4'4/($)34$$4$ 9=FG:
4$%(/)2(#-:7 F$%(/)2(#- 4$2 0)35*#3#$%
@40%)' BH /($2 %) 3)*#0+*#- )$ %"# -+'@40#
)@ %"# 54%"),#$ 4$2 4'# '#0),$(?#2 /& %"#
0)''#-5)$2($, '#0#5%)'-7 ;($0# %"# 4*6#)*4'
3),4,(/) 566$4*)*71
340')5"4,#- 04$$)% #@@#0%(6#*& <(** %"# 5"41
,)0&%)-#2 3&0)/40%#'(4. %"# /40%#'(4 04$
-+'6(6# ($%'40#**+*4'*&7 I$ @40%. %"#& 04$
#6#$ '#5*(04%# /& /*)0<($, 5"4,)-)3# 341
%+'4%()$7 8"# 3(,'4%()$ )@ 4*6#)*4' 340')1
5"4,#- %) %"# $#4'#-% *&35" $)2#- 40%(64%#-
4 810#**13#2(4%#2. -5#0(@(0 (33+$# '#1
-5)$-#7
/ 0(12+,#'( '* 3 45)+#*#+ #662() $)45'(4)-
!"#$%&#'()*+, '+%()#+-$.*. -#0'#%#- 5')%#($-
"
($%) %"# 5"4,)-)3#7 I$(%(4**&. %"#-# 5')%#($-
4'# #J5)'% 5')%#($-7 8"#& *4%#' @)'3 54'% )@
%"# 0#** A4** 4$2 +*%(34%#*& 94@%#' 4+%)*&-(-:
'#5'#-#$% ($%'40#**+*4' 5')%#($-7 K')0#--#2
@'4,3#$%- 0)$-(-%($, )@ DLMNL 43($) 40(2-
9FF: 4'# 5'#-#$%#2 )$ 0*4-- II GOB 3)*#1
0+*#-7 K#5%(2#- 0)$-(-%($, )@ PMDL 43($)
40(2- 4'# 5'#-#$%#2 )$ 0*4-- I GOB 3)*#1
0+*#-7 BCD. 4 2(-%4$% '#*4%(6# )@ 0*4-- I
GOB. 5'#-#$%- /40%#'(4* *(5)(2- %"4% 5'#@#'1
#$%(4**& -%(3+*4%# BCE 4$2 BCP 2)+/*#1$#1
,4%(6# 8 0#**-7 I$ 422(%()$. !Q" 8 0#**- 4'# 40%(1
64%#2 /& 3&0)/40%#'(4* 4$%(,#$- 0)$%4($($,
5")-5"4%# ,')+5-7 R) 5'#-#$%($, 3)*#0+*#
@)' %"(- 4$%(,#$ ,')+5 "4- &#% /##$ (2#$%(1
@(#27 I% (- 4--+3#2 %"4% %"# 5")-5")*(,4$2-
4'# 5'#-#$%#2 2('#0%*& )$ %"# 0#** -+'@40#7
7 8$3(29'63- F0%(64%#2 BCES 8 0#**- -#0'#%#
0"#3)<($#- %"4% 4%%'40% 0('0+*4%($, 3)$)1
0&%#- %) %"# -(%# )@ ($@*4334%()$7 8"#& 4*-)
-#0'#%# 8RT1#. A"(0" (- '#-5)$-(/*# @)' ,'4$1
+*)34 @)'34%()$7 B)35*#%# ($%'40#**+*4' <(**1
($, )@ 3&0)/40%#'(4 A(%"($ %"# ,'4$+*)34
!
04$ )00+' 2+# %) %"# 0&%)<($#13#2(4%#2 401
%(64%()$ )@ 340')5"4,#-7 I$ 3)-% 04-#-. ")A1
#6#'. %"# 54%"),#$ /#0)3#- 0)$0#$%'4%#2
A(%"($ %"# ,'4$+*)34. A"(0" /#0)3#-
-#4*#2 )@@ @')3 %"# -+'')+$2($,-7 8"# '#4-)$
889 @)' %"(- (- 8RT1#13#2(4%#2 %"(0<#$($, 4$2 @(1
/')-(- )@ %"# ,'4$+*)34 A4** 4$2 I=1E1($1
2+0#2 0)4*#-0#$0# )@ 340')5"4,#- %) @)'3
,(4$% 0#**- 9=4$,"4$-U 0#**-:7 I$ %"(- 04-#.
%"# ")-% (- ($@#0%#2 /+% 2)#- $)% 2#6#*)5 %+1
/#'0+*)-(- 98VB: /#04+-# %"# 3&0)/40%#'(4
4$2 %"# ,'4$+*)34U- 2#@#$-# -&-%#3 4'# 4%
/4*4$0#7 ITR1! 40%(64%#- %+/#'0+*)-%4%(0
340')5"4,#-. @)' #J435*#. /& 5')3)%($,
%"# -&$%"#-(- )@ 04*0(%'()*. 4 -+/-%4$0# %"4%
40%(64%#- 3(0')/(0(24* #@@#0%)' @+$0%()$7
8"# 40%(64%#2 340')5"4,#- '#*#4-# WN 3#%41
/)*(%#- 4$2 5')%#4-#- 4$2 %"+- 04+-# $#0')1
-(- ($ %"# 0#$%#' )@ %"# ,'4$+*)347 F0%(64%#2
BCPS 0&%)%)J(0 8 0#**- ($2+0# %"# *&-(- )@
340')5"4,#-. A"(0" '#*#4-# %"#(' 0)$%#$%-
($%) %"# $#0')%(0 ,'4$+*)34 0#$%#'7 8"#
,')A%" 0)$2(%()$- %"#'# 4'# *#-- @46)'4/*#
@)' %"# 3&0)/40%#'(4 /#04+-# )@ %"# *)A WN
%#$-()$ A(%"($ %"# 0#$%#' 4$2 /#04+-# )@
%"# %&5# )@ #$?&3#- '#*#4-#27
X$0)$%')**#2 0#** 2#-%'+0%()$. )$ %"# )%"#'
"4$2. *#42- %) 04-#4%()$ )@ %"# ,'4$+*)34.
A"(0" '#-+*%- ($ #J%#$-(6# %(--+# 2434,#7
8"# 3&0)/40%#'(4 04$ $)A #$%#' ($%) %"# 0('1
0+*4%()$ 4$2 0'#4%# $#A 0)*)$(#- ($ 6('%+4**&
4$& )@ %"# ")-%U- )',4$-7 I@ %"# '+5%+'#2 ,'4$1
+*)34 ,#%- 400#-- %) 4 /')$0"+-. %"# 3&0)1
/40%#'(4 04$ /# #J"4*#2 ($%) %"# #$6(')$1
3#$% 4$2 04$ 04+-# $#A ($@#0%()$- 9)5#$
8VB:7
: ;'659#+3,#'(4- C(-'+5%()$ )@ %"# /4*4$0#
/#%A##$ %"# 3&0)/40%#'(4 4$2 %"# ,'4$+*)1
34U- 2#@#$-# -&-%#3 04$ *#42 %) %"# @+'%"#'
-5'#42 )@ %"# ($@#0%()$7 O(*4' *&35" $)2# %+1
/#'0+*)-(-. 5*#+'4* #@@+-()$. 4$2 *#-()$- ($
%"# 45#J )@ %"# *+$,- 9;(3)$U- 45(04* @)0(:
4'# %&5(04* 0)35*(04%()$-7 Y#$#'4*(?4%()$ )@
%"# ($@#0%()$ 2+# %) "#34%),#$(0 -5'#42
*#42- %) %"# @)'34%()$ )@ %")+-4$2- )@ -34**
$)2+*#- ($ %"# *+$,. *(6#'. -5*##$. 4$2 3#1
$($,#- 93(*(4'& %+/#'0+*)-(-:7 B4-#4%($,
5$#+3)$(4 4$2 40+%# %+/#'0+*)+- -#5-(-
9=4$2)+?&U- -#5-(-: 4'# +-+4**& *#%"4* 0)31
5*(04%()$-7
 CR Fc"R IgG Complement
#$%&'($)*+,+
!
Proteins
Lymph Murein
Polysaccharides
nodes
Primary Outer Phosphatides
complex layer
Glycolipids
Primary lesion
Wax
CD14 LAM
4–12 week incubation period
1. Droplet infection 2. Phagocytosis by alveolar macrophages

CD4+ CD8+ CD4-/CD8- "/#

T cells T cells T cells T cells

3),4,(/) 566$4*)*71
!/$ TCR !/$ TCR !/$ TCR "/# TCR

MHC class I CD1 ?

MHC class II
Secretory proteins

ER M. tuberculosis

Phagosome
3. Induction of a specific immune response

"
Chemokines Fibrin layer

TNF-!
IL-4
IFN-"
Blood Cytotoxic
mono- Calcitriol T cell
cyte
O2
Open
tuber-
culosis
Langhans Proteases
giant cell
Blood
vessel

Tracheo-
Hematogenic bronchial
4. Granuloma spread system

a) b) c) d) Spinal e) f)
tap

!
Death after
a few days
Hilar lymph node Exudative Minimal Miliary Landouzy’s
tuberculosis pleuritis lesions tuberculosis Caseous sepsis
pneumonia
5. Complications
A. Tuberculosis
88:

"
! 1.&,( 2*0.,0.0

!"#$ %&#"' ()*&"*&* +",& -#(&%'$)#. )//-#01

'0.)2"' /&2+"#)*/*3 4#5)60($1/&()"5&( &77&25*
"%& 8%)/"%)'$ )#,0',&(9 :+&%&"* 2&''-'"% /&1
2+"#)*/* "%& '&** )/80%5"#53 ;//-#0'0.)2"'
()*&"*&* 07 5+& <)(#&$ /")#'$ "77&25 5+& .'01
/&%-'-*9 :+)2+ )* /0*5 ')<&'$ (-& 50 )5* 7)'5&%
7-#25)0#3 ;//-#0'0.)2"' 8%02&**&* %&'"5&( 50
,"*2-')5)2 8%02&**&* +",& #05 6&&# 5"<&# )#50
"220-#5 )# 5+)* 2+"85&%9 6-5 5+&$ "%& 0-5')#&(
)# 5+& 488&#()= >*&& ?"63 @A3
!" #$$%&'(')*+,( -.+/,&*0$0
4 *2+&/"5)2 )''-*5%"5)0# 07 5+& /0*5 )/80%5"#5
.'0/&%-'"% *5%-25-%&* )* 8%&*&#5&( )# >!A3 ;#
0%(&% 50 '&",& 5+& 2)%2-'"5)0# "#( &#5&% )#50
3(*&*+,( #$$%&'(')4
8%02&**3 G%05&"*&*9 2$50<)#&*9 &)20*"#0)(*9 0=)1
("#5*9 "#( #)5%)2 0=)(&* "%& -'5)/"5&'$ %&'&"*&(3
?+& 2$50<)#&* 2"# "55%"25 "#( "25),"5& ? 2&''*3
?+& .'0/&%-'"% ("/".& 2"# 2"-*& 5:0 ()*1
5)#25 *$/850/ 20/8'&=&*K 5+& #&8+%05)2 *$#1
(%0/& >'A "#( 5+& #&8+%)5)2 *$#(%0/& >(A3 ;#
#&8+%05)2 *$#(%0/&9 ("/".& 50 5+& &#(05+&')"'
2&''*9 6"*&/&#5 /&/6%"#&9 "#(L0% ,)*2&%"'
&8)5+&')-/ '&"(* 50 "# )#2%&"*&( 7)'5%"5)0# 07
8%05&)#* )# 5+& -%)#"%$ *8"2&3 ?+)* 2"-*&* &=5&#1
*),& 8%05&)#-%)" "#( "# "**02)"5&( '0** 07 '0:1
/0'&2-'"%1:&).+5 *-6*5"#2&*9 *-2+ "* "'6-/)#
"#( )//-#0.'06-')#*3 4* " %&*-'59 5+&%& )* " %&1
'"5),& )#2%&"*& )# ! M1 "#( "1.'06-')#* )# *&%-/3
N-& 50 5+& +$80"'6-/)#&/)"9 5+& 0*/05)2 8%&*1

*-%& 07 5+& 6'00( (&2%&"*&*9 %&*-'5)#. )# .&#&%1

5+& -%)#"%$ *8"2& 07 5+& .'0/&%-'-*9 " *0'-5&
"')O&( &(&/" :)5+ 8'&-%"' &77-*)0#* "#( "*2)5&*3
/-*5 7)%*5 /).%"5& 5+%0-.+ 5+& 7&#&*5%"5&( &#1
(05+&')-/ 07 5+& 2"8)''"%)&* "#( 5+&# 8&#&5%"5& 4 %&"25),& )#2%&"*& )# ')808%05&)# *$#5+&*)*
022-%* )# 5+& '),&%9 5+&%&6$ )#(-2)#. +$8&%1
5+& .'0/&%-'"% 6"*&/&#5 /&/6%"#& >BC!A3
')8)(&/)"3 ?+& 20/8&#*"50%$ *&2%&5)0# 07 "'1
?+& BC! 20#*)*5* 07 20''".&#9 '"/)#)#9 80'$"1
(0*5&%0#& '&"(* 50 *0()-/ %&5&#5)0# "#( +$8&%1
#)0#)2 8%05&0.'$2"#*9 7)6%0#&25)#9 "#( 05+&%
5&#*)0#3 F$"')#& "#( .%"#-'"% 2"*5* 2"# 6&
.'$208%05&)#*3 ?+& #&=5 '"$&% )* /"(& -8 07 ,)*21
&%"' &8)5+&')"' 2&''* >80(02$5&*A "#( 5+&)% 7005 (&5&25&( )# 5+& -%)#"%$ *&()/&#53 ?+& 2"-*&*
07 #&8+%05)2 *$#(%0/& ()77&% )# 2+)'(%&# "#(
8%02&**&*3 ?+& -%)#"%$ *8"2& )* '02"5&( 6&5:&&#
"(-'5*3 ?+& 2+)'(+00( 70%/ )* -*-"''$ 2+"%"25&%1
5+& ,)*2&%"' "#( 8"%)&5"' &8)5+&')" 07 C0:/"#D*
)O&( 6$ /)#)/"' 2+"#.& .'0/&%-'0#&8+%)5)*

"
2"8*-'&3 ?+& &#5)%& .'0/&%-'-* )* *-880%5&( 6$
:)5+ " 6&#).# 20-%*&9 :+&%&"* 5+& "(-'5+00(
5+& /&*"#.)-/9 " /"5%)= 5+"5 70%/* " /&*+1
:0%< )# :+)2+ /&*"#.)"' 2&''* "%& *2"55&%&(3 70%/ )* -*-"''$ "**02)"5&( :)5+ " *$*5&/)2 ()*1
&"*& "#( +"* " /0%& *&,&%& 8%0.#0*)*3
?+&*& /06)'& 8+".02$5)2 2&''* *&2%&5& /"5%)=9
P&8+%)5)2 *$#(%0/& 022-%* /0%& 7%&Q-&#5'$
20''".&#9 "#( " #-/6&% 07 6)0'0.)2"' /&()"50%*3
)# 2+)'(+00(3 ?+& 0#*&5 07 5+& ()*&"*& )* -*-"''$
4#5)60($1/&()"5&( %&#"' ()*&"*&* "%& )#1
2+"%"25&%)O&( 6$ 5+& *-((&# "88&"%"#2& 07
(-2&( 6$ 5+%&& /&2+"#)*/* >"A3 E)%2-'"5)#.9
6'00( )# 5+& -%)#& "#( %&(-2&( -%)#"%$ *&2%&1
8%&70%/&( )//-#& 20/8'&=&* "22-/-'"5&
5)0# )# "**02)"5)0# :)5+ "2-5& %&#"' 7")'-%& >0')1
*-6&#(05+&')"''$9 0# 5+& 2"8)''"%$ "*8&25 07
.-%)"A "#( +$8&%5&#*)0#3 ?+& ()*&"*& )* -*-"''$
5+& 6"*&/&#5 /&/6%"#& >"#A3 4'5&%#"5),&'$9
8%&2)8)5"5&( 6$ 80*5)#7&25)0-* 0% %"8)('$ 8%01
5+& "#5)60()&* /"$ %&"25 )# *)5- :)5+ 5+&
.%&**),& .'0/&%-'0#&8+%)5)*3
BC! >"$A 0% :)5+ "#5).&#* 07 5+& ,)*2&%"' 2&''*
>*012"''&( F&$/"##D* #&8+%)5)*A >"%A3 ?+& )/1
/-#0.'06-')#* "#( 20/8'&/&#5 2"# 6& /"(&
,)*)6'& -*)#. 7'-0%&*2&#5 "#5)*&%"3 G%&70%/&(
)//-#& 20/8'&=&* "#( "#5)60()&* 50 &8)5+&')"'
"#5).&#* "88&"% "* .%"#-'"%9 ()*20#5)#-0-*
7'-0%&*2&#5 *5%-25-%&*9 :+&%&"* "#5)60()&*
".")#*5 5+& 6"*&/&#5 /&/6%"#& 8%0(-2& "
')#&"%9 20#5)#-0-* 8"55&%#3
4#5)60($ (&80*)5* 2"# 2"-*& ()%&25 ("/".&
50 &8)5+&')"' 0% &#(05+&')"' 2&''* (-& 50 20/1
8'&/&#5 "25),"5)0# "#( 80%& 70%/"5)0# >&A3

!
H# 5+& 05+&% +"#(9 5+& "#5)60()&* 2"# "'*0
6)#( 50 5+& I2 %&2&850%* 07 /0#02$5&*9 /"2%01
8+".&*9 .%"#-'02$5&*9 "#( 8'"5&'&5*3 ?+)* '&"(*
50 5+& "25),"5)0# 0%9 )# 5+& 2"*& 07 8'"5&'&5*9
"..%&."5)0# 07 5+& 2&''*3 E0/8'&/&#5 2'&",".&
555 8%0(-25*9 &*8&2)"''$ EJ"9 &#+"#2& 5+& "25),"5)0#
 Parietal epithelium
#$$%&'(')*+,( -.+/,&*0$0

Periorbital
!
Immune complex edema
in capillaries
Endothelial cell
Hyper- Pleural
Glomerular basement tension effusion
membrane (GBM)
Podocyte with
foot processes Ascites
1. Anatomy

Hypo-
albuminemia
Proteinuria
Hyperlipidemia
Urine sediment;

3(*&*+,( #$$%&'(')4
Edema hyaline and
granular casts
2a. Immune 2b. Anti-GBM 2c. Anti-epithelial 1. Clinical symptoms
complex Ab cell Ab
deposition Children Adults

Membranous glomerulonephritis 5% 20%

Lipoid nephrosis
minimal change GN 60% 10%
Focal segmental
glomerulosclerosis 10% 10%

Direct
damage
Membranoproliferative
glomerulonephritis
Proliferative GN (focal, lgA....)
Systemic diseases: diabetes,
SLE, amyloidosis...

2. Causes of nephrotic syndrome

10%
10%
5%
5%
15%
40% "
(C5b-C9) B. Nephrotic syndrome

Periorbital
Secondary edema
T cell
migration
Proteinuria
Cytotoxicity Hypertension
Oliguria
C5a
Hematuria

Urine sediment;
Platelet Mesangial Red blood cell
aggregation cell casts
Neutrophil Monocyte activation 1. Clinical symptoms

!
activation activation
Postinfectious GN
Rapidly progressive GN
Proteases, eicosanoids,
NO, cytokines, growth factors IgA nephropathy

3. Mediators of glomerular damage 2. Causes of the nephritic syndrome

A. Mechanisms C. Nephritic syndrome
556

"
! >,%'( ;$9,'9,9

!" #$%$&'( )*'%+, -,.*/0.'1*2

!"#"$%& '(%#)* #*+(,-+%.(/0 -, 1&"+-"2 #*3
+(,-4"405 "4 % 6*#")# 2"4*%4*7 8. "4 .(* $-4. '-$3
)*#4 .(%. ?*,* :"&.*,*2 %#2 (%<* )-,$*2 2*3
+-4".47 ;(* 2"4*%4* "4 "2"-+%.("' "# SM N -: '%4*4H
". "4 4-$*."$*4 %44-'"%.*2 ?".( 4/4.*$"' 2"43
*%4*4 -, ?".( .(* 94* -: '*,.%"# $*2"'%."-#47
$-# '%94* -: '("&2(--2 #*+(,-."' 4/#2,-$*7
TQ+-49,* .- .-Q"' %)*#.4 '%# %&4- "#29'* $*$3
;(* )&-$*,9&" %++*%, #-,$%& 9+-# &")(. $"',-3
6,%#-94 )&-$*,9&-#*+(,"."47 ;/+"'%& :*%.9,*4
4'-+/0 %#2 *&*'.,-# $"',-4'-+/ ,*<*%&4 .(* &-44
"#'&92* 2"::94* .("'A*#"#) -: .(* 6%4*$*#.
-, :94"-# -: :--. +,-'*44*4 -: .(* <"4'*,%&
$*$6,%#* ?".( :94"-# -: .(* :--. +,-'*44*47
*+".(*&"%& '*&&47 =*+-4".4 >4** %,,-? -# +(-.-3
;(* "#(-$-)*#*-94 2"4.,"69."-# -: .(* 8)F
),%+(@ '%# 6* 2*.*'.*2 "# .(* +-2-'/.*4 2"3
%#2 OP 2*+-4".4 ,*49&.4 "# % ),%#9&%, +%..*,#
,*'.&/ -++-4".* .- .(* 6%4*$*#. $*$6,%#*7
9+-# "$$9#-:&9-,*4'*#'* >4** +(-.-),%+(@7
;(* :-,$%."-# -: 4-3'%&&*2 $"',-<"&&" >!@ "4 %#3
F&-$*,9&%, 4'&*,-4"4 $%/ -''9, "# .(* &%.*,
-.(*, ./+"'%& :*%.9,*7 ;(* '%94* -: $"#"$%&
4.%)* -: .(* 2"4*%4*7 O&"#"'%&&/0 $*$6,%#-94
'(%#)* #*+(,-+%.(/ "4 9#A#-?#7 ;3'*&& '/.-3
)&-$*,9&-#*+(,"."4 %++*%,4 %4 % ,*&%."<*&/
A"#*4 %,* +,*49$*2 .- 2*4.,-/ .(* +-2-'/.* %,3
$"&2 #*+(,-."' 4/#2,-$*7 K,-9#2 UM N -: .(*
'(".*'.9,*7 ;(* &-44 -: +-2-'/.* :9#'."-# &*%24
)($%$5'( ?&&8%0(0+2

+%."*#.4 ),%29%&&/ 2*<*&-+ +,-),*44"<* ,*#%&

.- %# "#',*%4* "# +,-.*"# :"&.,%."-#7 ;(* '(%#)*4
'%94*2 6/ $"#"$%& '(%#)* #*+(,-+%.(/ %,*
'-$+&*.*&/ ,*<*,4"6&*7 B"#*./ +*,'*#. -: %&&
'%4*4 ,*4+-#2 .- '-,."'-4.*,-"240 %&.(-9)(
4-$* +%."*#.4 ,*C9",* &-#)3.*,$ .(*,%+/7 8#
%29&.40 &%,)*, 2-4*4 -: 4.*,-"24 $94. 6* 94*20
%#2 .(* ,%.* -: ,*'9,,*#'* "4 $9'( (")(*, '-$3
+%,*2 ?".( '("&2,*#7
3" 405'( 6,+&,%1'( 7(0&,/8(095(,/09$9
:%"&9,*7 ;(* ,*4+-#4* .- '-,."'-4.*,-"24 "4 +--,7
;" #,&:/'%0./0($<,/'1$=,
7(0&,/8(0%,.*/$1$9
!*$6,%#-+,-&":*,%."<* )&-$*,9&-#*+(,"."4
>!VFB@ "4 '(%,%'.*,"G*2 6/ '(%#)*4 "# .(*
6%4*$*#. $*$6,%#* %#2 +,-&":*,%."-# -: $*3
4%#)"%& '*&&4 %#2 )&-$*,9&%, '*&&47 ;(*,* %,*
.?- 496./+*40 ?("'( %,* '&%44":"*2 %''-,2"#)

"
.- .(*", 2"::*,*#. +%.(-$*'(%#"4$47 !"#$ % >%+3
D-'%& 4*)$*#.%& )&-$*,9&-4'&*,-4"4 >DEFE@ "4
+,-Q"$%.*&/ .?-3.(",24 -: %&& '%4*4@ "4 %44-3
'(%,%'.*,"G*2 6/ .(* -''9,,*#'* -: 4'&*,-4"4
'"%.*2 ?".( EWT0 (*+%."."4 X0 %#2 (*+%."."4 O7
"# -#&/ % :*? )&-$*,9&"H $-,*-<*,0 -#&/ 4-$*
;(* 496*#2-.(*&"%& ."449* '-#.%"#4 '-$+&*3
+%,.4 >4*)$*#.4@ -: .(* "#<-&<*2 )&-$*,9&"
$*#. %#2 "$$9#-)&-69&"#40 ?("'( +,*49$3
%,* %::*'.*2 >4** +(-.-),%+(@7 ;(*4* '(%#)*4
%6&/ ,*+,*4*#. +,*:-,$*2 "$$9#* '-$+&*Q*47
-''9, "# %44-'"%."-# ?".( I8J "#:*'."-#0 2,9)
!"#$ %% >%,-9#2 -#*3.(",2 -: '%4*4@ "4 %44-'"%.*2
%694*0 %#2 8)K #*+(,-+%.(/0 -, %4 % 4*'-#2%,/
?".( %# %#."6-2/ %)%"#4. OP '-#<*,.%4*0 '%&&*2
'-$+&"'%."-# -: '-$+*#4%.-,/ (/+*,.,-+(/7
&' ($#)*+,+- ./-,0*7 ;(* %#."6-2"*4 4.%6"&"G* '-#3
;(* '%94* "4 -:.*# 9#A#-?#7 K,-9#2 LM N -:
<*,.%4*0 &*%2"#) .- % '-#4.%#. %'."<%."-# -: OP7
%&& #*+(,-."' 4/#2,-$*4 %,* %..,"69.%6&* .-
=*+-4".4 '-#.%"#"#) OP %#2 -.(*, 4964.%#'*4
:-'%& 4*)$*#.%& )&-$*,9&-4'&*,-4"47 ;(*4*
%,* &-'%.*2 ?".("# .(* )&-$*,9&%, 6%4*$*#.
'(%#)*4 +,*49$%6&/ ,*+,*4*#. % $-,* 4*<*,*
$*$6,%#*7 T&*'.,-# $"',-4'-+/ ,*<*%&4 .(*
<%,"%#. -: 1$"#"$%& '(%#)* 2"4*%4*75 ;(* %''93
+,*4*#'* -: '(%,%'.*,"4."'0 )$/1" $2$-,*0(34$(5$
$9&%."-# -: &"+"240 :"6,"#0 OP '-$+&*$*#.0 %#2
4$#05+,5 "# .(* 6%4*$*#. $*$6,%#* >4**
8)! "$$9#-)&-69&"#4 &*%24 .- % $*4%#)"%&
+(-.-),%+(@7 8# 6-.( ./+*4 -: !VFB0 .(* '%+"&3
,*%'."-# %44-'"%.*2 ?".( (/%&"#-4"4 %#2 4'&*,-4"47
&%,/ ?%&& %++*%,4 %4 % 2-96&*3&"#*2 4.,9'.9,*
I"4.-&-)"'%& 4*'."-#4 >4** +(-.-),%+(@ '&*%,&/
>.,%$.,%'A %++*%,%#'*@ 29* .- .(* %''9$9&%3
,*<*%& .(* 4*)$*#.%& #%.9,* -: 4'&*,-."' "#3
."-# -: $*4%#)"%& $%.,"Q 6*.?**# .(* 6%4*3
<-&<*$*#.7 DEFE ,*4+-#24 +--,&/ .- '-,."'-43
$*#. $*$6,%#* %#2 .(* *#2-.(*&"%& '*&&47
.*,-"247 K++,-Q"$%.*&/ RM N -: .(* +%."*#.4
;(* 2"4*%4*0 *4+*'"%&&/ .(* ./+* 88 :-,$0 (%4 %
2*<*&-+ ,*#%& :%"&9,* ?".("# LM /*%,47
+--, +,-)#-4"47 Y#&/ %,-9#2 PM N -: +%."*#.4
)" #,&:/'%089 7(0&,/8(0%,.*/$1$9 2- #-. 2*<*&-+ ,*#%& :%"&9,*7 ;(*,* "4 #- *::*'3

!
@@A
!*$6,%#-94 )&-$*,9&-#*+(,"."4 "4 '(%,%'.*,3
"G*2 6/ .(* :-,$%."-# -: "$$9#* '-$+&*Q*4
-# .(* 496*+".(*&"%& 49,:%'* -: .(* 6%4*$*#.
$*$6,%#*7 ;(* %#."6-2"*4 ,*%'. "# 4".9 ?".(
*#2-)*#-94 +-2-'/.* %#.")*#4 -, ?".( %#."3
."<* .,*%.$*#.7 ;(* <%&9* -: '-,."'-4.*,-"24 "4
'-#.,-<*,4"%&7
Podocyte
Loss of digital extensions
7(0&,/8(0%,.*/$1$1$9 B?C

Good response
!
to corticosteroids,
Albuminuria good prognosis
T-cell Lipid aggregation
cytokines
in tubular cells

Nephrotic
Fusion, loss of syndrome M
foot processes
A. Minimal change glomerulonephritis (GN) Electron microscopy

HIV-infection, Deposition
heroin of IgM, fibrin
Damage to Poor response
abuse epithelial cell to corticosteroids

)($%$5'( ?&&8%0(0+2
Secondary to
other GN Deposition of
proteins,
lipids, fibrin
Secondary to
compensatory
hypertrophy Mesangial
Idiopathic Loss of proliferation
foot processes
B. Focal segmental glomerulosclerosis Segmental sclerosis

"
Idiopathic >80%
Thickening of Poor response
(genetic predisposition)
basement membrane to corticosteroids
Infections
Carcinomas Nonselective
proteinuria
SLE
Drugs 40% - Progressive
Gold, mercury Loss of course with
foot processess renal failure
C. Membranous glomerulonephritis Granular IgG deposits

Type I
Nephrotic
syndrome
Hepatitis B, C acute nephritis
SLE
Infections?
Subendothelial
IgG, complement
deposition
40% - Progressive
renal failure Tramtrack effect
Type II
Ab against 30% - Partial
C3-convertase renal failure

!
Complement
activation, 30% - Persistent
consumption nephrotic
Intramembranous syndrome
C3 deposition
D. Membranoproliferative GN (MPGN) EM: Dense deposits
@@D

"
! 9*(10 .'%*1%*%
!" #$%&'()*+&'$,% -.')),%* #/$0')*/1&'2*3
40$5*/,0$(*67/'&'%
!"#$% &'($($)%&$'"'""*+ ,+'-%)#+'.%&/)0$0(
1!23456 0( $/% &)'$'$7&% &'($0.8%"$0'#( ,+'9
-%)#+'.%&/)0$0" :0(%*(%; <#$ 45 -*7 *+(' <%
"*#(%: <7 &.%#-'"'""0; ($*&/7+'"'""0; *.:
=0)#(%(> ?. -'($ "*(%(; 8%=%) *.: /%-*$#)0* :%9
=%+'& @0$/0. * 8%@ @%%A( *8$%) !"#$%"&'&''()9
0.:#"%: &/*)7.,0$0( ') (A0. 0.8%"$0'.> ?,49<%*)9
0., 0--#.% "'-&+%B%( *.: "'-&+%-%.$ *""#9
-#+*$% 0. $/% (#<%&0$/%+0*+ &')$0'. '8 $/% <*(%9
-%.$ -%-<)*.%> C0($'+',0"*+ (%"$0'.( &)%(%.$
* "%++9)0"/ &0"$#)% @0$/ :088#(% &)'+08%)*$0'. '8
%.:'$/%+0*+ *.: -%(*.,0*+ "%++( *.: *. 0.9
")%*(%: .#-<%) '8 +%#A'"7$%( 0. $/% "*&0++*)7
=0'('+10 >55,($0$<;
+#-0.*> D/% &)',.'(0( 0( ,'':; &*)$0"#+*)+7 0.
"/0+:)%.E "/)'.0" )%.*+ 8*0+#)% )*)%+7 '""#)(>
C'@%=%); "/)'.0" &)',)%((0'. :%=%+'&( 0.
*)'#.: FG H '8 *:#+$ &*$0%.$(>
8" 916':0; #/$</*%%'2*
40$5*/,0$(*67/'&'%
I*&0:+7 &)',)%((0=% ,+'-%)#+'.%&/)0$0( 1I2456
(/'#+: <% "'.(0:%)%: * (7.:)'-% )*$/%) $/*. *
"
(&%"080" :0(%*(%> I%,*):+%(( '8 $/% %$0'+',7; $/%
:0(%*(% 0( "/*)*"$%)0J%: <7 $/% 8')-*$0'. '8
K")%("%.$(L @0$/0. $/% ,+'-%)#+0> D/% ")%("%.$(
'""#) <%"*#(% '8 +%*A*,% '8 80<)0. 0.$' $/% #)0.9
*)7 (&*"% :#% $' $/% &)'+08%)*$0'. '8 $/% &*)0%$*+
%&0$/%+0*+ "%++( '8 M'@-*..N( "*&(#+% *.: 0.80+9
$)*$0'. @0$/ -'.'"7$%( *.: -*")'&/*,%(>
D/%)% *)% $/)%% (#<$7&%( '8 I245; @/0"/ *)%
"+*((080%: *""'):0., $' 0--#.'/0($'+',0"*+ 8%*9
$#)%(>
*+%$ , 0( "/*)*"$%)0J%: <7 $/% 8')-*$0'. '8
*#$'*.$0<':0%( :0)%"$%: *,*0.($ $/% 1,+'-%)#9
+*)6 <*(%-%.$ -%-<)*.% 1*.$094MO *.$0<'9
:0%(6> D/%(% *.$0<':0%( ('-%$0-%( ")'((9)%*"$
@0$/ $/% <*(%-%.$ -%-<)*.% '8 *+=%'+0 0.
$/% +#., *.: "*#(% K4'':&*($#)%N( (7.:)'-%;L
* :0(%*(% *(('"0*$%: @0$/ )%.*+ 8*0+#)% *.: &#+9
-'.*)7 /%-'))/*,%> ?--#.'/0($'+',0"*+ (&%9
"0-%.( 1(%% &/'$',)*&/6 %B/0<0$ :088#(%; +0.%*)
:%&'(0$0'. '8 ?,4 *.:; 0. -*.7 "*(%(; PQ *+'.,
$/% ,+'-%)#+*) <*(%-%.$ -%-<)*.%>
*+%$ ,, 0( "/*)*"$%)0J%: <7 $/% :%&'(0$0'. '8
0--#.% "'-&+%B%(> D/0( (#<$7&% '8 I245 0(
!
'<(%)=%: 0. (%=%)% ($)%&$'"'""*+ .%&/)0$0(;
?,! .%&/)'&*$/7; 3RS; *.: 3"/'T.+%0.UC%.'"/
&#)&#)* ') -*7 '""#) *( *. 0:0'&*$/0" :0(%*(%>
?. *+%$ ,,,; .%0$/%) *.$094MO *.$0<':0%( .')
0--#.% "'-&+%B%( *)% :%$%"$%:> C%."%; $/%
BBC :0(%*(% 0( :%(")0<%: *( K&*#"090--#.%>L D/0(
(#<$7&% '8$%. '""#)( 0. "'.V#."$0'. @0$/ =*(9
"#+0$0( *(('"0*$%: @0$/ *.$09,)*.#+'"7$% *.$0<'9
:0%( 1!5P!; (%% &> WXY6>
D/% "+0.0"*+ &0"$#)% '8 I245 0( $/*$ '8 * .%9
&/)0$0" (7.:)'-% @0$/ '+0,#)0* *.: *"#$% )%.*+
8*0+#)%> D/% &)',.'(0( :%&%.:( '. $/% .#-<%)
'8 ,+'-%)#+0 0.='+=%:> !,,)%((0=% 0--#.'(#&9
&)%((0=% $/%)*&7 0( ('-%$0-%( (#""%((8#+> 2/*(9
-*&/%)%(0( 0( 0.:0"*$%: 0. $/% &)%(%."% '8 *.$09
4MO *.$0<':0%(>
=" ><! ?*67/$61&7;
?,! .%&/)'&*$/7 0( $/% -'($ "'--'. ,+'9
-%)#+*) :0(%*(% @')+:@0:%> ?. "/0+:)%. *.:
$%%.*,%)(; $/% :0(%*(% $7&0"*++7 *&&%*)( *8$%)
* &)%"%:0., <'#$ '8 * 8+#9+0A% 0++.%((> 4%.%$0"
&)%:0(&'(0$0'. 0( *((#-%:> D/% /*++-*)A '8
$/% :0(%*(% 0( $/% :%&'(0$0'. '8 ?,! 0. $/% -%9
(*.,0#- 1(%% &/'$',)*&/6> 3"/'T.+%0.UC%.'"/
&#)&#)* *+(' +%*:( $' -%(*.,0*+ ?,! :%&'(0$0'.;
<#$ $/% :%&'(0$( *)% *+(' &)%(%.$ 0. $/% ,*($)'9
0.$%($0.*+ $)*"$; V'0.$(; *.: (A0.> D/% -%(*.,0*+
?,! 0--#.% "'-&+%B%( $)0,,%) *"$0=*$0'. '8 $/%
*+$%).*$0=% "'-&+%-%.$ &*$/@*7 *.: "%++ &)'9
+08%)*$0'.> Z%&%.:0., '. $/% (%=%)0$7 '8 $/% :0(9
%*(%; $/% 8%*$#)%( -*7 0."+#:% 8'"*+ (%,-%.$*+
"/*.,%( 1(%% &> [WG6 ') ")%("%.$( (0-0+*) $'
$/'(% '8 I245> P/0+:)%. /*=% * ,'': &)',.'(0(>
?. *:#+$(; $/% :0(%*(% /*( * "/)'.0" &)',)%((0=%
"'#)(%> O')% $/*. FG H '8 $/% &*$0%.$( :%=%+'&
$%)-0.*+ )%.*+ 8*0+#)%>
." @,A,0$'(&*/%&'&'10 ?*67/'&'%
?.8+*--*$')7 "/*.,%( 0. $/% 0.$%)($0$0*+ $0((#%(
-*7 '""#) :#% $' 0.8%"$0'.( ') -%:0"*$0'.( ')
-*7 '""#) @0$/'#$ *.7 0:%.$080*<+% "*#(%> !
"+0.0"*+ 0.=%($0,*$0'. )%=%*+( ,%.%)*+0J%: (7-&9
$'-(; '+0,#)0*; *.: *"#$% )%.*+ 0-&*0)-%.$\
:%/7:)*$0'. "*. 8#)$/%) @')(%. $/% "+0.0"*+ &0"9
$#)%> D/% -')&/'+',0"*+ 80.:0.,( )%=%*+ 0.80+$)*9
$0'. '8 $/% 0.$%)($0$0*+ $0((#%( <7 -'.'.#"+%*)
"%++(; ,)*.#+'"7$%(; *.: %'(0.'&/0+( 1(%% &/'$'9
,)*&/6\ ,)*.#+'-*( -*7 *+(' '""#) :#% $' &)'9
$)*"$%: :)#, %B&'(#)%> ! :%+*7%:9$7&% /7&%)9
(%.(0$0=0$7 )%*"$0'. 0( *((#-%:> D/% 8*"$ $/*$
('-% &*$0%.$( %B/0<0$ 0.")%*(%: +%=%+( '8 ?,S
(#,,%($( $/*$ * $7&% ? /7&%)(%.(0$0=0$7 )%*"$0'.
-*7 &+*7 * )'+% 0. ('-% "*(%(> P'-&+%$% .')9
-*+0J*$0'. '""#)( *8$%) :0("'.$0.#*$0'. '8 $/%
'88%.:0., -%:0"*$0'.>
 Immune complex deposits
40$5*/,0$(*67/'&'% ->>3 1(: >(&*/%&'&'10 ?*67/'&'%

Common symptoms, No specific

!
hematuria therapy
Hypercellularity
in all glomeruli
Children Adults

> 80% ~50%

Healing Healing
A. Postinfectious (acute proliferative) GN Hypercellularity

Type I Anti-basement membrane Ab

with/without pulmonary bleeding Aggressive
immunosuppression:
Type II With immune high-dose steroids

=0'('+10 >55,($0$<;
complexes: Renal insufficiency in 90%
idiopathic, cyclophosphamide
systemic
diseases,
postinfectious,
Schönlein-
Henoch
Type III Pauci-immune:
idiopathic,
Wegener’s,
PAN
B. Rapidly progressive GN Crescent Linear IgG deposition

Genetic
predisposition,
infections

Increased
Infection of airways

Hematuria, kidney pain

No specific
therapy "
IgA Children Adults
synthesis

High Slowly
IgA immune Mesangial IgA deposition, healing rate progressive
complexes mesangial proliferation

C. IgA immune complexes IgA deposits

Idiopathic
Medications Rehydration
? Steroids??
Infections Drugs Fever, eosinophilia,
exanthema (25%)

Renal damage
Interstitial (hematuria,
deposition
proteinuria,

Granuloma formation
Interstitial edema,
kidney enlargement
D. Tubulointerstitial nephritis
leukocyturia)

Renal insufficiency
(avoid dehydration)

Eosinophil infiltrates
!
BBD

"
! 5*$&9%3(? =(+*&+*+

!" !#$%&'$()*'+ %, $-* .-/0%(1 23&'1

!"# $%&#'()' *(&+(&$', *')-+.#/ &",')(-0/&(0
1+2$&(%3 ")'1)%# 4!5678 9"(." :(%-/ &) !56
")'1)%# *')-+.&()% 1)'# *#'/(/&#%&2, &"$%
%$&+'$22, )..+''(%3 !56< !L== $'# $2/) *'#/#%&
(% *$&(#%&/ 9(&" M'$J#/N -(/#$/# 4"7< !"#/# (10
1+%)32):+2(%/ :2).K &"# :(%-(%3 )D !56
'#.#*&)'/ 4!56;7 )% &",')(- .#22/< =)-(-# (/ /+:0
&"')+3")+& &"# #%&('# #?&'$.#22+2$' -)1$(% )D
/#>+#%&2, )?(-(@#- &) ()-(%# 4=A7 $%- (%.)'*)0
&"# !56 '#.#*&)'< C#*#%-(%3 )% &"# #?&#%& &)
'$&#- (%&) &,')/(%#< B)%)()-)&,')/(%# 4B=!7
9"(." &"(/ )..+'/8 &"# $DD#.&#- *$&(#%& 9(22
$%- -(()-)&,')/(%# 4C=!7 :(%- &) &",')32):+2(%
"$J# #(&"#' ",*#'&",')(-(/18 #+&",')(-(/18 )'
4!37 $%- $'# &'$%/D)'1#- &) &'(()-)&",')%(%#
",*)&",')(-(/1<
4!E7 $%- &#&'$()-)&",')%(%# 4!F7 :, &",')(- *#'0
!"#$%&'"( $&)'*$+,*-. 4#7 1$(%2, )..+'/ (%
)?(-$/# 4!GH7< ID&#' .2#$J$3# )D &",')32):+2(%8
$//).($&()% 9(&" M'$J#/N -(/#$/#8 :+& 1$, $2/)
!E $%- !F $'# '#2#$/#- (%&) &"# .('.+2$&()%<
)..+' (%-#*#%-#%&2,< S?)*"&"$21)/ 4/## *")&)0
!"# $D)'#1#%&()%#- *')&#(%/ .$% :# (11+%)0
3'$*"7 (/ .$+/#- :, #-#1$ )D ).+2$' 1+/.2#/
3#%(. &$'3#&/8 $%- $%&(:)-(#/ .$% :# D)+%- (%
4/## T! (1$3#78 *')2(D#'$&()% )D '#&')0)':(&$2
&"# :2))- )D *$&(#%&/ 9(&" &",')(- -(/#$/#/<
.)%%#.&(J# &(//+#8 $%- (%D(2&'$&()% 9(&" 2#+K)0
:3('(?&3 677#'%3%)/

.,&#/< !"# ).+2$' 1+/.2#/ *)//(:2, /"$'#

4" 5%+$ 678%0$&'$ !#$%&'$(9%1(*+
.')//0'#$.&(J# #*(&)*#/ 9(&" !56< ;#&')0)':(&$2
!"# *$&")3#%#&(.$22, '#2#J$%& $+&)$%&(:)-(#/ D(:'):2$/&/ $**#$' &) /#.'#&# !56;02(K# 1)2#0
$'# 1$(%2, &")/# -('#.&#- $3$(%/& &"# '#.#*&)' .+2#/ $%- $-"#/()% 1)2#.+2#/ &"$& 1$K# &"#1
D)' !56< !"#, .$% (1(&$&# &"# %)'1$2 $.&()% )D '#.#*&(J# &) !56; $+&)$%&(:)-(#/<
!56 4&",')(-0/&(1+2$&(%3 (11+%)32):+2(%8
!5=78 2#$-(%3 &) &",')(- ",*#'$.&(J(&, 4",0 =" >&+-(7%$%<+ .-/0%(1($(+
*#'&",')(-(/178 )' 1$, .)1*2#&#2, :2).K !56
C#/&'+.&()% )D &"# &",')(- 32$%- -+# &) 6$/"(0
/&(1+2$&()% 4&",')(- /&(1+2$&()%0:2).K(%3 (10
1)&)N/ &",')(-(&(/ 46!7 (/ $ .)11)% .$+/# )D ",0
1+%)32):+2(%8 !5L=78 &"#'#:, (%"(:(&(%3 &",')(-
*)&",')(-(/1< U$&(3+#8 .)2- (%&)2#'$%.#8 :'$-,0
32$%- D+%.&()% 4",*)&",')(-(/17< I &"('- 3')+*

"
)D $%&(:)-(#/ 4!56 :(%-(%30(%"(:(&(%3 (11+%)0
32):+2(%/8 !L==7 (/ .$*$:2# )D /&(1+2$&(%3 !56
'#.#*&)'/ 9"(2# /(1+2&$%#)+/2, :2).K(%3 &"#
:(%-(%3 )D %$&+'$2 !56< !"(/ .$% '#/+2& (% #(&"#'
",*#'&",')(-(/1 )' ",*)&",')(-(/1<
:" 20&;*+< =(+*&+*
M'$J#/N -(/#$/# (/ &"# *')&)&,*# (11+%)3#%(.
",*#'&",')(- -(/#$/#< =& )..+'/ 1$(%2, (% 9)0
1#% $%- (/ $//).($&#- 9(&" &"# "$*2)&,*#/
6OI0C;E $%- 6OI0LP< !"# 1$(% D#$&+'# (/ -(D0
D+/# #%2$'3#1#%& )D &"# &",')(- 43)(&#'7Q )&"#'
&,*(.$2 D#$&+'#/ (%.2+-# *')&'+/()% )D &"# #,#0
:$22/ 4#?)*"&"$21)/7 $%- *'#&(:($2 1,?#-#1$8
$ /K(% &"(.K#%(%3 -+# &) &"# $..+1+2$&()% )D
1+.)*)2,/$.."$'(-#/< !"# (%.'#$/#- *')-+.0
&()% )D &",')(- ")'1)%#/ !E $%- !F (%.'#$/#/
&"# *$&(#%&N/ /#%/(&(J(&, &) .$&#.")2$1(%#/8 '#0
/+2&(%3 (% %#'J)+/%#//8 /9#$&(%38 "#$& (%&)2#'0
$%.#8 9#(3"& 2)//8 -($''"#$8 &'#1)'8 $%- &$.",0
.$'-($<
I+&)(11+%(&, &) &"# !56 '#.#*&)' (/ *'#0
.$'-($8 $%- 9#(3"& 3$(% $'# &,*(.$2 /,1*&)1/
4$7< B,?#-#1$8 $ 3#%#'$2(@#- .+&$%#)+/ #-#1$
1)/& .)11)%2, -#&#.&#- )% &"# D$.# 4/##
*")&)3'$*"78 (/ .$+/#- :, &"# /9#22(%3 )D 1+.)0
*)2,/$.."$'(-#/ (% &"# /K(%< !"# +%-#'2,(%3
.$+/# )D 6! $**#$'/ &) :# !6V &,*# ! .#22/
&"$& '#2#$/# !WU8 =O0A8 $%- =UW0!8 &"#'#:, /&(1+0
2$&(%3 &"# TCPX ! .#22/ '#/*)%/(:2# D)' &"# -#0
/&'+.&()% )D &",')(- &(//+#< !"# !0.#2201#-($&#-
-$1$3# &) &",')(- .#22/ *'#/+1$:2, 2#$-/ &) &"#
'#2#$/# )D $%&(3#%/ $%- &) /#.)%-$', *')-+.&()%
)D !GH0/*#.(D(. )' &",')32):+2(%0/*#.(D(. $+&)0
$%&(3#%/< =%D(2&'$&()% 9(&" 2,1*").,&#/ $%-8 (%
/)1# .$/#/8 D)'1$&()% )D .)1*2#&# 2,1*"
D)22(.2#/ .$% :# -#&#.&#- (% &",')(- &(//+# 4/##
*")&)3'$*"7< 6$/"(1)&)N/ &",')(-(&(/ (/ .2)/#2,
$//).($&#- 9(&" 6OI0C;E $%- 6OI0C;Y $%-
1$(%2, )..+'/ (% D#1$2#/< !"# *$&(#%&/ )D&#% '#0
1$(% $/,1*&)1$&(. D)' 1$%, ,#$'/ $%- -#J#2)*
.2(%(.$2 /,1*&)1/ )D ",*)&",')(-(/1 )%2, $D&#'
$-J$%.#- -#/&'+.&()% )D &"# &",')(- D)22(.2#/ "$/
)..+''#-<

!
/+1$:2, .$+/#- :, J('$2 $%&(3#%/ 9(&" $ "(3"
-#3'## )D ")1)2)3, 9(&" &"# '#.#*&)' 4!7<
! .#22/ )D &"# !6A &,*# (%-+.# *2$/1$ .#22 -(DD#'0
#%&($&()% $%- $%&(:)-, D)'1$&()% J($ =O0F $%-
=O0R< I+&)$%&(:)-(#/ $.&(%3 $/ $3)%(/&/ 4!5=7
@@A :(%- &) &"# !56 '#.#*&)'8 &"#'#:, /&(1+2$&(%3
 TSH
Target Ab
!#$%(77#'* .-/0%(1 =(+*&+*+

Effect of antibody
!
TSH Thyroglobulin (Tg) Tg-Ab
receptor
Microsomal TPO-Ab Decreased iodination of Tg
(TSHR)
antigen, thyroid-
TPO peroxidase TPO

T3 TSI Thyroid stimulating

I2 I 2 immunoglobulin:
I2 TSH-
I2 hyperthyroidism (Graves’ disease)
T4 Receptor
I2
TBII TSH-binding inhibitory
immunoglobulin:
T4 T3 hyper- or hypothyroidism
Thyro- TSBI Thyroid-stimulation
globulin blocking immunoglobulin:
hypothyroidism

:3('(?&3 677#'%3%)/
A. Autoantigens of thyroid B. Most important autoantibodies

APC TH2
Exophthalmos
Goiter
Viral
Heat antigen
intolerance Palpitations “mimicry”
Tachycardia of

Tremor

HLADR3+
Diarrhea

Weight
loss B cell
IL-4, IL-6 TSHR?

Exophthalmus
"
HLAB8+ Pretibial
myxedema
T3,T4
TSH TSHR
1. Clinical symptoms CT scan of the eye muscles
C. Graves’ disease 2. Immunopathogenesis 3. Endocrine orbitopathy

? HLA DR5 HLA DR3 Thin Goiter

Activation hair (often small)
IFN-!
of TNF CD8
IL-2 Macroglossia
CD4 cells
Deep,
hoarse
Damage voice
to thyroid cells
Bradycardia
Hashimoto (histology)
Release of
autoantigen
Cold
intole-

!
rance
Hypo-
TPO and reflexia
Tg Ab

D. Immunopathogenesis of Myxedema
Hashimoto’s thyroiditis E. Clinical signs of hypothyroidism
@@B

"
! )+-(?.$%' 6%,+(,+,
!"#$%&"' ( )*+(,-%&. /-0)-"*' 0*1$%(+*# +/*
*"+02 -3 1%$.-#* 30-) +/* ,%--4 &"+- +/* .*%%#5
6&(,*+*# )*%%&+$# .(" 4*7*%-8 4$* +- &"#$%&"
4*3&.&*".2 9+28* ! 4&(,*+*#: &"#$%&";4*8*"4*"+
4&(,*+*# )*%%&+$#' !66<= -0 4$* +- +(01*+ +&##$*
0*#&#+(".* +- &"#$%&" 9+28* !! 4&(,*+*#=5 >28* !
4&(,*+*# &# )-#+ .-))-"%2 (++0&,$+(,%* +- (
8(+/-%-1&.(% ($+-&))$"* 0*(.+&-"5
!" #$%&%'($ )(&%*+,-(-%.&,
>28* ! 4&(,*+*# -..$0# )(&"%2 &" 2-$"1*0 8(;
+&*"+#5 >/* &"(,&%&+2 +- &".-08-0(+* 1%$.-#*
&"+- +/* .*%%# 0*#$%+# &" &".0*(#*4 ,%--4 1%$.-#*
%*7*%# ("4 &".0*(#*4 8%(#)( -#)-%(0&+25 >/&#' &"
+$0"' %*(4# +- -#)-+&. 4&$0*#&# ?&+/ &".0*(#*4
#$%&%'($ 5::9&.$.8;
$0&"(02 30*@$*".2 98-%2$0&(=' +/&0#+' ("4 &";
.0*(#*4 3%$&4 &"+(A* 98-%24&8#&(=5 >/* 8(+&*"+#
/(7* (" &".0*(#*4 (88*+&+* 98-%28/(1&(=' ,$+
%-#* ?*&1/+ ,*.($#* +/* ,-42 &# $"(,%* +-
$#* +/* 1%$.-#*5 B(++2 (.&4# (0* 0*%*(#*4 30-)
3(++2 +&##$*# ("4 (0* )*+(,-%&C*4 ,2 +/* %&7*0
&"+- A*+-"* ,-4&*#' %*(4&"1 +- )*+(,-%&. (.&4-;
#&#5 D*##*% 4()(1* 94&(,*+&. )&.0-("1&-8(+/2=
&# 4$* +- (..$)$%(+&-" -3 1%2.-#2%(+*4 80-+*&"#
("4 8-%28*8+&4*# &" +/* 7*##*% ?(%%5 E%2.-#2%(;
"
+&-" *"4;80-4$.+# .($#* .0-##;%&"A# ,*+?**"
8-%28*8+&4*#' +0(88&"1 -3 %&8-80-+*&"#' ("4
.*%% (.+&7(+&-"' %*(4&"1 +- (+/*0-#.%*0-#&#5 >/&#
&# ( )(F-0 %(+* .-)8%&.(+&-" -3 4&(,*+*#' ?/&./
.(" %*(4 +- #+0-A*' A&4"*2 3(&%$0*' ,%&"4"*##' ("4
/*(0+ 3(&%$0*5
/" 0+&+-%' 12+3%,4.,%-%.& %& 566)
>/* 80*#*".* -3 GHI;6J ("4 ;6K (%%*%*#' ?/&./
.-"+(&" ( #*0&"*' (%("&"*' -0 7(%&"* 10-$8 (+ 8-;
#&+&-" LM -3 +/* ! ./(&"' &".0*(#*# +/* 0&#A -3
!66< 9#** (%#- 85 LN=5 >/* 80*#*".* -3 (#8(0+(+*
&" +/&# 8-#&+&-" &# (##-.&(+*4 ?&+/ ( 4*.0*(#*4
&".&4*".* -3 !66<5 O-;.(%%*4 P4&(,*+-1*"&.Q
(%%*%*# (88(0*"+%2 ,&"4 8*8+&4*# ?&+/ ( "*1(;
+&7* ./(01* (+ 8-#&+&-" R' ?/*0*(# 4&(,*+*#;
0*#&#+("+ (%%*%*# ?&+/ (" (#8(0+(+* )-%*.$%* (+
8-#&+&-" LM ,&"4 8*8+&4*# ?&+/ ( 8-#&+&7*%2
./(01*4 #*0&"*' 1%2.&"*' -0 (%("&"* )-%*.$%*
(+ 8*8+&4* 8-#&+&-" R5 O$./ 8*8+&4*# (88*(0
+- +$0" +/* &))$"* 0*#8-"#* +-?(04# ( >GS;
+28* 0*#8-"#*' ?/*0*(# "*1(+&7*%2 ./(01*4
8*8+&4*# +*"4 +- &"4$.* ( .2+-+-T&. &))$"*
!
@AB
0*#8-"#* -3 +/* >GU +28*5
#" 1(-7.8+&+-%' #.&'+4-,
>/* #*0$) -3 !66< 8(+&*"+# .-"+(&"# ($+-("+&;
,-4&*# +- 7(0&-$# &#%*+ .*%% ($+-("+&1*"#' #$./ (#
&"#$%&"' /*(+ #/-.A 80-+*&" VW 9/#8VW= ("4'
)-#+ &)8-0+("+%2' 1%$+()(+* 4*.(0,-T2%(#*
VL 9EI6VL=5 O&".* X-T#(.A&*7&0$# 80-+*&"#
/(7* ( 10*(+ 4*10** -3 /-)-%-12 ?&+/ +/*
EI6VL ("+&1*"' +/* 80-4$.+&-" -3 .0-##;0*(.+;
&"1 ("+&,-4&*# &# (##$)*4 +- -..$05 >/* ("+&,-;
4&*# .($#* &"3%())(+&-" -$+#&4* +/* 8(".0*(+&.
,*+( &#%*+ .*%%# 98*0&;&"#$%&+&#=' ?/&./ 0*#$%+# &"
+/* 0*.0$&+)*"+ -3 ("+&1*";80*#*"+&"1 .*%%#5
>/*#* .(" .(8+$0* ("+&1*"# 30-) +/* 4()(1*4
&#%*+ .*%%# ("4 &"4$.* ( >;.*%% 0*#8-"#* ?&+/&"
+/* ,*+( &#%*+ .*%%# 9&"+0(;&"#$%&+&#=5 I .2+-+-T&.
>GU 0*#8-"#* 80*4-)&"(+*# &" &"4&7&4$(%#
?&+/ +/* 80*4&#8-#&"1 GHI (%%*%*#5 Y".* +/*
80&)(02 &"3*.+&-" /(# -..$00*4' #*7*0(% 2*(0#
)(2 8(## ,*3-0* +/* 3$%%;,%-?" 4&#*(#* )("&;
3*#+# ,*.($#* #)(%% @$("+&+&*# -3 &"#$%&" (0*
#$33&.&*"+ +- 80*7*"+ #2)8+-)#5
6" !9-.%::9&+ 1.$;8$(&39$(2 <;&32.:+
=!1<>
IZO 4*7*%-8# (# ( 0*#$%+ -3 )$%+&8%* 1*"*+&. 4*;
3*.+# ?/&./ -..$0 #&)$%+("*-$#%2 -0 4$* +- ("
&))$"* 0*#8-"#* (1(&"#+ ("+&1*"# *T80*##*4
,2 4&33*0*"+ *"4-.0&"* -01("#5 >/0** #$,+28*#
.(" ,* 4&#+&"1$&#/*45 !"#$ % &# )-#+ .-))-"
&" +**"(1*0# ("4 )("&3*#+# (# (40*"-.-0+&.(%
&"#$33&.&*".2 9&))$"* 0*#8-"#* +- SU;/240-;
T2%(#*' SU;YG=' /28-8(0(+/20-&4&#) 9($+-;
("+&,-4&*# +- 8(0(+/20-&4 .(%.&$) #*"#-0='
("4 0*.$00*"+ )$.-.$+("*-$# .("4&4(% &"3*.;
+&-"#5 G28-1-"(4&#) #-)*+&)*# -..$0# 4$*
+- ($+-("+&,-4&*# +- 8NLW #&4* ./(&" .%*(7(1*
*"C2)* 98NLW#..= ("4 UM";YG *"C2)*5 IZO
&# #-)*+&)*# (##-.&(+*4 ?&+/ ./0-"&. (.+&7*
/*8(+&+&# 9($+-("+&,-4&*# +- )&.0-#-)(% ("+&;
1*"# -3 +/* %&7*0 ("4 A&4"*2=5 Z*0"&.&-$# ("*)&(
)(2 (%#- -..$0 &3 ($+-("+&,-4&*# +- &"+0&"#&.
3(.+-0 (0* 80*#*"+ 9#** 85 SW[=5
I1*;&"4*8*"4*"+ &"#$ %% IZO &# ./(0(.+*0&C*4
,2 +/* .-;-..$00*".* -3 (40*"-.-0+&.(% &"#$33&;
.&*".2 ("4 ($+-&))$"* +/20-&4 4&#*(#* 9#**
85 SUN=5 >/&# #$,+28* &# (##-.&(+*4 ?&+/ !66<
&" LW \ -3 .(#*#5 !"#$ %%% &# ./(0(.+*0&C*4 ,2
+/* F-&"+ -..$00*".* -3 +/20-&4 4&#*(#* ("4
-+/*0 ($+-&))$"* 4&#*(#*# &" +/* (,#*".* -3
(40*"-.-0+&.(% &"#$33&.&*".25
 6%(?+-+, )+$$%-9, (&3 !9-.%::9&+ 1.$;8$(&39$(2 <;&32.:+

Microangiopathy
Risk
P1
!
Stroke TCR
Binding of
Retinopathy DRB1-0405 peptides with
Cataract, DQB1-0201 negative charge
glaucoma DQB1-0302 P11 at position 9
Hypertension DQB1-0502 (Asp/Glu) IFN-!
TNF-"
Ischemic Serine/Ala TH1 IL-12
cardiopathy at AA 57
Keto- Glomerulo- P1
acidosis sclerosis Protection
Autonomous
Polydipsia neuropathy TCR
Binding of
Polyphagia Peripheral DRB1-0403 peptides with
vasculopathy DQB1-0301 positive charge
Polyuria Gangrene DQB1-0602 P11 at position 9

#$%&%'($ 5::9&.$.8;
(Ser/Gly/ALA)
Aspartate IL-4
1. Early symptoms 2. Late complications at AA 57 TH2 IL-10

A. Clinical manifestations B. Genetic control

#-islet
Disease
Mass of #-cells signs

Peri-insulitis Intrainsulitis
TH1
5 10 20 15 25
Years after disease onset

Release of
other
"
autoantigens
(e.g. insulin)
APC
Infection Molecular Anti-GAD-
e.g. Cox- mimicry immune
sackie virus of GAD response Local immune response
C. Hypothetical pathogenesis

Genetic Adrenal 21-OH Type I: juvenile form

defects cortex Adrenocortical insufficiency
Hypoparathyroidism
Parathyroid Calcium- Candidiasis
gland sensor
Auto- Hypogonadism,
anti- chronic hepatits,
bodies Interstitial 17"-OH/ pernicious anemia
with Leydig p450scc less frequently
multiple cells
reactivity Type II:
Cytochrome Adrenocortical insufficiency

!
Liver p 450IID6 Autoimmune thyropathy

Gastric Intrinsic Type III:

parietal cell factor Autoimmune thyropathy
Molecular Hypogonadism
mimicry Antigens in steroid-producing cells Ovarian insufficiency
D. Autoimmune polyglandular syndrome (APS)
@AC

"
! =%(.) 6*4%(4%
!" #$%&'()*+ ,%-%.
!"#$%&'() *#+#, -!./ (0 &1 (1*2&%%&'3,4 5,36
)#00 (1+32+(17 '"# "#&,'8 93(1'08 0:(18 &1; )#1',&2
1#,+3$0 040'#% -!/8 <"()" $0$&224 =#7(10
&,3$1; >?@ <##:0 &*'#, & '310(22&, (1*#)'(31
<('" 7,3$5 A 0',#5'3)3))(B C"# &)$'# 04%56
'3%08 <"()" %&4 5#,0(0' *3, & *#< <##:0 $5
'3 0#+#,&2 %31'"08 03%#'(%#0 )&$0# (,,#+#,0(6
=2# ;&%&7#B D&2+$2&, *(=,30(08 *3, #E&%52#8 (0
31# 3* '"# %30' )3%%31 )&$0#0 3* &)F$(,#;
"#&,' ;(0#&0# (1 )"(2;,#1 &1; '##1&7#,0B G&,;('(0
&1; 5324&,'",('(0 &,# '"# %30' )3%%31 )2(1()&2
%&1(*#0'&'(310B C"# )&,;('(0 %&4 (1+32+# '"#
#1;3)&,;($% -+&2+#0/8 %43)&,;($%8 &1; 5#,(6
)&,;($%H %(',&2 +&2+# (1+32+#%#1' (0 '45()&2B
57*:*+(7 >''&:272?1
C"# &,'()$2&, (1+32+#%#1' %&1(*#0'0 &0 %(7,&6
'3,4 5324&,'",('(0 %&(124 (1+32+(17 '"# 2&,7#
93(1'0B C<#1'4 5#,)#1' 3* 5&'(#1'0 "&+# (1+36
2$1'&,4 %$0)2# )33,;(1&'(31 ;(03,;#,0 -I4;#16
"&%J0 )"3,#&/B K'"#, 2#00 )3%%31 %&1(*#0'&6
'(310 (1)2$;# #,4'"#%& %&,7(1&'$%8 &
1315,$,('()8 #+&1#0)#1' ,&0" 5,3;$)(17 ,#;;(0"
053'0 <('" ,3$1;#; =3,;#,0 &1; & 5&2# )#1'#,8
&1; 0$=)$'&1#3$0 13;$2#0 31 '"# #E'#103, 0$,6
*&)# 3* '"# 93(1'0B C"# &*3,#%#1'(31#; %&1(*#06
"
'&'(310 ,#5,#0#1' '"# %&93, ;(&7130'() ),('#,(&
-L31#0 ),('#,(&/ *3, ,"#$%&'() *#+#,B C"# %(13,
),('#,(& &,# *#+#,8 #2#+&'#; MI! &1; G!N8 &1; &
5,32317#; N! (1'#,+&2 -MOP/B
N"&,4173'310(22('(0 ;$# '3 (1*#)'(31 <('"
7,3$5 A !6"#%324'() !"#$%"&'&''() &2<&40 5,#6
)#;#0 ,"#$%&'() *#+#, -"/B Q3<#+#,8 3124
&,3$1; @ R 3* &22 $1',#&'#; )&0#0 3* 0',#5'3)3)6
)&2 5"&,417('(0 2#&; '3 !.H 0',#5'3)3))&2 (1*#)6
'(310 3* '"# 0:(1 1#+#, ;3B K124 +(,$2#1'8 #1)&56
0$2&'#; 0',&(10 '"&' (1;$)# & 0',317 (%%$1#
,#05310# '3 0',#5'3)3))&2 &1'(7#10 -#/ &,# )&56
&=2# 3* (1;$)(17 !.B C"#0# !"#$%"&'&''() 0',&(10
&,# %&(124 S '45#0 >8 @8 T8 U8 &1; >VB C"# 0',#56
'3)3))&2 &1'(7#10 ),3006,#&)' <('" "$%&1 )&,6
;(&) '(00$#8 #05#)(&224 0&,)32#%%() 5,3'#(10
&1; )&,;(&) %430(18 =$' &203 <('" &1'(7#1 0',$)6
'$,#0 (1 '"# 93(1'0 3, =,&(1B M5(;#%(3237()&2 0'$6
;(#0 "&+# ;#%310',&'#; & *&%(2(&2 ;(0530('(31
&003)(&'#; <('" '"# QWA "&523'45#0 X!>8
X!Y8 X!@8 &1; X!ZB
C"# 7,&1$23%&0 &003)(&'#; <('" !. &,# ,#6
*#,,#; '3 &0 *)'+&,,-) .&/0$)B C"#0# '45()&224 ;#6
!
@A@
+#235 1#&, '"# 0%&22#, +#00#20 3* '"# "#&,' -$/B
C"#4 &,# )"&,&)'#,([#; =4 )#1',&2 &,#&0 3* *(=,(6
13(; 1#),30(0 -;#7#1#,&'(31 3* )322&7#1/ <('"
=$1;2#; %$0)2# *(=#,0 '"&' &,# 0$,,3$1;#;
=4 %3131$)2#&, )#220 &1; *(=,3"(0'(3)4'() A0)"6
3**J0 )#220 &1;8 (1 03%# )&0#08 %$2'(1$)2#&'#
A0)"3**J0 7(&1' )#220B A0)"3**J0 =3;(#0 ;#+#235
&0 & ,#0$2' 3* ;(,#)' )#22 ;&%&7# &1; (%%$1#
)3%52#E 5,#)(5('&'(31 &*'#, '"# ,&5(; *3,%&'(31
3* &1'(=3;(#0 '3 +&,(3$0 ),3006,#&)'(17 0',#5'36
)3))&2 &1'(7#10B \1;$)'(31 3* '"(0 (%%$1# ,#6
05310# '&:#0 52&)# (1 23)&2 24%5" '(00$# ;$,(17
5"&,(17('(0]'310(22('(0 -"/B
/" 012+(.3*)*4
12&'3#/0"0) (0 )&$0#; =4 & 1$%=#, 3* 5&'"36
7#10B \1 '"# ^#0'#,1 <3,2;8 G3E0&):(#+(,$0#0
&,# '"# %30' )3%%31 )&$0#B \1 I3$'" A%#,()&8
31 '"# 3'"#, "&1;8 (' (0 %30' 3*'#1 )&$0#; =4
5&,&0('#0 -G"&7&0J ;(0#&0#8 )&$0#; =4 4#2%35&6
)&73 '#(80/B \1 '"# (1('(&2 5"&0#8 ,#52()&'(31 3*
'"# 5&'"37#1 (1 '"# %43)4'#0 2#&;0 '3 )#22 240(0
&1; %431#),30(0B SQG %32#)$2#0 &1; )#22 &;6
"#0(31 %32#)$2#08 #05#)(&224 \GAS6>8 &,# #E6
5,#00#; 31 '"# %43)4'#0B W3)&2 5,#0#1'&'(31
3* +(,&2 &1'(7#10 '"#1 3))$,08 2#&;(17 '3 '"# (16
;$)'(31 3* "$%3,&2 &1; )#22$2&, (%%$1# ,#6
05310#0B C_. 5,3%3'#0 '"# 7#1#,&'(31 3* )4'36
'3E() C )#2208 &1; ),3006,#&)'(17 &1'(=3;(#0 2#&;
'3 (1),#&0#; )#22 ;&%&7#B C"# ;#0',$)'(31 3*
%43)&,;(&2 '(00$#0 2#&;0 '3 '"# ,#2#&0# 3* (1',&6
)#22$2&, 5,3'#(108 0$)" &0 %430(18 <"()" <#,#
5,#+(3$024 (713,#; =4 '"# (%%$1# 040'#%B
5" 6.%447%.84 91:3.2'% (:3
;24)<%.*+(.3*2)2'1 91:3.2'%
9&)"672&'3#/03: 05,3#'"0&5 )25/#&7$ -;#$)):$#-)
)25/#&7$/ (0 &1 &)$'# ;(0#&0# &003)(&'#; <('"
*#+#,8 5#,()&,;('(08 &1; 52#$,('(0 <"()"8 (1
%30' )&0#08 0'&,'0 <('"(1 >?Y <##:0 '3 & *#<
%31'"0 &*'#, &)$'# %43)&,;(&2 (1*&,)'(31B
9&)"6%$#0'3#/0&"&72 )25/#&7$ %&1(*#0'0 <('"
0(%(2&, 04%5'3%0 &1; ;#+#2350 <('"(1 Y <##:0
3* "#&,' 0$,7#,4B `3'" ;(0#&0#0 &,# &003)(&'#;
<('" '"# *3,%&'(31 3* &1'(%43)&,;(&2 &1'(=36
;(#0 '"&' (1;$)# *#+#, &1; 5#,()&,;(&2 (1*2&%6
%&'(31B I(1)# (' 3))$,0 (1 '"# &=0#1)# 3* &
0',317 (1*2&%%&'3,4 0'(%$2$08 '"# &$'3(%6
%$1# 5,3)#00 (0 0#2*62(%('#;B C,#&'%#1' )316
0(0'0 %&(124 3* =#; ,#0' &1; 1310'#,3(;&2
&1'(6(1*2&%%&'3,4 ;,$70B
Minor criteria
#$%&'()*+ ,%-%.B 012+(.3*)*4B (:3 ;24)*:C(.+)*2: 91:3.2'%

Major criteria
!
Fever (Pan-)carditis

Erythema
marginatum
Arteriole
High ESR Chorea
(uncontrol-
lable
CRP movements)
3. Histopathological picture
Subcutaneous
nodules
Long PR interval
Arthritis

57*:*+(7 >''&:272?1
1. Primary manifestations

Cross
reactivity:
myosin,
Capsule tropomyosin,
Cell wall synovia,
cartilage, Streptococcal Lymph
Protein brain pharyngitis nodes/tonsils

"
antigens = M
Cytoplasm

Group- Valves
specific
carbohydrates
Neurons of
Mucopeptide subthalamic
Cytoplasmic and caudate
membrane nuclei
Valvular Aschoff’s Fibrinous
2. Streptococcal antigens vegetations bodies pericarditis
A. Rheumatic fever 4. Pathogenesis

Cytotoxic
reaction

Bacteria

CD8
Spirochetes MHC II 1 week– After
4 months cardiothoracic
CD4 after myocardial surgery
infarction
Parasites
Release of
myocardial
Rickettsia antigens

!
Anti-
Fungi Infection Expression sarco-
of microbial lemmal Ab
antigens, Cross-
adhesion- Anti-
Viruses reactive
molecules myosin Ab
antibodies
B. Myocarditis C. Dressler’s syndrome
@AA

"
! @68%$($)*+,( >*06,060
!"#$%&#' ()#'*+(%( !"#$ %& ' (%&)'&) *+ ,-) .)/,0'1
/)02*3& &4&,)5 *+ 3/6/*7/ ),%*1*849 :, %& .-'0;
'.,)0%<)( =4 ,-) >0)&)/.) *+ 531,%>1) +*.% *+ ();
54)1%/%<',%*/ !>1'?3)&$ ,-', 1',)0 =).*5)
&.1)0*,%.9
!" #$%&'$($)*+,( ,-. /*01$&,1'$($)*+,(
2*-.*-)0
@)80'(',%*/ *+ ,-) 1%>%(;0%.- %&*1',%/8 1'4)0 *+
/)02) >0*.)&&)& !'A*/&$B 7-%.- %& +*05)( =4
*1%8*()/(0*.4,)&B *..30& %/ ,-) ()54)1%/%<';
,%*/ <*/)&9 C'014 1)&%*/& !!$ '>>)'0 '& >)0%2);
/31'0 <*/)& *+ 145>-*>1'&5'.4,%. %/+%1,0',%*/
7%,- ()54)1%/%<',%*/ *+ %/(%2%(3'1 'A*/&9
D',) 1)&%*/& '0) .-'0'.,)0%<)( =4 ,-) %/2*12);
<(*-*+,( =778-$($)9
5)/, *+ 531,%>1) 'A*/& !"$9 E1%'1 +%=0%1& '/(
+*'54 .)11& '0) >0)&)/,9 F-)&) %/.13() 5'.0*;
>-'8)& *0 5%.0*81%'1 .)11& !,-) GH#;0)&%()/,
5'.0*>-'8)&$ ,-', -'2) >-'8*.4,*&)( 54)1%/9
F-) +*.% *+ ()54)1%/%<',%*/ .'/ =) 2%&3'1%<)(
*/ 5'8/),%. 0)&*/'/.) %5'8%/8 !"I:$J ,-)%0
1*.',%*/ .*/&,'/,14 .-'/8)& *2)0 ,-) .*30&)
*+ ,%5) !#$9
3" 45&6%*76-1,( !81$*778-6
"
4-+6&',($796(*1*0 :4!4;
K/ '/%5'1 5*()1 +*0 "# .'/ =) %/(3.)( =4
%553/%<%/8 '/%5'1& !5%.)B 0',&$ 7%,- >30%+%)(
54)1%/ >0*,)%/&B &3.- '& 54)1%/ ='&%. >0*,)%/
!"LM$B >0*,)*1%>%( >0*,)%/ !MDM$B 54)1%/;*1%8*;
()/(0*.4,) 814.*>0*,)%/ !"NE$B '/( 54)1%/;
'&&*.%',)( 814.*>0*,)%/ !"KE$9 K.,%2',)( F .)11&
+0*5 ,-) %553/%<)( '/%5'1& .'/ ,0'/&5%, ,-)
(%&)'&) ,* -)'1,-4 '/%5'1&9
<" =778-$&,1'$)6-61*+ #6+',-*070
K 8)/),%. >0)(%&>*&%,%*/ !ODK '&&*.%',%*/P
@IQRS@TU$ ,*8),-)0 7%,- )A,)0/'1 +'.,*0& !>0);
&35'=14 2%0'1 %/+).,%*/B )989B 7%,- -35'/ -)0;
>)&2%03& U$ .'/ 1)'( ,* ,-) 5%80',%*/ *+ '3,*;
0)'.,%2) F .)11& ,-0*38- ,-) =1**(V=0'%/
='00%)0 %/,* ,-) GH#9 F-%& %& 5)(%',)( =4 ,-) )A;
>0)&&%*/ *+ '(-)&%*/ 5*1).31)& */ 145>-*;
.4,)& '/( )/(*,-)1%'1 .)11&9 "%.0*81%' >0)&)/,
54)1%/ >)>,%()& ,* ,-) '.,%2',)( F .)11&B 7-%.-
(%++)0)/,%',) 1*.'114 %/,* FOQ '/( FOW .)11&9 F-)
FOW .)11& %/(3.) L;.)11 '.,%2',%*/ '/( ,-)
!
>0*(3.,%*/ *+ 54)1%/;0)'.,%2) '3,*'/,%=*(%)&B
7-%.- .'/ %/.0)'&) 54)1%/ ()8)/)0',%*/
'/( %/(3.) ,-) '((%,%*/'1 0)1)'&) *+ '/,%8)/&9
F-%& %& 0)+1).,)( =4 +%/(%/8& *+ '/ *1%8*.1*/'1
!;81*=31%/ +0'.,%*/ %/ .)0)=0*&>%/'1 +13%( !G#X$9
ABC FOQ .)11& '.,%2',) '&,0*.4,)&B 5%.0*81%'B '/(
5'.0*>-'8)& 7-%.-B %/ ,30/B 0)1)'&) :D;QB
FHX;"B /%,0%. *A%() !HN$B OWNWB '/( +0)) 0'(%.'1&9
F-)&) %/(3.) '>*>,*&%& *+ *1%8*()/(0*.4,)&
'/( >0*5*,) ,-)%0 >-'8*.4,*&%& =4 5%.0*81%'
'/( 5'.0*>-'8)&9
>" <(*-*+,( 26,18%60
F-) ()54)1%/%<',%*/ *+ 'A*/& .'/ %5>'%0 *0 )/;
-'/.) /)30*/'1 &%8/'1 ,0'/&5%&&%*/B ()>)/(%/8
*/ 7-),-)0 &,%531',*04 *0 %/-%=%,*04 /)30*/&
'0) '++).,)(9 :+ &,%531',*04 /)30*/& '0) (';
5'8)(B 1%5= 7)'6/)&&B %5>'%0)( 2%&%*/B '/(
','A%' .'/ *..309 C/-'/.)5)/, *+ &%8/'1 ,0'/&;
5%&&%*/ (3) ,* ,-) ('5'8) *+ %/-%=%,*04 /)3;
0*/& 1)'(& ,* ,*/%. .*/,0'.,%*/&B >'0)&,-)&%'B
'/( D-)05%,,)Y& &%8/ !,-) *..300)/.) *+ )1).;
,0%.;1%6) &-*.6& ,-', &>0)'( +0*5 ,-) /).6
(*7/ ,* ,-) 1)8& 3>*/ +1)A%*/ *+ ,-) -)'($9
F-) (%&)'&) >0)&)/,& %/ 5*&, .'&)& 7%,- '.3,)
)>%&*()& +*11*7)( =4 >'0,%'1 0)5%&&%*/& !0)1'>;
&%/8;0)5%,,%/8 "#$B =3, -'& ' .-0*/%. >0*80)&;
&%2) .*30&) %/ '=*3, QZVQR [9 F-) &45>,*5& '0)
5%1( %/ .'9 WR [ *+ ,-) >',%)/,&9
4" !&&%$,+'60 1$ ?%6,176-1
G*0,%.*&,)0*%(& '0) ,-) 5*&, %5>*0,'/, (038&
+*0 ,0)',5)/, *+ 0)1'>&%/8;0)5%,,%/8 "# !!$9
K0*3/( */);,-%0( ,* */);-'1+ *+ ,-) >',%)/,& 0);
&>*/( ,* :XH;#B =3, ,-) (038Y& )A'., 5).-'/%&5
*+ '.,%*/ %& 3/6/*7/9 #4/,-),%. >*14>)>,%()
.*5=%/',%*/& !813,%0'5)0 '.),',)$ %5%,',) ,-)
&,03.,30) *+ "LM '/,%8)/& '/( '0) 0)>*0,)(
,* 0)&,*0) ,*1)0'/.)9 K<',-%*>0%/)B ' >30%/) '/';
1*83)B %/-%=%,& =*,- '/,%=*(4 >0*(3.,%*/ '/(
,-) .)1131'0 %553/) 0)&>*/&)9 :/,0'2)/*3&
-%8-;(*&) %553/*81*=31%/& .'/ =) =)/)+%.%'19
K 5*/*.1*/'1 '/,%=*(4 ,* "\ %/,)80%/ -'& 0);
.)/,14 &-*7/ .1%/%.'1 '.,%2%,49
F0)',5)/, *+ .-0*/%. >0*80)&&%2) "# 0);
?3%0)& &,0*/8)0 %553/*&3>>0)&&'/,&B &3.- '&
5),-*,0)A',)B .4.1*>-*&>-'5%()B '/( .4.1*&;
>*0%/)J :XH;# '1&* '>>)'0& ,* =) )++).,%2) %/
&*5) *+ ,-)&) >',%)/,& !"$9 CA>)0%5)/,'1 ,0)',;
5)/, &,0',)8%)&B %/.13(%/8 ,-) 3&) *+ '/,%.4,*;
6%/) '/,%=*(%)& *0 54)1%/ >)>,%()& ,* '/)08%<)
54)1%/;0)'.,%2) F .)11&B -'( (%&'>>*%/,%/8 0);
&31,& *0 %/(3.)( 7*0&)/%/8 *+ ,-) (%&)'&)9 :/
>'0,%.31'0B ,0%'1& 7%,- FHX;=1*.6%/8 '/,%=*(%)&
7)0) &,*>>)( =).'3&) *+ 7*0&)/%/8 *+ &45>;
,*5&9
 #8(1*&(6 D+(6%$0*0
!

1. Early lesion 2. Late lesion 3. MRI

A. Morphological and histopathological findings

<(*-*+,( =778-$($)9
Myelin proteins: Genetic Reduced Phago-
MBP predisposition myelin synthesis, cytosis
PLP (DR15, DQ6) + noxious agent apoptosis
MOG (Virus? Mimicry?)
MAG

IL-1, TNF-!, NO, H2O2

Release of
Encephalitis myelin antigens

T cell transfer

Disease
transfer
Diapedesis of
autoreactive
T cells

CD4
Macro-
phage

Microglia
Astrocytes

TH1
IL-2
TNF-!
IFN-"
Myelin
auto-Ab

"
IL-4
TH2 IL-10
Activation
B. Experimental autoimmune
encephalitis (EAE) C. Immunopathogenetic mechanisms

Reduced signal transmission Increased signal transmission 1. Treatment of

relapsing-remitting MS
Stimulating
neuron Corticosteroids, IFN-#,
polypeptides (glutiramer),
Stimulating Inhibitory azathioprine,
neuron neuron intravenous immunoglobulins

2. Treatment of primary
2. progressive MS

Paresis
Impaired
vision

D. Clinical features
Ataxia Paresthesia

Tonic
contractions
Lhermitte’s
syndrome
Methotrexate,
cyclophosphamide, (IFN-#),
cyclosporine

E. Treatment approaches
!
ABE

"
! =,$+1&1>%7'& ?%4,'4,4
!" #$%&&'%()*'++,- ./(0+12,
!"#$$%#&'(%))*+ ,-&.)/0* 1!(234 /) 5!"#$% &'()*
+%#,',!-."#(.$./46 #, %& %7"8* .*0-*$#&#9#&: #&;
<$%00%8#/& /< 8=* >*)#>=*)%$ &*)?*, 7=%)%78*);
#9*. @- %,7*&.#&:4 ,-00*8)#7%$ 0/8/) >%)%$-,#,
/< 8=* 0",7$*, /< 8=* $#0@,4 *-*,4 <%7*4 %&. )*;
,>#)%8/)- 8)%78 1!3A B=* >)/:&/,#, #, ://.A C&$*,,
,*?*)* )*,>#)%8/)- <%#$")* .*?*$/>,4 0/,8 >%;
8#*&8, )*7/?*) 7/0>$*8*$-A B=* 0/)8%$#8- )%8*
#, %)/"&. D EA F/)* 8=%& 8G/;8=#)., /< 8=* >%;
8#*&8, )*>/)8 % >)*7*.#&: #&<*78#/&4 ","%$$- G#8=
0!1&)('2!"$%, 3%3#+.4 @"8 %$,/ G#8= 7-8/0*:%;
$/?#)", 1HFI3 /) J>,8*#&'(%)) ?#)", 1J(I3A
B=#, ,"::*,8, 8=%8 0/$*7"$%) 0#0#7)- G#8= >*);
#>=*)%$ 0-*$#& #, #&?/$?*. #& 8=* .*?*$/>0*&8
;&%(%7'& @22$(1&1>/
/< !(2 1"3A 2"):#7%$ #&8*)?*&8#/&, 8=%8 7%",* 8=*
)*$*%,* /< &*")/& %&8#:*&, 7%& %$,/ >)*7#>#8%8*
8=* .#,*%,*4 %, 7%& $-0>=/0%, 8=%8 #&."7*
%"8/)*%78#?* B;7*$$ >)/$#<*)%8#/&A B=* %"8/%&8#;
:*&, #&?/$?*. %)* 8=/":=8 8/ @* 0-*$#& %&8#;
:*&, 1KL4 KM4 KN3 %&. :%&:$#/,#.*,A O78#?%8*.
%&8#:*&;>)*,*&8#&: 7*$$, 1OKH,3 >)*,*&8 8=*
%"8/%&8#:*&, %&. #&."7* BPM %&. BPN )*;
,>/&,*,A O78#?%8*. 0%7)/>=%:*, >=%:/7-8/,*
0-*$#& %&. >)/."7* >)/#&<$%00%8/)- 7-8/;
"
Q#&*,4 )*%78#?* /R-:*& )%.#7%$,4 &#8)#7 /R#.*4
%&. >)/8*%,*,A K$%,0% 7*$$, ,8#0"$%8*. @- BPN
7*$$, >)/."7* %"8/%&8#@/.#*, 8/ 0-*$#&A 2#&7*
8=* %"8/%&8#@/.#*, >$%- %& #0>/)8%&8 )/$* #&
8=* >%8=/:*&*,#, /< !(24 #8 #, &/8 ,")>)#,#&:
8=%8 >$%,0%>=*)*,#, =%, % @*&*<#7#%$ *<<*78 /&
8=* 7$#&#7%$ 7/"),* /< 8=* .#,*%,* 1#3A P#:=;
./,* #&8)%?*&/", #00"&/:$/@"$#&, 1SIS!,3
,**0 8/ @* *?*& 0/)* *<<*78#?*A SIS!, 7/&8%#&
&%8")%$$- /77"))#&: %&8#;#.#/8->#7 %&8#@/.#*,
8=%8 >)/@%@$- #&=#@#8 8=* @#&.#&: /< 0-*$#&;
,>*7#<#7 %"8/%&8#@/.#*,A B=* #00"&/:$/@"$#&,
%$,/ ,%8")%8* 8=* T7 )*7*>8/), /& 0%7)/>=%:*,4
8=*)*@- #&=#@#8#&: 8=* >=%:/7-8/,#, /< %"8/%&8#;
@/.-;7/%8*. >*)#>=*)%$ &*)?* 7*$$,A
*" 3'42$44,(54 6(7,89'&%:%4
U%,0",,*&V, *&7*>=%$#8#, #, % .#,*%,* /< 7=#$.;
=//.4 G=#7= #, 7=%)%78*)#9*. @- ,*?*)*4 "&8)*%;
8%@$* *>#$*>8#7 %88%7Q, G#8= .*0*&8#% %&. </7%$
7*)*@)%$ #&<$%00%8#/&A O"8/%&8#@/.#*, 8/ 8=*
8=#). ,"@"&#8 /< 8=* :$"8%0%8* )*7*>8/)
!
1!$"UW3 7%& @* .*8*78*. #& ,/0* /< 8=* >%8#*&8,A
!$"8%0%8* #, %& *R7#8%8/)- &*")/8)%&,0#88*)
8=%8 $*%., 8/ 8=* .*>/$%)#9%8#/& /< 7*&8)%$ &*";
)/&,A O&8#;!$"UW %"8/%&8#@/.#*, %78 %, )*7*>8/)
%:/&#,8, 8=%8 @#&. 8/ 8=* )*7*>8/) 0"7= $/&:*)
ABC 8=%& :$"8%0%8*A P*&7*4 )*7*>8/) ,8#0"$%8#/&
@- 8=* %:/&#,8 #, 0"7= 0/)* $/&:;%78#&: 8=%&
"&.*) >=-,#/$/:#7%$ 7/&.#8#/&, %&. 8=*)*</)*
$*%., 8/ 0%,,#?* *>#$*>8#7 &*")%$ *R7#8%8#/&4
%, ,=/G& @- 8=* .*>/$%)#9%8#/& 7")?* #& 8=*
>)*,*&7* /< %"8/%&8#@/.#*,A
;" <'+'(,18&'4:%7 =,$+1&1>%7'&
./(0+12,4
K%)%&*/>$%,8#7 &*")/$/:#7%$ ,-&.)/0*, 1KX23
","%$$- .*?*$/> %, %& #00"&* )*,>/&,* 8/ %&8#;
:*&, 8=%8 %)* *R>)*,,*. @- 8"0/) 7*$$, @"8
G=#7= %$,/ /77") #& 8=* &/)0%$ &*)?/", ,-,8*0A
X*")/$/:#7%$ ,-0>8/0, /<8*& >)*7*.* 8=* 8";
0/) .#%:&/,#,A B=* 0/,8 G#.*$- )*7/:&#9*.
%0/&: 8=*,* %&8#:*&, #, 8=* P" %&8#:*&4 % &";
7$*%) >)/8*#& 8=%8 #, >)*,*&8 #& %$$ 7*&8)%$ %&.
>*)#>=*)%$ &*")/&,A P" >)/8*#&, %)* *R>)*,,*.
#& ,0%$$;7*$$ $"&: 7%&7*) %&. &*")/@$%,8/0%A
O&8#;P" %&8#@/.#*, %)* %,,/7#%8*. G#8= ,*&,/)-
&*")/>%8=- %&. *&7*>=%$/0-*$#8#,A K%8#*&8,
G#8= ,0%$$;7*$$ $"&: 7%)7#&/0% %&. $/G 8#8*),
/< %&8#;P" %&8#@/.#*, G#8=/"8 ,#:&, /< KX2
8*&. 8/ =%?* ,0%$$*) 8"0/),4 )*,>/&. @*88*)
8/ 8)*%80*&84 %&. ,")?#?* $/&:*)YG=#7= ,":;
:*,8, 8=%8 8=*,* %&8#@/.#*, 0%- 0*.#%8* %&
*<<*78#?* %&8#8"0/)%$ )*,>/&,*A
C&$#Q* 8=* P" >)/8*#&4 8=* &*")/&%$ &"7$*%)
>)/8*#& U# #, )*,8)#78*. 8/ 8=* 7*&8)%$ &*)?/",
,-,8*0A U# >)/8*#& =%, @**& #.*&8#<#*. %, % 8%);
:*8 /< %"8/%&8#@/.#*, #& >%8#*&8, G#8= :-&*7/;
$/:#7%$ 8"0/), %&. @)*%,8 7%&7*) G#8= 7/&7/0#;
8%&8 *-* 0/?*0*&8 .#,/).*), 1/>,/7$/&",3A
Z/ >)/8*#&, %)* *R>)*,,*. #& 8=* 7-8/>$%,0 /<
K")Q#&[* 7*$$, 1&*")/&, /< 8=* 7/)8*R 7*)*@*$$#3
%&. %)* %$,/ *R>)*,,*. #& ,/0* :-&*7/$/:#7%$
8"0/), %&. @)*%,8 7%&7*),A O, % )*,"$8 /< %&
%&8#@/.- )*%78#?#8- %:%#&,8 Z/ %&8#:*&,4 0%&-
/< 8=*,* >%8#*&8, ,"<<*) <)/0 >%)%&*/>$%,8#7 .*;
:*&*)%8#/& /< 8=* 7*)*@*$$"0A F/,8 >%8#*&8,
G#8= 7*&8)%$ >%)%&*/>$%,8#7 ,-&.)/0*, ./ &/8
@*&*<#8 <)/0 >$%,0%>=*)*,#, /) #00"&/,">;
>)*,,%&8,A B"0/) )*0/?%$ /) )*0#,,#/& #&."7;
8#/& @- 0*.#7%$ /) )%.#/8=*)%>- 8)*%80*&8 7%&
$*%. 8/ %& #0>)/?*0*&8 /< ,-0>8/0,A
 !$:1'(:%D10/E2,0%':,0 ?%4,'4,4
!
Surgery Campylo- Tumors
bacter jejuni, (malignant
EBV/CMV lymphomas)
Ascending Dysphagia Respiratory
symmetrical failure
muscle weakness vegetative disorders Antigen Molecular Autoreactive
1. Clinical features release mimicry T cells

;&%(%7'& @22$(1&1>/
Neutralizing APC
antibodies
CD4+ T cell

TH2 TH1

Blocking of
Fc-receptors TNF-! Proteases
a) Plasmapheresis
3. Therapy
A. Guillain-Barré syndrome
b) High-dose i.v.
b) immunglobulins

2. Pathogenesis
NO O2

"
Central Hu antigen
neuron Ri antigen
Anti- Neuroblastoma
Uncontrollable glutamate
epileptic seizures receptor Ab
Lung carcinoma
Physiological
Anti-glutamate
Na+
R3 Ab
Na+ Na+ Na+ Na+ Breast carcinoma
Na+
Na+ Glu
Peripheral Hu antigen
neuron

Na+ Na+
Na+ Na+
mV Na+ Ovarial carcinoma
+20

!
0
Purkinje Yo antigen
cell
-90

B. Rasmussen’s encephalitis C. Paraneoplastic neurological syndromes

ABF

"
! 8)9-5:5;+<%: =+&)%&)&
!" #$%&'()*+% ,-%.+&
! "#$%$&'# ()'*+,)-. !"#$%&'()# *+#,)$ -!./ )$
#( #0%1#(%)213"45'3)#%'36 7+1*+'$$),'6 '84
'+9)$'43'7'(3'(% 3)$'#$' 9&#+#9%'+):'3 2"
;'#<('$$ #(3 7+'5#%0+' =#%)*0' 1= %&' ,14
>0(%#+" 50$9>'$? @()%)#> )(,1>,'5'(% 1= %&'
'"' 50$9>'$ )$ 91551(? A&' %"7)9#> ='#%0+'
)$ 3+117)(* 1= %&' '"'>)3$ -7%1$)$/ #(3 3102>'
,)$)1( -3)7>17)#/? B&'( %&' 7#%)'(% >11<$
07 =1+ # ;&)>'6 %&' =#%)*0'3 '"'>)3$ 2'*)(
%1 3+117 -$'' 7&1%1*+#7&$/? A&' 3)$'#$' +'4
5#)($ >)5)%'3 %1 %&' 190>#+ 50$9>'$ )( CD E
1= 7#%)'(%$6 20% 2'915'$ *'('+#>):'3 )( 51$%
9#$'$ -!//? A&' #2)>)%" %1 9&';6 $;#>>1;6 #(3
$7'#< 5#" 2' )57#)+'3? !. 5#" $7+'#3 %1
>:+*+<%: ?119*5:5;$
%&' '8%+'5)%)'$ #(3 ','( %1 %&' +'$7)+#%1+"
%+#9%? F>'9%+17&"$)1>1*)9#> $%03)'$ -!&/ $&1;
# %"7)9#> 3'9+'5'(%#> 3'9+'#$' )( 50$9>'
71%'(%)#> #=%'+ +'7'#%'3 $%)50>#%)1(? A&' 714
%'(%)#> #57>)%03' 3+17$ 2" 51+' %&#( GD E
=+15 %&' G$% %1 H%& $%)50>0$? I=%'+ #35)()$4
%+#%)1( 1= #( #9'%">9&1>)(' '$%'+#$' )(&)2)%1+6
%&' 50$9>' 71%'(%)#> +'5#)($ #% # 91($%#(%
>','> #(3 #( )57+1,'5'(% 1= 7%1$)$ 9#( 2'
12$'+,'3?
"
0 1'*234)%)-$-. A&' #++),#> 1= #( #9%)1( 71%'(4
%)#> #% %&' %'+5)(#> #81( )(309'$ %&' +'>'#$'
1= #9'%">9&1>)(' -IJ&/ %1 %&' $"(#7%)9 9>'=%6
;&'+' )% 2)(3$ %1 %&' #9'%">9&1>)(' +'9'7%1+
-IJ&K/? I9%),#%)1( 1= %&' IJ&K >'#3$ %1
$02$'L0'(% 3'71>#+):#%)1( 1= %&' 50$9>'
9'>> -0'/?
M'71>#+):#%)1( )$ %&'( %'+5)(#%'3 2" #9'%">4
9&1>)('$%'+#$'45'3)#%'3 &"3+1>"$)$ 1= #9'%">4
9&1>)('? N#%)'(%$ ;)%& 5"#$%&'()# *+#,)$
&#,' # 3'9+'#$'3 ('0+150$90>#+ %+#($5)$4
$)1( 9#7#9)%" 30' %1 %&' 7+'$'(9' 1= IJ&K
#(%)213)'$? A&'$' #(%)213)'$ )(&)2)% IJ&K
#9%),)%" 2" )(309)(* 9157>'5'(%45'3)#%'3
>"$)$ #% %&' 71$%$"(#7%)9 5'52+#(' -0//?
IJ&K #0%1#(%)213)'$ 9#( #>$1 2>19< IJ&
2)(3)(* $)%'$? O0+%&'+51+'6 %&' +#%' 1=
IJ&K 3'*+#3#%)1( )(9+'#$'$ 1(9' )% &#$
2''( )(%'+(#>):'3 071( =1+5#%)1( 1= %&'
#0%1#(%)213"P+'9'7%1+ 9157>'8? A&' IJ&
91(9'(%+#%)1( )( %&' $"(#7%)9 9>'=% 9#( 2'
5#)(%#)('3 #% &)*&'+ >','>$ 2" #9'%">4
9&1>)('$%'+#$' )(&)2)%1+$6 >'#3)(* %1 # %'54
!
71+#+" )57+1,'5'(% 1= $"57%15$? I7#+%
=+15 IJ&K6 7+1%')($ 1= %&' $%+)#%'3 50$9>'$
-'?*?6 #9%)(6 5"1$)(6 #(3 %)%)(/ 5#" #>$1 #9% #$
#0%1#(%)*'($?
!"#$%&'()# *+#,)$ )$ #$$19)#%'3 ;)%& $5#>>6
@AB 0$0#>>" 2'()*( '7)%&'>)#> %&"515#$ )(
#+10(3 QD E 1= 9#$'$ -0&/? A&' %051+$ *'('+4
#>>" '8&)2)% #2(1+5#> '87+'$$)1( 1= ('0+14
=)>#5'(%$6 ;&)9& $&#+' '7)%17'$ ;)%& IJ&K
#(3 %)%)(? I$ # +'$0>% 1= 51>'90>#+ 5)5)9+"6
IJ&K4$7'9)=)9 #(3 %)%)(4$7'9)=)9 A 9'>>$ #+'
71$)%),'>" $'>'9%'3 )( %&' %&"50$ #(3 #9%)4
,#%'3 10%$)3' %&' %&"50$6 #>>1;)(* %&' 7+14
309%)1( 1= #0%1#(%)213)'$?
I77+18)5#%'>" RD E 1= 7#%)'(%$ ;)%& !.
&#,' # >"57&1=1>>)90>#+ %&"5)%)$ -05/? A&'
)(=)>%+#%)(* S 9'>>$ =1+5 9157>'%' *'+5)(#>
9'(%'+$ -$'' 7&1%1*+#7&/? !. )$ =+'L0'(%>"
#$$19)#%'3 ;)%& %&' TUI4SV #(3 TUI4MKQ #>4
>'>'$? IJ&K42'#+)(* 9'>>$ %&#% +'$'52>' 50$4
9>' 9'>>$ -5"1)3 9'>>$/ #+' 7+'$'(% )( %&' %&"4
50$? A&' 5"1)3 9'>>$ =1+5 %&"5)9 #**+'*#%'$
;)%& 3'(3+)%)9 INJ$6 ;&)9& #+' %&10*&% %1 2'
9#7#2>' 1= 7+'$'(%)(* IJ&K #(%)*'($ %1 JMWX
A 9'>>$6 +'$0>%)(* )( %&' 7+1309%)1( 1= IJ&K4
$7'9)=)9 #(%)213)'$ 3)+'9%>" )( %&' %&"50$?
A&)$ )$ $0771+%'3 2" %&' =#9% %&#% %&' #0%1#(4
%)213)'$ =10(3 )( %&"5)%)$4#$$19)#%'3 !.
$7'9)=)9#>>" +'91*():' %&' '52+"1(#> =1+5
1= IJ&K6 ;&)9& )$ =10(3 71$%7#+%05 1(>"
)( %&' %&"50$ #(3 %&' '"' 50$9>'$?
/" 0%12)-'34%'5* 6$*7-51)
U#52'+%PF#%1( 5"#$%&'()9 $"(3+15' -UFY/ )$
$)5)>#+ %1 5"#$%&'()# *+#,)$ 20% )$ 9&#+#9%'+4
):'3 2" 7+)5#+" )(,1>,'5'(% 1= %&' 7'>,)9 50$4
9>'$ #$ 1771$'3 %1 %&' =#9)#> 50$9>'$? Z(>)<'
!.6 UFY 7+1309'$ #0%1(15)9 $"57%15$6 $09&
#$ 510%& 3+"('$$ #(3 5)9%0+)%)1( 3)$%0+4
2#(9'$? I(%)9#>9)05 9&#(('> #(%)213)'$ %&#% )(4
&)2)% %&' +'>'#$' 1= IJ& #+' 7+'$'(% )( %&' 7+'4
$"(#7%)9 5'52+#(' 1= 7#%)'(%$ ;)%& UFY? A&)$
2>19<$ %&' %+#($5)$$)1( 1= $%)50>) %1 %&' 71$%4
$"(#7%)9 5'52+#('? I=%'+ $'+)#> $%)50>#%)1(6
%&' 7+'$"(#7%)9 2>19< )$ %'571+#+)>" 1,'+915'
#(3 #9'%">9&1>)(' 9#( 2' +'>'#$'3 )( &)*&'+
91(9'(%+#%)1($6 >'#3)(* %1 #( )(9+'#$' 1= %&'
71%'(%)#> #57>)%03' 1,'+ %&' 2#$'>)(' >','>?
UFY ;#$ =)+$% 3'$9+)2'3 #$ # 7#+#('17>#$%)9 $"(4
3+15' #$$19)#%'3 ;)%& 9'+%#)( %"7'$ 1= 9#(9'+6
'$7'9)#>>" $5#>>49'>> >0(* 9#+9)(15#? @% $15'4
%)5'$ 7+'9'3'$ 9#(9'+ 3'%'9%)1(? A&'+' )$ ',)4
3'(9' $0**'$%)(* %&#% 9'+%#)( #(%)213)'$ 5#"
9+1$$4+'#9% ;)%& %&' %051+ 9'>>$?
 #$%&'()*+% ,-%.+& %*7 0%12)-'34%'5* 6$*7-51)

mV
0
!
Diplopia Nasal
voice
Chewing Dysphagia
-90
problems
Decremental response to repetitive
stimulation
mV
0

Failure of
-90
respiratory musculature
Improvement after administration

>:+*+<%: ?119*5:5;$
of acetylcholinesterase inhibitor

a) Ocular form b) Generalized form c) Electrophysiology

1. Clinical features of myasthenia gravis

Antibody Defective T cell

production interactions
Expression of
AChR/titin in
tumor tissue
c) Thymoma-associated MG

Na+ Na+
Comple-
ment-
mediated
lysis
Myogenous cells in thymus

APC
HLA-DR3
HLA-B8

CD4
+
"
Reduced AChR count
a) Neuromuscular b) Changes d) Thymitis-
a) junction b) in MG d) associated
2. Pathogenesis d) MG
A. Myasthenia gravis (MG)

Dry
mouth
Lung cancer

Weakness Reduced ACh release

of Cross-
shoulder reactivity of Low
0

!
and pelvic tumor cells baseline potential
muscles with pre-
synaptic calcium
Micturition channels
disturbances
-90
B. Lambert–Eaton syndrome Serial stimulation
@AC

"
! <8*%*$0'23 =25+$5+5
!"#$ %&$ '#"( )(* %&$ +,-.,' +$+/0)($'1 %&$
$2$ "' -.('%)(%32 $45.'$* %. $(6"0.(+$(%)3 7)-8
%.0'1 ',-& )' /)-%$0")1 6"0,'$'1 *,'%1 )(* ,3%0)8
6".3$% 3"9&%: ;&$ $2$ &)' ) 3"+"%$* 0$)-%".( 5.8
%$(%")31 )(* "%' )()%.+"- '%0,-%,0$' )0$ -.+53$4
)(* 70)9"3$: <.0$.6$01 %&$ $2$ -.(%)"(' )( $48
%$('"6$ ($%=.0# .7 /3..* 6$''$3'1 =&$0$ "+8
+,($ -.+53$4$' -)( $)'"32 )--,+,3)%$ )(*
=&$0$ "++,($ -$33' -)( 0)5"*32 +"90)%$
70.+ %&$ -"0-,3)%".(: >6$( '3"9&% 5)%&.3.9"-)3
-&)(9$' "( %&$ .-,3)0 6$''$3' -)( &)6$ ) *0)8
+)%"- "+5)-% .( 6"',)3 5.=$0 )(* )-,"%2:
?$(-$1 ',-& -&)(9$' /$-.+$ -3"("-)332 +)("8
7$'% +,-& +.0$ @,"-#32 %&)( '"+"3)0 -&)(9$'
"( %&$ 6$''$3' .7 %&$ "(%$0()3 .09)(': A,0%&$08
602#23$0 .''/#&0&1(
+.0$1 5)%&.3.9"-)3 50.-$''$' "( %&$ /3..* 6$'8
'$3' .7 %&$ $2$ -)( /$ *"0$-%32 ./'$06$* /$-),'$
%&$ 0$%"()3 6$''$3' .7 %&$ 7,(*,' )0$ 6"'"/3$:
!" !#$%&'( &) %*+ ,(+
B *"'%"(-%".( "' +)*$ /$%=$$( $4%0).-,3)0 )(*
"(%0).-,3)0 "(73)++)%".(: ;&$ -.(C,(-%"6)1 -.08
($)1 )(* '-3$0) )0$ $4%0).-,3)0 '%0,-%,0$'1
=&$0$)' %&$ "0"'1 3$('1 -"3")02 /.*21 6"%0$.,'
/.*21 0$%"()1 )(* -&.0."* )0$ "(%0).-,3)0 '%0,-8
"
%,0$': ;&$ -.0($)1 3$('1 )(* 6"%0$.,' /.*2 *.
(.% -.(%)"( /3..* 6$''$3': ;&$ '-3$0) "' '5)0'$32
6)'-,3)0"D$*1 =&$0$)' %&$ "0"'1 -"3")02 /.*21
)(* -&.0."* )0$ *$('$32 6)'-,3)0"D$* ="%& )
'5.(9$3"#$ ($%=.0# .7 6$''$3': ;&"' 6$''$38
0"-& 5)0% .7 %&$ $2$ "' -)33$* %&$ !"#$: ;&$ 0$%"()
)3'. &)' )( $4%$('"6$ ($%=.0# .7 -)5"33)0"$': ;&$
$(*.%&$3")3 -$33' .7 %&$ -"3")02 /.*2 )(* -&.0."*
)0$ 7$($'%0)%$* )(* %&,' 5$06".,' %. 3)09$ 50.8
%$"( +.3$-,3$':
-" .''/#&0&123$0 4$%*&'+3*$#25'5
;&$ $2$3"*'1 -.(C,(-%"6)1 )(* ) %&"( 3)2$0 .7 %$)0
73,"* 50.%$-% %&$ $2$ 70.+ $(6"0.(+$(%)3 "00"8
%)(%': E7 )(2 .7 %&$'$ '%0,-%,0$' "' *)+)9$*1 /)-8
%$0")1 6"0,'$'1 *,'% 5)0%"-3$'1 )(* .%&$0 $4.9$(8
.,' (.4)$ -)( $4$0% %&$"0 $77$-%' .( %&$ "(%$0()3
'%0,-%,0$' .7 %&$ $2$: ;&$ $2$ *.$' (.% &)6$ )
90$)% *$)3 .7 0$'"'%)(-$ %. +$-&)("-)3 *)+)9$:
E( 5$07.0)%"(9 =.,(*'1 %&$ .%&$0="'$ =$338"'.8
3)%$* '%0,-%,0$' .7 %&$ $2$ )0$ *"0$-%32 $45.'$*
%. 5)%&.9$(' )(* 7.0$"9( )(%"9$(': ;&$0$7.0$1
$6$( ) 0$3)%"6$32 +"3* "(73)++)%.02 0$'5.('$
!
>?@
-)( &)6$ ) *0)+)%"-)332 &)0+7,3 $77$-%:
F"(-$ %&$ ,6$) &)' ) 5)0%"-,3)032 0"-& /3..*
',55321 '$-.(*)02 -.3.("D)%".( .7 /)-%$0") .0
6"0,'$' -)( .--,0 *,$ %. &$+)%.9$("- '50$)*:
B(%"/.*"$' )(* 50$7.0+$* "++,($ -.+53$4$'
-)( )3'. )--,+,3)%$ "( %&$ $2$: G0.''80$)-%"6"%2
/$%=$$( /)-%$0")31 6"0)31 5)0)'"%"-1 .0 7,(9)3
)(%"9$(' )(* $(*.9$(.,' )(%"9$(' .7 %&$ $2$
+)2 .--,0 *,$ %. +.3$-,3)0 +"+"-02: ;&$ +.*8
"7"-)%".( .7 ),%.)(%"9$(' /2 "(%$0)-%".( ="%& %&$
+"-0..09)("'+' -)( )3'. "(*,-$ ) 0$)-%".(
)9)"('% (.0+)3 '%0,-%,0$':
B(.%&$0 ,("@,$ 7$)%,0$ .7 %&$ $2$ "' %&$
H'$@,$'%0)%".(I .7 )(%"9$(' "( %&$ 3$('1 -.0($)1
)(* 6"%0$.,' /.*2 *,$ %. %&$ 3)-# .7 /3..*
6$''$3'J )%"9$(' ="%&"( %&$'$ '%0,-%,0$' )0$ "(8
)--$''"/3$ %. %&$ "++,($ '2'%$+: ?.=$6$01 "7
%&$ 50.%$-%"6$ /)00"$0 "' *)+)9$*1 %&$'$ )(%"8
9$(' )0$ '$% 70$$ )(* -)( /$ 0$-.9("D$* /2 -$33'
.7 %&$ "++,($ '2'%$+: ;&"' +$-&)("'+ 53)2'
)( "+5.0%)(% 0.3$ "( %&$ *$6$3.5+$(% .7 5&)8
-.9$("- ,6$"%"' K'$$ 5: LMNO:
6" ,78+92'+#%$0 !/%&2''/#+
:;+&9+%2#2%25
P$'%0,-%".( .7 %&$ 0$%"()3 5&.%.0$-$5%.0' -)(
/$ "(*,-$* $45$0"+$(%)332 /2 "++,("D"(9 -$08
%)"( )("+)3' K9,"($) 5"9'1 +"-$1 0)%'1 )(* 50"8
+)%$'O ="%& 0$%"()3 )(%"9$(' K$:9:1 0$%"()8F )(%"8
9$( .0 "(%$05&.%.0$-$5%.0 0$%"(."*8/"(*"(9
50.%$"(1 EQRSO: ;&"' )("+)3 +.*$3 "' -)33$* $48
5$0"+$(%)3 ),%."++,($ ,6$.0$%"("%"' K>BTO
)(* "' )'',+$* %. 0$73$-% %&$ 5)%&.9$($'"' .7
'.+$ ),%."++,($ *"'$)'$' .7 %&$ &,+)(
$2$: ;0)('7,'".( .7 ; 32+5&.-2%$' 70.+ %&$
"++,("D$* )("+)3' -)( "(*,-$ %&$ *"'$)'$ "(
&$)3%&2 )("+)3': ?.=$6$01 .(32 ) 5.0%".( .7
%&$ )("+)3' ="33 *$6$3.5 >BT )7%$0 %&$ %0)('8
7,'".(: U(32 )("+)3' ="%& ) ;?V8%25$ "++,($
0$'5.('$ "('%$)* .7 ) ;?L8%25$ 0$'5.('$ )0$
','-$5%"/3$: ;&"' 0$'5.('$ +)2 /$ *,$ %.
BSG'1 ',-& )' *$(*0"%"- -$33'1 =&"-& 0$3$)'$
E!8VL =&$( )-%"6)%$*1 %&$0$/2 "(*,-"(9 ) ;?V
0$'5.('$: >4.9$(.,' E!8VL -)( "(*$$* 0$(*$0
0$'"'%)(% )("+)3' ','-$5%"/3$ %. >BT: >45$0"8
+$(%)3 ),%."++,($ ,6$.0$%"("%"' "' ,'$* )'
)( )("+)3 +.*$3 %. '%,*2 %&$ *$6$3.5+$(%
.7 '2+5)%&$%"- .5&%&)3+") K'$$ 5: LMNO:
 !#$%&'( $#A 4$%*&1+#+525
!
Sclera Ciliary body
Extraocular inflammation

Intraocular inflammation
Retina
Conjunctiva Iris

Lens

Cornea Vitreous body

Retina

Choroid Choroid
Sclera
A. Anatomy of the eye

602#23$0 .''/#&0&1(
1. Direct antigen invasion 2. Hematogenic spread

"
a) Loss of protection b) Perforating of germs or deposition
wound of preformed immune complexes

Autoantigen
Foreign
antigen

3. Modification of autoantigens, 4. Release of lens antigens

molecular mimicry induces autoimmune reaction
against different eye antigens
B. Immunological pathomechanisms

Photoreceptor APC TH1 CD4

Immunization IL-12
with IRBP
Lymphocyte transfer
to a healthy animal

C. Experimental autoimmune uveoretinitis (EAU)

Uveitis Uveitis !
>?B

"
! <=,&,-50)( 7)/'-/'/

!" #$%&'(&)*' +'(,-.)/0/

!"# #$#%&'( )*+, - ,#."-/&.-% 0-++&#+ 1"-1 2+*3
1#.1( 1"# #$#0-%%4 !"#$ .*/1-&/ (#0-.#*5(
1* 1"*(# *) <#+/-% .*/;5/.1&<&1&( 051 &( .-5(#'
0$ "$2#+(#/(&1&<&1$ 1* .*/1-.1 %#/(#(4

7" #-&,%5%68 %9 &,' 2%$.'-

6%-/'(7 (8#-1 6%-/'(7 -/' %-.+&,-% 6%-/'(4
!"# +#65%-+ 0%&/9 +#)%#: #/(5+#( 1"-1 1"# .*/3
;5/.1&<- (1-$( ,*&(14 !"# 1#-+ )%5&' .*/(1-/1%$
+&/(#( 6#+,( -/' '5(1 2-+1&.%#( *51 *) 1"#
#$#4 !#-+( -%(* "-<# -/ -/1&,&.+*0&-% #))#.1 0#3
.-5(# 1"#$ .*/1-&/ =6> -/1&0*'&#(7 %$(*?$,#7
%-.1*)#++&/7 -/' .*,2%#,#/1 -%*/6 8&1" ,*/*3
.$1#( -/' 6+-/5%*.$1#(4 @#/.#7 1#-+ )%5&' (#+<#(
-( - 2+&,-+$7 /*/(2#.&)&. 0-++&#+ 1"-1 8-+'( *))
&/)#.1&*/( -/' -/1&6#/(4 >AB( -+# -%(* 2+#(#/1
&/ 1"# .*/;5/.1&<-4
25).)(-5 >004.%5%68
!"# .*+/#- &( - .+$(1-% .%#-+7 1+-/(2-+#/1 (1+5.3
15+#7 8"&." )*+,( 1*6#1"#+ 8&1" 1"# (.%#+- 1"#
,*(1 &,2*+1-/1 2+*1#.1&<# 8-%% )*+ 1"# #$#4 =/3
)%-,,-1&*/ *) 1"# .*+/#- &( .-%%#' '()!"%"%. -/'
.-/ %#-' 1* (.-++&/6 -/' 0%&/'/#((4 !"# ,*(1
.*,,*/ .-5(# *) 9#+-1&1&( &( &/)#.1&*/ 8&1"
"#+2#( (&,2%#: <&+5( D@HFG4 !$2# K @HF .*/3
1-&/( 2+*1#&/( 1"-1 -+# (1+5.15+-%%$ +#%-1#' 1*
1"*(# *) 1"# /*+,-% .*+/#-4 > 9#+-1*6#/&. 2#23
1&'# "-( +#.#/1%$ 0##/ &(*%-1#'4 U*.-% &/)#.1&*/
8&1" @HF &/'5.#( /#*<-(.5%-+&?-1&*/ -/' &/3

1" 2%.34.(&)*)&)/ .+#-(#( 1"# ."-/.# *) - .+*((3+#-.1&<# &,,5/#

+#(2*/(# 1* 1"&( 2#21&'#4 !"# 2#/#1+-1&*/ *)
C-.1#+&-7 <&+5(#(7 )5/6&7 2-+-(&1#(7 -/' ."#,&.-%
<#((#%( &/ 1"# /*+,-%%$ -<-(.5%-+ .*+/#- %#-'(
-/' 2"$(&.-% &++&1-/1( D#4647 -.&'(7 EF %&6"1G .-/
1* 1"# ,&6+-1&*/ *) %$,2"*&' -/' &/)%-,,-1*+$
&/'5.# .*/;5/.1&<&1&(4 !"# &/&1&-% 2"-(# &( ."-+3
.#%%( 1* 1"# .*+/#-4 !"# +#%#-(# *) .$1*9&/#(
-.1#+&?#' 0$ &/.+#-(#' 0%**' (522%$ D"$2#+#3
%#-'( 1* #2&1"#%&-% '-,-6#V &#)*(!0 ,0&(). ,-$
,&-G7 &1."&/67 -/' %&6"1 &/1*%#+-/.# D2"*1*3
-%(* '#<#%*2 D(## 2"*1*6+-2"G4
2"*0&-G4 !"# &/)%-,,-1&*/ &( ,*+# (#<#+# &/
2-1&#/1( 8&1" +#'5.#' 1#-+ 2+*'5.1&*/4 =/ :" #-&,%5%68 %9 &,' ;(5'$-
H;*I6+#/J( ($/'+*,#7 )*+ #:-,2%#7 1"# 2+*'5.3
1&*/ *) 1#-+ )%5&' &( (#<#+#%$ +#'5.#' -/' 1"# !"# (.%#+- &( 1"# 8"&1# 2-+1 *) 1"# #$#4 =1 ,-9#(

" .*,2*(&1&*/ *) 1"# )%5&' &( -%1#+#' D(## 2"*1*3

6+-2" -/' 24 KLMG4

2" !55'$6)( 2%.34.(&)*)&)/

A*%%#/ -/' 6+-(( -+# 1"# ,*(1 .*,,*/ .-5(#(
*) (#-(*/-% -%%#+6&. .*/;5/.1&<&1&(7 8"#+#-(
52 1"# *51#+ %-$#+ *) 1"# #$#0-%% -/' 6&<#( &1
(1+#/61" -/' (522*+14 H#<#+-% 0%**' <#((#%(
2-(( 1"+*56" &17 051 &1( *8/ 0%**' (522%$ &(
,#-6#+4 3$%.&0()%"%. &( -/ &/)%-,,-1&*/ *) 1"#
(52#+)&.&-% %-$#+( *) 1"# (.%#+-7 8"#+#-( .&0()%"%.
&/<*%<#( 1"# '##2 %-$#+(4 !"# &/)%-,,-1&*/ &(
*)1#/ '5# 1* &/)#.1&*/7 051 &/ ,-/$ .-(#( &1 &(
'5(17 )#-1"#+(7 "*5(# '5(1 ,&1#(7 -/' -/&,-%
'&))&.5%1 1* '&(1&/65&(" 0#18##/ 1"# '&+#.1 #)3
"-&+ .-5(# ."+*/&.7 (#-(*/-%%$ &/'#2#/'#/1
)#.1( *) - 2-1"*6#/ -/' - 2-1"*%*6&.-% &,,5/#
.*/;5/.1&<&1&(4 C*1" )*+,( *) 1"# '&(#-(# +#2+#3
+#(2*/(#4 H.%#+-% &/)%-,,-1&*/( *)1#/ *..5+ &/
(#/1 -/-2"$%-.1&. 1$2# = "$2#+(#/(&1&<&1$ +#-.3
.*/;5/.1&*/ 8&1" - ($(1#,&. '&(#-(#7 (5." -(
1&*/( D(## 24 NOG &/ 8"&." '#6+-/5%-1&*/ *)
+"#5,-1*&' -+1"+&1&(7 .*//#.1&<# 1&((5# '&(*+3
,-(1 .#%%( -/' 0-(*2"&%( *..5+(4 !"# =6P %#<#%(
'#+(7 *+ <-(.5%&1&(4 =,,5/# .*,2%#:#( ,-$ -.3
&/ (#+5, -/' 1#-+ )%5&' -+# #%#<-1#'4 Q-/$ 2-3
.5,5%-1# &/ -/' -+*5/' 0%**' <#((#%(7 %#-'&/6
1&#/1( -%(* "-<# 8-1#+$ /-(-% '&(."-+6# D+"&/*+3
1* .*,2%#,#/1 -.1&<-1&*/7 ."#,*1-:&( *) 6+-/3
+"#-G4 !"# .*3*..5++#/.# *) -%%#+6&. .*/;5/.1&<&3
5%*.$1#( -/'7 5%1&,-1#%$7 /#.+*(&( D(## 2"*1*3
1&( -/' -1*2&. '#+,-1&1&( &( +#)#++#' 1* -( !"#$%&
6+-2"G4 !"# ,*(1 (#+&*5( .*,2%&.-1&*/ &( 2#+)*3
'()!"#&#*+,*&"%-%"%.4
+-1&*/ *) 1"# #$#0-%%4
/()*!0 &#*+,*&"%-%"%. &( - 0&%-1#+-%7 +#.5++#/17
.*/;5/.1&<-% &/)%-,,-1&*/ ."-+-.1#+&?#' 0$ 1"#
*..5++#/.# *) .*00%#(1*/#3%&9# 6&-/1 2-2&%%-# *)
1"# 522#+ .*/;5/.1&<- D(## 2"*1*6+-2"G4 !"#
.*/'&1&*/ *..5+( ,-&/%$ &/ ."&%'+#/ 8&1" #.?#3

!
,- *+ -(1",-4 !"# 2+#(#/.# *) ,-(1 .#%%(7 #*(&3
/*2"&%(7 -/' BRST ! .#%%( &/ 1"# 6&-/1 2-2&%%-#
(566#(1( 1"-1 - '#%-$#' 1$2# .#%%5%-+ "$2#+(#/3
(&1&<&1$ +#-.1&*/ D1$2# =FG ,5(1 *..5+ -)1#+ 1"#
1$2# = "$2#+(#/(&1&<&1$ +#-.1&*/4 1%!*" $!$%00!)2
?@? &#*+,*&"%-%"%. 2+*'5.#( ,-/&)#(1-1&*/( (&,&%-+
 Secretory
:A&$-%(45-$ >.95-00-&)%./
!
IgA

Lysozyme

Monocyte

Granulocyte
Lacrimal gland Mechanical protection Antimicrobial activity Langerhans cell
A. Protective mechanisms in conjunctiva

UV

25).)(-5 >004.%5%68
1. Causes 2. Dry eye 3. Sjögren’s syndrome
B. Conjunctivitis

Pollen, grass,
blossoms
IgE-bound
antigens
C. Allergic conjunctivitis

Viruses (HSV),
Binding to
mast cells
Histamine
release Vernal conjunctivitis
"
Tear film bacteria,
parasites
Idiopathic form,
GVHD
Cornea
Rheumatoid arthritis,
Sjögren’s syndrome,
panarteritis, SLE,
Wegener’s
granulomatosis
1. Normal 2. Etiology 3. Neovascu- 4. Epithelial lesion Corneal ulcer
1. cornea 3. larization
D. Pathology of the cornea

Retina Viruses (HSV, HZV),

fungus,
parasites
Choroid
Idiopathic form 50%
Sclera

!
Rheumatoid arthritis,
Sjögren’s syndrome,
panarteritis, SLE,
Wegener’s
Episclera granulomatosis
1. Normal sclera 2. Etiology 3. Episcleritis 4. Scleritis Necrotizing scleritis
E. Pathology of the sclera
?@B

"
! ;<=$=09.'8 >'+%0+%+
!"#$%$& $& '( $()*'++'%$,( ,) %-# ."#'* %/'0%1
%-# "#&&#*2/$0- 3'/% ,) %-# #4# 0,(&$&%$(5 ,)
%-# $/$&1 %-# 0$*$'/4 6,741 '(7 %-# 0-,/,$7&8
9()*'++'%,/4 3/,0#&&#& ,) %-# /#%$(' :/#%$($%$&;
'(7 "$%/#,.& 6,74 :"$%/$%$&; +'4 '*&, 6# /#)#//#7
%, 64 %-$& ('+#8 <,/ 7$7'0%$0 /#'&,(&1 =# =$**
.&# '( '('%,+$0'* 0*'&&$)$0'%$,( ,) ."#$%$&8
!" !#$%&'(& )*%'$'+
>(%#/$,/ ."#$%$& :>!; $& '( $()*'++'%$,( ,)
%-# $/$& :$/$%$&;1 0$*$'/4 6,74 :040*$%$&;1 ,/ 6,%-
:$/$7,040*$%$&;8 >! +'4 ,00./ $( 0,(?.(0%$,(
=$%- @A>2BCD2'&&,0$'%#7 &3,(74*'/%-/,3'%-4
:&## 38 EDF;1 $()#0%$,.& 7$&#'&#&1 ,/ &4&%#+$0 7$&2
#'&#&8 G-# 0,++,( H$7$,3'%-$0I ),/+& ,) '(%#2
19'#'809 -..6#(9(?@
/$,/ ."#$%$& '/# 0*,&#*4 '&&,0$'%#7 =$%- @A>2BCD8
!"#"$%&'$%()& *+")#), :<.0-&J 7$&#'&#; $& ' &.62
%43# 0-'/'0%#/$K#7 64 7#3$5+#(%'%$,( '(7 )'72
$(5 ,) %-# '))#0%#7 $/$& '(7 ' +$($+'* $()*'++'2
%,/4 /#&3,(&#8 L,*#0.*'/ +$+$0/4 '33'/#(%*4
*#'7& %, %-# 3/,7.0%$,( ,) 0/,&&2/#'0%$(5 '(%$2
6,7$#& %-'% &.6&#M.#(%*4 '00.+.*'%# '& $+2
+.(# 0,+3*#N#& '(7 $(7.0# )./%-#/ 7'+'5#8
G-# +'$( 0*$($0'* )#'%./#& :&## 3-,%,5/'3-;
'/# #7#+'%,.& &=#**$(51 7#3$5+#(%'%$,( '(7
"
)'7$(5 ,) %-# $/$&1 '(7 0,(%/'0%$,( ,) %-# 3.3$*
:$//$%'%$"# +$,&$&;8 9( $/$7,040*$%$&1 ,3'0$%4 ,)
%-# "$%/#,.& 6,74 $& '*&, ,6&#/"#78 >7-#&$,(
,) %-# $/$& %, %-# '(%#/$,/ 0'3&.*# ,) %-# *#(&
0'( ,00./ 7.# %, %-# #N.7'%$,( ,) &#0/#%$,(&
$(%, %-# '(%#/$,/ 0-'+6#/8 G-#&# &#0/#%$,(&
'/# .&.'**4 5#*'%$(,.& 6.% &,+#%$+#& -#+,/2
/-'5$08
," -#$%&.%/'0$% )*%'$'+
9()*'++'%$,(& ,) %-# "$%/#,.& 6,74 :"$%/$%$&;1
3'/& 3*'(' ,) %-# 0$*$'/4 6,74 :3'/& 3*'($%$&;1
,/ '(%#/$,/ &#5+#(%& ,) %-# /#%$(' :3#/$3-#/'*
/#%$($%$&; '/# .&.'**4 $7$,3'%-$0 :DOPQO R;8 S'/2
0,$7,&$&1 +.*%$3*# &0*#/,&$&1 '(7 A4+# 7$&#'&#
'/# /'/# 0'.&#&8 G-# 7$&#'&# $& 0'.&#7 64 +$5/'2
%$,( ,) *#.T,04%#& $(%, %-# "$%/#,.& 6,741 =-#/#
%-#4 '55/#5'%#1 ),/+$(5 H&(,=6'**&8I G-$& *#'7&
%, 3/,5/#&&$"# ,3'0$%4 ,) %-# "$%/#,.& 6,748 G-#
5*$' ,"#/ %-# 3'/& 3*'(' 3/,*$)#/'%#1 0'.&$(5 &,2
0'**#7 H&(,=7/$)%&8I 9( %-# *'%# &%'5#&1 %-# "$%/2
#,.& 6,74 +'4 &-/$(T '(7 7#%'0- )/,+ %-# /#2
%$('1 '(7 #7#+'& +'4 ),/+ $( %-# +'0.*'8 9% $&
!
ABB
'&&.+#7 %-'% '0%$"'%#7 G 0#**& %-'% &#0/#%# 9<U2!
$(7.0# %-# ),/+'%$,( ,) &,20'**#7 -$5-2#(2
7,%-#*$'* "#(.*#& :@VW1 &## 38 FX;8 G-#&# '0%$2
"'%#7 #(7,%-#*$'* 0#**& #N-$6$% $(0/#'&#7 #N2
3/#&&$,( ,) '7-#&$,( +,*#0.*#& '(7 L@Y
0*'&& 99 +,*#0.*#&8 G-$& #('6*#& %-# @VW %,
3/#&#(% '.%,'(%$5#(& %, %-# G *4+3-,04%#&1
%-#/#64 %/$55#/$(5 '( '.%,$++.(# /#&3,(&#8
L,/#,"#/1 @VW 0'( 0,(%/$6.%# %, %-# *,0'* /#2
0/.$%+#(% ,) G 0#**&8
123" 4(+$%&'(& )*%'$'+5 106+%+7
!++(8'0$'(#+7 0#/ 19'#'809 :%0$6&%+
G-# +,&% 0,++,( ),/+ ,) 3,&%#/$,/ ."#$%$& $&
0-,/$,/#%$($%$&Z $&,*'%#7 0-,/,$7$%$& $& /'/#8
G-#&# $()*'++'%$,(& '/# 0'.&#7 64 6'0%#/$'*1
"$/'*1 3'/'&$%$0 ,/ +40,%$0 $()#0%$,(&1 &4&%#+$0
7$&#'&#& :#8581 "'&0.*$%$&;1 '(7 5/'(.*,+'%,.&
7$&#'&#&1 #&3#0$'**4 &'/0,$7,&$&8 G-# 0'.&#& ,)
&,+# &.6%43#& '/# .(T(,=(1 #8581 6$/7&-,% /#2
%$(,3'%-41 '0.%# 3,&%#/$,/ +.*%$),0'* 3*'0,$7
3$5+#(% #3$%-#*$,3'%-4 :>[L[[V;1 '(7 &#/3$5$2
(,.& 0-,/,$7$%$&8 > )#= $+3,/%'(% #(%$%$#& =$**
6# 3/#&#(%#7 6#*,=8
-%.%/01,(%,), :!; $& ,(# ,) %-# +,&% 0,+2
+,( 0'.&#& ,) ."#$%$& $( $++.(,0,+3#%#(% 3'2
%$#(%&8 G-# 0,(7$%$,( +'4 ,00./ '& ' +.*%$&4&2
%#+ 7$&#'&# '0M.$/#7 "$' %-# 3*'0#(%' ,/ '&
$&,*'%#7 /#%$(,0-,/,$7$%$& $( '7.*%-,,78 W$%/$%$&
$& .&.'**4 3/#&#(%1 '(7 /#%$($%$& =$%- +'0.*'/
#7#+' '(7 &#5+#(%'* "'&0.*$%$& +'4 '*&, 6#
),.(78 G/#'%+#(% =$%- '(%$6$,%$0& $& /#M.$/#7
3'/%$0.*'/*4 $) 3,&%#/$,/ *#&$,(& '/# 3/#&#(%
'(7 ),/ $++.(,0,+3/,+$&#7 3'%$#(%&8
9( ,1$&%)2%,), :";1 5/'(.*,+'& +'4 6# 3/#2
&#(% $( '** 3'/%& ,) %-# #4#1 0'.&$(5 0,(?.(0%$"$2
%$&1 T#/'%$%$&1 $/$7,040*$%$&1 /#%$('* "'&0.*$%$&1 '(7
5/'(.*,+'%,.& 3'3$**$%$&1 =-$0- 0'( 7#&%/,4 %-#
(#/"# )$6#/& ,) %-# 3'3$**'8 \#%$('* $(",*"#+#(%
,00./& $( 0,(?.(0%$,( =$%- YUS $(",*"#+#(%8
9( '),#%/01,(%,), :#;1 -43#/&#(&$%$"$%4 %, '(%$2
5#(& ,) !),#%/01,(1 &1/,*01#*( /#&.*%& $( '
0-/,($0 $++.(# /#&3,(&# =$%- &.6/#%$('* 3/,2
*$)#/'%$,(8 S0'/& +'4 ),/+ $( %-# +'0.*' '(7 $(
3#/$3'3$**'/4 '(7 3#/$3-#/'* /#5$,(& ,) %-#
0-,/,$78
G-#/# $& '( #N%/#+#*4 &%/,(5 '&&,0$'%$,(
6#%=##( @A>2>C] '(7 3)$2,'%# &'%$)%$"#)4%5
/1#'61 ' /'/# 7$&#'&# ,) +$77*#2'5#71 ,%-#/=$&#
-#'*%-4 $(7$"$7.'*& :$;8 G-# /#*'%$"# /$&T :\\;
),/ @A>2>C] $(7$"$7.'*& $& CCX %$+#& $(0/#'&#78
>( $++.(# /#&3,(&# %, /#%$('* 3#3%$7#& '32
3#'/& %, 6# /#&3,(&$6*# ),/ %-# 5/'(.*,+'%,.&
0-'(5#& =$%-$( '(7 6#*,= %-# /#%$('1 =-$0- '32
3#'/ '& H0/#'+20,*,/#7 &3,%&I $( %-# ).(7.&8
<,0'* 7#3$5+#(%'%$,( ,) 0-,/,$7'* +#*'(,04%#&
$( '('*,54 %, "$%$*$5, ,) %-# &T$( $& 3/#&.+#78
 Idiopathic 50 %
)*%'$'+ C-D
!
HLA-B27 associated Molecular
mimicry HLA-B27
Spondyloarthropathy
associated
Herpes infection, Polyclonal
yersiniosis, borreliosis B-cell
activation
Heterochromic uveitis
(Fuchs’ disease)
Iritis Cyclitis Immune
Behçet’s disease, complex
Iridocyclitis JRA, sarcoidosis deposition
A. Anterior uveitis Iritis

Posterior Peripheral 70 % Antigen? T-cell

cyclitis retinitis Idiopathic
activation

19'#'809 -..6#(9(?@
Vitritis
Sarcoidosis
Snow IFN-!
balls Endo- HEV
Snow thelium
banking
Lyme borreliosis
Antigen
presentation
Cystoid Multiple sclerosis
macular edema
T-cell proliferation Vitreous cells
B. Intermediate uveitis

Syphilis
Tuberculosis
Borreliosis
Leprosy
Whipple’s disease
Brucellosis
CMV
EBV
HSV
VZV
HIV
Histoplasmosis

Toxoplasmosis
PAN
Behçet’s disease

Sarcoidosis
Birdshot retinopathy
ApMPPE
?
Sepiginous choroiditis
"
C. Posterior uveitis: Causes/associations

Congenital/acquired Retinal vasculitis

Vitritis Granulomatous
Retinitis/papillitis papillitis
Inflammation of
anterior chamber

Destruction
Retinal infiltrates of
+ pigmented scars neural fibers
Scar focus Choroidal infiltrates
D. Toxoplasmosis E. Sarcoidosis

Hypersensitivity HLA-A29: RR=224!!

to histoplasma Ag
Binding of
S-antigen-peptides?
Subretinal neovascu-
larization, bleeding
Peripheral +
peripapillary scars
F. Histoplasmosis
Macular lesion
Granulomatous
intra-/subretinal
inflammation
Pigment defects
G. Birdshot chororetinopathy
!
ABE

"
! ED3*3$A?)0 6)+($+(+

!" #$%&'()*)+, -$&+(+ $%. !++/0)$*)/%+

!"#$%&'(') ') "# '#*+",,"('-# -* (.& &#('/&
$%&"+ (/"0(1 2( ') 0-,,-#+3 0"$)&4 53 5"0(&/'"+
8'(. %'(/'(')1 2#*&0('-# 8'(. I7)(&'#PB"// %'/$)
.") 5&&# 7/-7-)&4 ") " 7-))'5+& 0"$)&1

C" >;?D$*3(*)0 ED3*3$A?)$

'#*&0('-#)6 &)7&0'"++3 8'(. )7'/-0.&(&) 9&1:16
;3,& 5-//&+'-)') "#4 )37.'+')<6 %'/"+ '#*&0('-#)
9&)7&0'"++3 =>? "#4 @2?<6 "$(-',,$#& /&"0A
('-#) (/'::&/&4 53 "$(-"#(':&#) -* (.& &3&6
0./-#'0 :/"#$+-,"(-$) 4')&")&)6 "#4 %")0$+'(')1
1" 2'()*)+ )% 1(304(*5+ 6)+($+(
B&.0C&(D) 4')&")& 9)&& 71 EFG< ') -#& -* (.& ,-)(
0-,,-# 0"$)&) -* "0H$'/&4 5+'#4#&)) '# (.&
>'44+& I")( "#4 J"7"#1 @"7+-(37& @;KABL ') ")A
)-0'"(&4 8'(. (.& 4')&")&M (.& /&+"('%& /')N ') O1
-A)%)0$A G??&%/A/8;
_3,7"(.&('0 -7.(."+,'" 9_`< ') " 5'+"(&/"+6
:/"#$+-,"(-$) '#*+",,"('-# -* (.& $%&" (."(
,"3 /&)$+( '# 5+'#4#&))1 a&#&('0 *"0(-/) ."%&
" 7/&4')7-)'#: &**&0(1 S.& 0-#4'('-# ') $)$"++3
(/'::&/&4 53 " 7&#&(/"('#: 8-$#4 (- (.& &3&
"#46 /"/&+36 4$& (- &3& )$/:&/31 2#*+",,"(-/3
0."#:&) -00$/ '# (.& '#b$/&4 &3& "/-$#4 (8-
8&&N) (- (./&& ,-#(.) "*(&/ (.& '#b$/31 K$(-"#A
(':&#) "/& 7/&)$,"5+3 7/&)&#(&4 (- =XZ[ S 0&++)
53 /&('#"+ &7'(.&+'"+ 0&++) "#4 >$c++&/D) 0&++)1
>$+('7+& :/"#$+-,") +"(&/ 4&%&+-7 '# (.&

I3& '#%-+%&,&#( -00$/) '# FGPQG R -* "++ 7"A

&#('/& $%&"+ (/"0( -* (.& "**&0(&4 &3& "#4 '#
('&#() 8'(. B&.0C&(D) 4')&")&1 S.& /&0$//&#0&
(.& .&"+(.3 d)3,7"(.'V'#:e &3&1 =3(-(-T'0
-* )(&/'+& !"#$#"$%&6 8.'0. "/& ")&7('0 7$) 4&A
S 0&++) "/& (.& 7/&4-,'#"#( 0&++ (37& "( (.')
7-)'() '# (.& "#(&/'-/ 0.",5&/ -* (.& &3& 9)&&
7-'#(1 K (37'0"+ *&"($/& -* (.& 4')&")& ') (.&
7.-(-:/"7.<6 ') " (37'0"+ *&"($/& -* (.& 4')&")&1
7/&)&#0& -* '()*%+,-.!& %$/-)*&6 8.'0. 0-#A
IT",'#"('-# -* (.& -0$+"/ *$#4$) /&%&"+) %")A
)')( -* .')('-03(&) "#4 4&7':,&#(&4 0&++) -*
0$+'(') 8'(. 7&/'%")0$+"/ &T$4"('-# '#%-+%'#:
(.& 7':,&#(&4 +"3&/ -* (.& /&('#"+ &7'(.&+'$,1
5-(. "/(&/'&) "#4 %&'#)6 8.'0. 5&0-,& 4'+"(&4
K+(.-$:. ',,$#-)$77/&))'-# 0"# )+-8 4-8#
"#4 (-/($-$)1 U&0/-('V'#: +&$N-03(-0+")('0 %")A
(.& 7/-:/&))'-# -* (.& 4')&")&6 &"/+3 &#$0+&"A
0$+'(') $+(',"(&+3 -00$/) 4$& (- (.& +-0"+ "00$A
('-# -* (.& '#b$/&4 &3& ') (.& -#+3 8"3 (- (-A
,$+"('-# -* ',,$#& 0-,7+&T&) "#4 0-,7+&A

"
("++3 "%-'4 )3,7"(.&('0 -7.(."+,'"1
,&#( "#4 (.& +-0"+ /&0/$'(,&#( -* #&$(/-7.'+
0!(.$1*%2. -3*242& ') "# "$(-',,$#& /&"0A
:/"#$+-03(&) 53 2;AF1
('-# '#4$0&4 53 (.& 7/&)&#0& -* +&#) "#(':&#)
'# (.& %'(/&-$) 5-43 *-++-8'#: 0"("/"0( )$/:&/31
-" 7/8*9:/;$%$8)9<$=$.$ >;%.=/?(
S.& 4')&")& .") 5&0-,& '#0/&")'#:+3 /"/& 4$&
?-:(PW-3"#":'P@"/"4" 9?W@< )3#4/-,& ') (- ',7/-%&,&#() '# )$/:'0"+ (&0.#'H$&1
0."/"0(&/'V&4 53 (.& &T7/&))'-# -* 0+")) 22
>@= ,-+&0$+&) -# ,&+"#-03(&) 4$&6 7&/."7)6 F" E0&A$= @$%)B(+*$*)/%+ /B >;+*(?)0
(- " %'/"+ '#*&0('-#1 =+")) 22 >@= &T7/&))'-# 7&/A 6)+($+(
,'() (.& 7/&)&#("('-# -* "$(-"#(':&#) (- S 0&++)1
`0$+"/ ,"#'*&)("('-#) "/& "))-0'"(&4 8'(. "
@;KAXYZ[ "#4 @;K8L\[ '#4'%'4$"+)6 /&)7&0A
#$,5&/ -* )3)(&,'0 4')&")&)6 )$0. ") /.&$,"A
('%&+36 ."%& "# '#0/&")&4 /&+"('%& /')N -* E]
(-'4 "/(./'(') 9YK<6 )7-#43+-"/(./-7"(.'&)
"#4 \Z (- "0H$'/& (.& 4')&")&1 ^%&'(') )("/()
9_!K<6 )3)(&,'0 +$7$) &/3(.&,"(-)$) 9_;I<6
8'(. )3,7(-,) -* 5'+"(&/"+ .37&/&,'" "#4 &4&A
_b-c:/&#D) )3#4/-,& 9_J_<6 b$%&#'+& /.&$,"(-'4
," *-/,"('-# '# (.& 7-)(&/'-/ 0.-/-'41 _$5/&(A
"/(./'(') 9JYK<6 f&:&#&/D) :/"#$+-,"(-)') 9fa<6
'#"+ *+$'4 "00$,$+"('-# (.&# -00$/)1 2/'(') "#4
7"#"/(&/'(') #-4-)" 9!KU<6 B&.0C&(D) 4')&")&
&4&," *-/,"('-# '# (.& 0'+'"/3 5-43 ,"3 "+)-
9B&.0C&(<6 "#4 )"/0-'4-)')1 S.& ,-)( 0-,,-#
-00$/ '# (.& +"(&/ 0-$/)& -* (.& 4')&")&1 >&#'#A
"))-0'"('-#) "/& 7/&)&#(&4 '# (.& ("5+&1
:'), "#4 .&"4"0.& "/& (37'0"+ =U_ )3,7(-,)6
8.'0. ,"3 5& "))-0'"(&4 8'(. .&"/'#: +-))6 ('#A
#'($)6 "#4 %&/(':-1 !"(0.3 4&7':,&#("('-# -*
(.& )N'# 9%'('+':-< "#4 &3&5/-8) 97-+'-)')< "#4
."'/ +-)) 9"+-7&0'"< ,"3 "+)- -00$/1

!
HIJ
6" @&A*)B/0$A -3/=/).)*)+ $%. #$%&'()*)+
S.& 0"$)& -* (.') 4')&")& ') $#N#-8#1 S.& 0-#A
4'('-# ') " *-/, -* 0.-/'-/&('#'(') 0."/"0(&/'V&4
53 (.& 7/&)&#0& -* ,$+('7+& */&). +&)'-#) "#4
*'5/-('0 0."#:&)1 2( -*(&# -00$/) '# "))-0'"('-#
 2'()*)+ KGGL $%. E0&A$= @$%)B(+*$*)/%+ /B >;+*(?)0 6)+($+(

Sympathetic
!
?
Syphilis CMV Behçet’s disease Vogt-Koyanagi-Harada
ophthalmia syndrome
Borreliosis EBV
Yersiniosis HIV Phacogenic Sarcoidosis Multifocal chorioiditis and
uveitis panuveitis

A. Panuveitis: Causes and associations

IL-8

Obliterative vasculitis
of the retina Hypopyon Neuritis, accompanying
B. Uveitis with Behçet’s disease vasculitis

-A)%)0$A G??&%/A/8;
Bilateral panuveitis EBV??

CNS symptoms Vitritis

Meningism Chorioretinal
Headache lesions (fundus)
Pleocytosis Scar formation
in macula
Hearing loss, tinnitus
Chronic outcome
Vitiligo, alopecia Choroid detachment Choroid lesions with recurrent disease

"
C. Vogt-Koyanagi-Harada Syndrome D. Multifocal choroiditis and panuveitis

HLA-A11 Per- Anti-S-100

forating Anti-IRBP
wound CD8
Injured
eye

Right eye: scar

Attack
CD8
on
healthy
CD4 eye
TNF
Granuloma
CD8 formation
Müller cells

E. Sympathetic ophthalmia Left eye: beginning iritis

RA SPA SLE SJS JRA Wegener PAN Behçet Sarcoidosis
Conjunctivitis
sicca
Keratitis,
corneal ulcer
Episcleritis,
scleritis
Anterior uveitis
Vasculitis
Choroiditis,
panuveitis
F. Ocular manifestations of systemic diseases
!
HIM

"
! :';/3*%5-+3& #$$%&303<1

!" #$$%&'()'*+,-'* #&.'/-+0+-1

!"#$ %&'$()%#%)* !"# $!!%& '%( )$ )*( '(+(,$-.
/(#) $0 "%)$"#)12$'1(3 )$ 3-(&/")$4".3-(!101!
"!&$3$/", "#)15(#3 $& /(/2&"#( -(-)1'( "#)1.
5(#3 )*") 1//$21,14( )*( 3-(&/ 6!78 +$,"#$ %&-
'$()%#%)* /"9 2( !"%3(' 29 13$"#)12$'1(3 )$
3-(&/ $& "%)$"#)12$'1(3 )$ 4$#" -(,,%!1'" "#)1.
5(#3 )*") 1#*121) )*( "!!%/%,")1$# "#' -(#(.
)&")1$# $0 3-(&/ 1# )*( (55 !(,, 6"78 :))(/-)1#5
)$ ,$;(& )*( "#)12$'9 !$#!(#)&")1$# 29 -&(.
+(#)1#5 "#)15(# (<-$3%&( $& 29 1//%#$3%-.
-&(331$# 13 " -$3312,( "--&$"!* )$ )&(")/(#)
6#78 =#)&"%)(&1#( 1#3(/1#")1$# 13 "#$)*(& ",)(&.
#")1+(8 >*( 2(3) &(3%,)3 "&( "!*1(+(' 29 1# +1)&$
0(&)1,14")1$#8 =#)&"!9)$-,"3/1! 3-(&/ 1#?(!)1$#
60+&+5,0 #$$%&303<1
)*( (<-&(331$# $0 C"3 ,15"#'3 $# )&$-*$2,"3)1!
)133%(8 >*13 (#3%&(3 )*( (,1/1#")1$# $0 C"3.(<.
-&(331#5 "!)1+")(' /")(&#", > ,9/-*$!9)(3 29
"-$-)$3138
6" 7'3&,-,0 !%-3+$$%&' 81&*/3$'9
M")(&#", "%)$"#)12$'1(3 !"# !&$33 )*( -,"!(#)"
"#' )*(&(29 2( )&"#3/1))(' )$ )*( 0()%38 =#
1//%#( )*&$/2$!9)$-(#1! -%&-%&" 6=>ID 3((
-8 HFP7D "%)$"#)12$'1(3 "5"1#3) -,")(,() 5,9!$.
-&$)(1#3 (#)(& 1#)$ )*( 0()%3D ;*(&( )*(9 /"9
-&$'%!( *(/$&&*"51! 39/-)$/3 &"#51#5
0&$/ /1,' 2,(('1#5 )$ 1#)&"!&"#1", *(/$&&*"5(8
C&(Q%(#),9D )*13 $!!%&3 3*$&),9 "0)(& 21&)*8 >AE
21#'1#5.1#*121)1#5 1//%#$5,$2%,1#3 6>J==7

6=@A=7 /"B(3 1) -$3312,( )$ !$/-,()(,9 (+"'(
)*( 1//%#$,$51!", 2"&&1(&38
2" ),-'/&3.'-,0 430'/,&5'
C$& )*( /$)*(&D )*( 0()%3 &(-&(3(#)3 " B1#' $0
",,$5(#(1! )&"#3-,"#) "5"1#3) ;*1!* "# 1//%#(
&(3-$#3( /%3) 2( 3%--&(33('8 =# " #$&/",
-&(5#"#!9D *%/$&", 1//%#1)9 -&(+"1,3 '%( )$
"# 1#!&("3(' &(,("3( $0 >EF !9)$B1#(38 >*( *%.
/$&", 1//%#( &(3-$#3( !*"#5(3 0&$/ " !9)$.
!"# 1#'%!( )&"#31(#) !$#5(#1)", *9-$)*9&$1'.
13/ 1# 1#0"#)3 2$&# )$ /$)*(&3 ;1)* "%)$1/.
/%#( )*9&$1'1)13 63(( -8 FFR78 >*( )*9&$1'.3)1.
/%,")1#5 1//%#$5,$2%,1#3 6>A=7 )*") $!!%& 1#
G&"+(3S '13("3( !"# !"%3( #($#")", *9-(&)*9&.
$1'13/8 K($#")", )&"#31)$&9 /9"3)*(#1" 63((
-8 FTR7 /"9 '(+(,$- '%( )$ )*( )&"#3/1331$#
$0 "#)1.:@*U "%)$"#)12$'1(38
:#)1!"&'1$,1-1# "%)$"#)12$'1(3 1#!&("3( )*(
&13B $0 )*&$/2$313D ;*1!* /"9 &(3%,) 1# )&"#31.

"
)$&9 13!*(/1! "))"!B3 $& "-$-,(<98 :#$)*(& -$.
)$<1! =5GF 6>EH.1#'%!('7 &(3-$#3( )$ #$#!9)$.
)(#)1", !$/-,1!")1$# 13 -,"!(#)", 1#0"&!)1$#D
)$<1! =5GH 6>EF.1#'%!('7 "#)12$'9 -&$'%!)1$#8
;*1!* 13 &(3-$#312,( 0$& )*( 1#!&("3(' &")( $0
: -&('$/1#")1#5 >EH.)9-( &(3-$#3( 13 "33$.
/13!"&&1"5(3 1# ,%-%3 -")1(#)38 >*( -&(3(#!(
!1")(' ;1)* " )(#'(#!9 )$ 3-$#)"#($%3 "2$&.
$0 "#)1!"&'1$,1-1# "#)12$'1(3 1# )*( -&(5#"#)
)1$#8 A(!$#',9D -&$5(3)(&$#( 1#'%!(3 )*( -&$.
;$/"# 13 0&(Q%(#),9 "33$!1")(' ;1)* )*&$/2$.
'%!)1$# $0 -&$5(3)(&$#(.1#'%!(' 2,$!B1#5
!9)$-(#1"8 K($#")", ,%-%3 63(( --8 HRRD HVO7 !"#
0"!)$& 6I=JC7 1# ,9/-*$!9)(38 I=JC 3%--&(33(3
$!!%& 1# 1#0"#)3 2$&# )$ /$)*(&3 ;1)* ANW $&
)*( -&$,10(&")1$# $0 ,9/-*$!9)(3D )*( "!)1+")1$#
A?$X5&(#S3 39#'&$/( '%( )$ )*( )&"#3-,"!(#)",
$0 KL !(,,3D "#' )*( -&$'%!)1$# $0 >KC8 =# ;$.
)&"#30(& $0 AA.: 6"#)1.U$7 "#' AA.J 6"#)1.N"7
/(# ;1)* /%,)1-,( /13!"&&1"5(3D $#,9 " +(&9
"%)$"#)12$'1(38 K($#")", ,%-%3 13 !*"&"!)(&14('
3/",, #%/2(& $0 ,9/-*$!9)(3 3(!&()( I=JC8
29 " )&"#31(#) &"3* 31/1,"& )$ )*") 3((# 1# '13.
M$&($+(&D -&$5(3)(&$#( "#' I=JC -&$/$)(
!$1' ,%-%3D !9)$-(#1"D "#' !$#5(#1)", ")&1$+(#.
>EF.)9-( 1//%#( &(3-$#3(38
)&1!%,"& *("&) 2,$!B ;1)* 2&"'9!"&'1"8
>*( )&$-*$2,"3) ",3$ -&$'%!(3 "# 1//%#$.
3%--&(331+( 0"!)$&8 >*( "#)1"2$&)1+( (00(!)3 $0
=N.HO $23(&+(' 1# "#1/", 3)%'1(3 3%55(3) )*")
1) 13 "# 1/-$&)"#) !9)$B1#( 1# -&(5#"#!98
C%&)*(&/$&(D )*( *%/"# -,"!(#)" ,"!B3 )*(
!,"331! !,"33 = EN: "#)15(#3 :D JD "#' @8 >*13 -&(.
+(#)3 &(!$5#1)1$# $0 )*( -")(&#", "#)15(#3 -&(.
3(#) 1# )*( -,"!(#)" 29 /")(&#", > !(,,3 2%)
/"B(3 -,"!(#)", )133%(3 " )"&5() 0$& #")%&", B1,,.

!
(& !(,,3D ;*1!* !"# &(!$5#14( !(,,3 ;1)*$%) !,"33
= EN: /$,(!%,(38 E$;(+(&D )*( #$#!,"331! !,"33
=2 EN: /$,(!%,(D EN:.GD 13 (<-&(33(' $# )*(
/")(&#", 31'( $0 )*( -,"!(#)"D "#' )*13 1#)(&"!)3
;1)* 1#*121)$&9 &(!(-)$&3 $# KL !(,,3D -&$)(!).
=>? 1#5 )*( -,"!(#)" 0&$/ KL./('1")(' !9)$)$<1.
!1)98 :# "''1)1$#", -&$)(!)1+( /(!*"#13/ 13
Spermatocyte
peptide antigen
:';/3*%5-+3& #$$%&303<1

Prevention of sperm
!
Infertile Infertile exposure for 6 to 12 months
due to due to
Acro- auto-Ab auto-Ab
Intrauterine insemination
somal or
antigen iso-Ab
(anti- Immunosuppression
spermato-
cyte) In vitro fertilization
Zona pellucida (intracytoplasmic sperm
antigens, ZPI injection)
Oocyte
ZPII
1. Antigens ZPIII 2. Auto- or isoimmunity 3. Treatment options
A. Immune-mediated infertility

NK cell T cell TH0 TH2

60+&+5,0 #$$%&303<1
Progesterone IL-4
IL-10
PIBF Fetus:
TNF paternal
MHC- IgG1
IL-10 antigens =
foreign
Trophoblast cell
APC Trophoblast
derived factor

HLA-G NK cell FAS-L FAS

Placenta Trophoblast
cell

B. Maternofetal tolerance
CD94
Inhibitory
signal
Trophoblast T cell Apoptotic
cell "
Transient hypothyroidism Transient ~20% of
myasthenia pregnancies
of myasthenic
Transient Difficulty mothers
hyperthyroidism in swallowing
TBII Ab and breathing
id
Thyr o itis M AChR
e ya Partially
as s Ab
endogenous
ise

TSI
th

auto-Ab
en
’s d

Ab
formation
ia g
G r av e

rav i s

ITP
ba

Anti
I TP

Anti-
AC

Ib/IX
cardiolipin
A

Ab
Ab
SL E, S j ögr en Stroke,
Day 1 to 7 after birth

!
SS-A Ab SS-B Ab thrombosis
Discoid AV-block
skin
change Bradycardia Cytopenia
Transient neonatal lupus syndrome
C. Neonatal autoimmune syndromes
=>@

"
! #$%%&'$(&)'0

! "##$ %&''()* +,-. /,0/(00 +&)1 2*3,(2*+*).-4

56* "#&0 #/ .6* (++,)(7&.(#) (- .# 82#.*'. .6*
2*'(8(*). /2#+ .6* $(-*&-* () 3,*-.(#) 96(0*
'&,-()" &- /*9 -($* *//*'.- &)$ 2(-:- &- 8#--(;0*4
56* 82#.*'.(%* &'.(#) #/ .6* %&''()* -6#,0$ ($*<
&001 ;* '#+80*.* &)$ 0#)"<0&-.()" =/#2 -*%*2&0
1*&2- #2 & 0(/*.(+*>4 56* '#-.- #/ +&),/&'.,2()"
.6* %&''()* -6#,0$ ;* 0#9 *)#,"6 .# +&:* (.
&//#2$&;0* .# & 0&2"* 8#2.(#) #/ .6* 8#8,0&.(#)4
?#2*#%*2@ .6* %&''()* -6#,0$ ;* 9($*01 &%&(0<
&;0* &)$ 6&%* & 0#)" -6*0/<0(/*4 56* )**$ /#2 &
%&''()* $*8*)$- #) .6* ',22*). *8($*+(#0#"(<
'&0 -(.,&.(#) &)$ .6* "#&0 #/ (++,)(7&.(#)@ *4"4@
()$(%($,&0 82#.*'.(#)@ 6*2$ (++,)(.1 ='*2.&()
8&.6#"*)- $# )#. ;*'#+* *)$*+(' 96*)
*+&'&%$+ 1223')+)45
,-()" '#).(),#,-01 ,8$&.*$ ()/#2+&.(#)4 56*
-'6*$,0* ()'0,$*- %&''()&.(#)- /#2 .*.&),-@
$(86.6*2(&@ 8#0(#+1*0(.(-@ ;.,3"45$62& $+<62,+0
=.,@ +*&-0*-@ +,+8-@ 2,;*00&@ &)$ 6*8&.(.(- H4
56* /&'. .6&. .6*-* %&''()&.(#)- &2* 2*'#+<
+*)$*$ ;1 .6* 8,;0(' 6*&0.6 -*2%('*- *)-,2*-
.6&. .6* '#-.- 9(00 ;* '#%*2*$ ;1 ()-,2&)'*
'#+8&)(*- &)$ .6&. '#+8*)-&.(#) 9(00 ;*
8&($ () 2*'#")(7*$ '&-*- #/ %&''()&.(#)<2*0&.*$
$&+&"*4 F) G*2+&)1@ HIG &)$ 8*2.,--(- %&''(<
)&.(#)- &2* 2*'#++*)$*$ #)01 () 6("6<2(-: -(<
.,&.(#)-4 E*)'*@ .6*1 &2* '#)-($*2*$ .# ;* #8<
.(#)&0 #2 )**$<#)01 %&''()&.(#)- =!>4
56* /#00#9()" /&'.#2- &2* '#)-($*2*$ .# ;*
"*)*2&0 '#).2&()$('&.(#)- /#2 (++,)(7&.(#)B

#)01 & 82#8#2.(#) #/ .6* 8#8,0&.(#) (- (++,<
)(7*$>@ #2 .#.&0 *2&$('&.(#) #/ .6* 8&.6#"*)@
&- 9&- 8#--(;0* 9(.6 .6* -+&008#A %(2,- %&''(<
)&.(#)4 56* %&''()*- /#2 &'.(%* (++,)(7&.(#)
'&) ;* $(%($*$ ().# /#,2 "2#,8-B .#A#($-@ -80(.
%(2,- %&''()*-@ ()&'.(%&.*$ %&''()*-@ &)$ 0(%*
%&''()*-4
!"#"$%&' C6*) .6* (++,)* 2*-8#)-* (- $(<
2*'.*$ &"&()-. '*2.&() 82#$,'.- 82#$,'*$ ;1 &
8&.6#"*)@ *4"4@ &"&()-. .6* .#A()- #/ (")*+,-./0
1,)$23 %$4515,)$., #2 (6"&1)$%$23 1,1.+$@ (. (-
&',.* ()/*'.(#,- $(-*&-*-@ 6*+&.#0#"('&0 $(-<
*&-*-@ '#)"*)(.&0 &)$ &'3,(2*$ (++,)* $*/*'.-@
618*2-*)-(.(%(.1 .# &)1 ()"2*$(*).- () .6* %&'<
'()&.(#)4 !00 0(%* %&''()*- *A'*8. .6* 0(%* #2&0
8#0(#%(2,- %&''()* &2* -.2('.01 '#).2&()$('&.*$
$,2()" 82*")&)'14 F)&'.(%&.*$ %&''()*-@ -,'6
&- .6* '6#0*2& %&''()*@ '&) &0-# ()$,'* %(#0*).
(++,)* 2*-8#)-*-4 J(%* %&''()*- -6#,0$ )#. ;*
&$+()(-.*2*$ 9(.6() 0*-- .6&) &882#A(+&.*01
/#,2 9**:- #/ *&'6 #.6*24

" 8#--(;0* .# '2*&.* & %&''()* ,-()" #)01 .6&. 8#2<

.(#) #/ .6* .#A() 2*-8#)-(;0* /#2 .6* )*,.2&0(7()"
(++,)(.14 56* .#A#($ (- ,-,&001 &$+()(-.*2*$
.#"*.6*2 9(.6 & '&22(*2 -,;-.&)'* =&$D,%&).>
.6&. /,2.6*2 *)6&)'*- .6* (++,)* 2*-8#)-*4
746$108$)2& 8.//$+,& &2* %&''()*- +&$* #/ 8,2<
(/(*$ -,;,)(.- #/ & %(2,-@ ,-,&001 .6* '#&.4 E#9<
*%*2@ (/ '&2;#61$2&.* '&8-,0*</#2+()" ;&'.*2(&
&2* ,-*$@ .6* (++,)(7&.(#) ,-,&001 9(00 )#.
;* -,//('(*).@ *-8*'(&001 () -+&00 '6(0$2*)4
9+./1$8.1,% 8.//$+,& &2* 82*8&2*$ ,-()" ()&'<
.(%&.*$ ;&'.*2(& &)$ &2* *//*'.(%* &"&()-. *A.2&<
'*00,0&2 #2"&)(-+-4 56*1 ()$,'* &) &$*3,&.*
6,+#2&0 (++,)* 2*-8#)-*@ /#2 *A&+80*@ .#
'6#0*2&4 56* &).(;#$1 82#.*'.(#) 82#%($*$ ;1
.6*-* %&''()*- (- #/ #)01 0(+(.*$ $,2&.(#)4
E*)'*@ /2*3,*). ;##-.*2 -6#.- &2* 2*3,(2*$4
:$8, 8.//$+,& 6&%* .6* 6("6*-. 2&.* #/ -($* */<
/*'.- &)$ .6* 6("6*-. 2(-: #/ ()$,'()" (00)*--4
E#9*%*2@ .6*1 &2* +#-. *//*'.(%* () ()$,'()"
&$*3,&.* %&''()* 82#.*'.(#)@ *-8*'(&001 96*)
.6* (++,)* 2*-8#)-* .# .6* .&2"*. #2"&)(-+

!
(- +*$(&.*$ ;1 5 '*00-4

!" #$%%&'$(&)' *$+,'-$. &' */&+-/))-

F) G*2+&)1@ .6* 8,;0('01 2*'#++*)$*$ %&''(<
)&.(#)- -.&2. () *&201 '6(0$6##$ &)$ /#00#9 &
678 2*",0&2 (++,)(7&.(#) -'6*$,0* *-.&;0(-6*$
 Basic immunization Booster vaccinations
9:,.:&,;
!
Tuber- H. influenzae, Measles Rubella
culosis diphtheria, mumps vaccination
pertussis, rubella for girls
(Still
performed
tetanus
in some Poliomyelitis- DT Polio- PPD-test
countries)
oral vaccination myelitis

BCG DPT
i.cutan. S.C.
Vaccine
titer test

*+&'&%$+ 1223')+)45
Birth 3 15 18 6 10 11–14 14
Age in months Age in years
A. Vaccination calendar in childhood

Pathogen Indications Side effects Contraindications

HBV – Hospital staff, Short – Pregnancy
recombinant – Dialysis patients, fever reaction – Known allergy

"
HBsAg-vaccine – Family members of
HBV-carriers
– prostitutes
– Homosexuals
– Drug users
– Travel in endemic regions

Influenza Very ill patients Allergic – Acute diseases

killed vaccine > 60 y reactions (rare) – Egg albumin allergy

Rabies – After exposure Fever, Before exposure:

killed vaccine (animal bite) lymph node allergy to
– Before exposure swelling neomycin and
in veterinarians, tetracycline
forest-workers, in vaccine
hunters, etc.

Pneumococci – Splenectomy Mild local Ongoing

dead vaccine – Sickle cell anemia reaction pneumococcal infection,
capsular polysaccharides chronic purulent diseases
in 14 serotypes

For journeys in endemic regions

Cholera Low grade fever Allergies
killed vaccine

Yellow fever Low grade fever – Pregnancy

live vaccine – Egg albumin allergy
attenuated
D17-strain

Typhoid fever
live vaccine

B. Optional vaccinations
No problems Use killed
vaccine in
high-risk patients !
67<

"
! 74**)%4&)1%.

!"#$%& '( '") *#++,$)& #*#,-#.-) '(/#01 2#$0 ,$3

4)+',(5& /,&)#&)& +#$ $(6 .) -#78)-0 97)*)$')/
(7 #-2(&' +(29-)')-0 )7#/,+#')/ ,$ 2#$0 #7)#&
&57*,*#- ',2) (4 '") 9#'"(8)$ 25&' .) -($8 )$3
(58" '( ,$/5+) # 97(')+',*) ,225$) 7)&9($&):

(4 '") 6(7-/: ;(6)*)71 '")7) ,& &',-- # -#+% (4 *#+3 +;5)<)(- 8=!
+,$)& 4(7 -($83')72 +($'7(- (4 2#$0 9#'"(8)$&
L57,4,)/ MNF 97)9#7#',($& 5&)/ #& *#++,$)&
6,'" /,44)7)$' 2)+"#$,&2& 4(7 )*#/,$8 '")
+($'#,$ '") 8)$) 4(7 '") 9#'"(8)$,+ #$',8)$
"(&'<& ,225$) /)4)$&) &0&')2: =(2) 97(2,3
#$/ # &5,'#.-) O97(2(')7:P C$+) ,$')87#')/
$)$' )>#29-)& #7) 20+(.#+')7,#- ,$4)+',($& ,$'( '") "(&' +)--&1 )$(58" (4 '") MNF *#++,$)
?):8:1 '5.)7+5-(&,&@ #$/ 9#7#&,',+ /,&)#&)& ?):8:1
,& '7#$&+7,.)/ '( )$&57) '"#' '") #$',8)$ ,& 7)3
2#-#7,# #$/ -),&"2#$,#&,&@: A)&)#7+")7& #7)
-)#&)/: !",& )$#.-)& '") #$',8)$ '( 97(/5+) #
+577)$'-0 4(+5&,$8 ($ '") /)*)-(92)$' (4
I3+)-- 7)&9($&)1 97(*,/)/ '"#' '") #$',8)$,+
$)6 *#++,$)& .0 ')+"$,B5)& (4 8)$)',+ )$8,3
8)$) +($'#,$& '") &)B5)$+) 7)B5,7)/ .0 '") &,83
$))7,$8: $#- 9)9',/): F 47#+',($ (4 '") 97(+)&&)/ #$',3
8)$& +#$ .) 97(+)&&)/ ,$'7#+)--5-#7-0 #$/ 97)3
!" #$%&'(&)* +(,&)-(.
&)$')/ ($ '") +)-- &574#+) '(8)'")7 6,'" +-#&& H
69)%)*49 >22;%191?$

=0$'")',+ 9)9',/)& +($'#,$ ($-0 '") )9,'(9) (4 #
97(')+',*) #$',8)$: C'")7 9#7'& (4 '") 97('),$
'"#' )>)7' $)8#',*) ?&5997)&&,*)@ )44)+'& ($
'") ,225$) 7)&9($&)1 "#*) '(>,+ )44)+'&1 (7
+7(&&37)#+' 6,'" )$/(8)$(5& 97('),$& #7)
'")7)4(7) #.&)$': D(&' 9)9',/)& ,$/5+) # "53
2(7#- ,225$) 7)&9($&)1 '") 9(')$+0 (4 6",+"
*#7,)& /)9)$/,$8 ($ '") 7)&9)+',*) ;EF '09):
C9',2#- *#++,$) 97(')+',($ +#$ '")7)4(7) .)
#+",)*)/ ,$ ($-0 # 97(9(7',($ (4 '") 9(95-#',($:
D;J 2(-)+5-)&1 -)#/,$8 '( '") &',25-#',($ (4 #
!3+)-- 7)&9($&): !") 5&) (4 957,4,)/ MNF *#+3
+,$)& ,$ )>9)7,2)$'#- #$,2#-& 97(/5+)/ 97(3
2,&,$8 7)&5-'&: !")&) &5.&'#$+)& 6)7) 7)+)$'-0
97(9(&)/ #& # *#++,$) 4(7 FHM= ?&)) 9: QQR!@:
;(6)*)71 # $52.)7 (4 B5)&',($& 25&' .) #$3
&6)7)/ .)4(7) '")0 +#$ .) 5&)/ ,$ "52#$&:
!") 2#,$ B5)&',($& ,$*(-*) '"),7 4#') ,$ '")
"(&'1 ,:):1 '"),7 9(')$',#- 4(7 '7#$&4(72,$8 ,$'(
*,75-)$' MNF1 "(6 -($8 '")0 9)7&,&' ,$ '")

"
"(&' 8)$(2)1 #$/ 6")'")7 '")0 7)9-,+#') '")7):
/" 0(*123)%4%& +51&()%.
A)+(2.,$#$' 97('),$& +#$ .) 2#$54#+'57)/ ,$
-#78) B5#$',',)&: !") 2#,$ #/*#$'#8) ,& '"#'1
5$-,%) +($*)$',($#- *#++,$)&1 '")0 #7) 47))
47(2 '") "#7245- 47#82)$'& (4 '") 9#'"(8)$ 7)3
&9($&,.-) 4(7 &,/) )44)+'&: G$8,$))7)/ *#++,$)&
+#$ #-&( .) 5&)/ ,$ +#&)& 6")7) '") 9#'"(8)$
+#$$(' .) +5-'57)/ (7 ,& *)70 /,44,+5-' '( +5-',3
*#') ?):8:1 *,75&)&@: ;(6)*)71 '"),7 5&) 7)B5,7)& #
&5,'#.-) )>97)&&,($ &0&')2 ?):8:1 ,$ !" #$%&@ #$/
)#&0 7)2(*#- (4 '") *#++,$) 47(2 '") +)--& ,$
6",+" ,' 6#& 97(/5+)/:

6" 0(*123)%4%& 74**)%( #&54)%.

H4 # 7)+(2.,$#$' 97('),$ ,& 5$#.-) '( ,$/5+) #$
#/)B5#') ,225$) 7)&9($&)1 )&9)+,#--0 (4 !
+)--&1 ,' ,& 9(&&,.-) '( +-($) ,'& 8)$) ,$ # &5,'#.-)
+#77,)7 2)/,52 ?):8:1 ,$ *#++,$,# (7 IJK@: !(3
8)'")7 6,'" #$',8)$& ,$ '") +#77,)7 2)/,521
'") 7)+(2.,$#$' 97('),$ +#$ '")$ )>)7' 97(')+3
',*) ,225$,'0:

!
@A@
8" 8(9(&)1% :;&4%&.
!") /)-)',($ (4 8)$)& )&&)$',#- 4(7 '") *,75-)$+)
(7 *,#.,-,'0 (4 # 9#'"(8)$ 6,'",$ # "(&' (78#$3
,&2 +#$ 2#%) '") 9#'"(8)$ ,$+#9#.-) (4 97(/53
+,$8 # /,&)#&) ,$ '") "(&': ;(6)*)71 '") 7)/5+)/
 +
=(B 74**)%(.
!
Antigen Synthetic MHC class II
peptide

Processing Strong B-cell response

A. Synthetic peptides by APC weak T-cell response

69)%)*49 >22;%191?$
E. coli

Plasmid with gene Selection of plasmid-bearing Centrifugation Recombinant

for vaccine and E. coli by antibiotics and purification vaccine
with antibody- production and export of
resistant genes vaccine into supernatant
B. Recombinant proteins

Recombinant
Plasmid
Bacille
Calmette-
Guérin
(BCG)
Vaccination
"
vaccine alone Cloning into Protected by
is ineffective suitable carrier T cells
C. Recombinant vaccine strains

Restriction endonuclease Single strand-specific Ligase

nuclease S1
Wild-type virus: Isolation
highly virulent of genome
Virus receptor

Reduced replication –
but strong stimulation

!
of immune response

CD8 MHC class I

D. Deletion mutants Low virulence
@AC

"
" /114%( <=,)1,;$-$52

!" #$%&'()$*+,- !%'*./%0-,11,'$)2 3)45&

6#7!/3&8
!"#$%& '()*+,*+* -'). ).* /+0&)1231(4'( 5*)16
703'&5 78 '(.'7')'(2 989300:82*(1&*; <.0&/.06
3'/1&* #= )+'22*+& ).* +*3*1&* 0, 1+19.'40('9 19'4
,+05 /.0&/.03'/'4& '( ).* 9*33 5*57+1(*; #+16
9.'40('9 19'4 &*+>*& 1& 1 &?7&)+1)* ,0+ ).* /+06
4?9)'0( 0, *'90&1(0'4&@ 3*?A0)+'*(*&@ ).+056
70:1(*@ /+0&)19893'(@ 1(4 /+0&)1231(4'(&; B.*
50&) '5/0+)1() &)*/ '( ).* &8().*&'& 0, /+0&)16
231(4'(& '& ).* /+04?9)'0( 0, /+0&)1231(4'( C=
).+0?2. 989300:82*(1&*; B-0 0, ).*'+ '&06
*(D85*&@ EFGH 1(4 EFG=@ .1>* 7**( '4*()'6
,'*4;
!"#$ '& +*&/0(&'73* ,0+ ).* /+04?9)'0( 0,
>-*%*;,- /114%$-$52
19)'>1)'0( 0, 9*+)1'( 2*(*&@ ).* /+04?9)& 0,
-.'9. '(.'7') ).* &/+*14 0, '(,31551)'0(;
O0+*0>*+@ ).* /+04?9)'0( 0, '(,31551)'0(6*(6
.1(9'(2 /+0)*'(& P*;2;@ *(D85*& '(>03>*4 '(
/+0&)1231(4'( 5*)1703'&5Q 1+* 13&0 '(.'7')*4
78 '()*+19)'0(& -'). !R!L 1(4 0).*+ )+1(&9+'/6
)'0( ,19)0+& 0( ).* 2*(* 3*>*3;
$( .'2.*+ 90(9*()+1)'0(&@ *,,*9)& ).1) 91((0)
7* 1))+'7?)*4 )0 2*(05'9 19)'>')'*& 099?+ '( 9*+6
)1'( )8/*& 0, 9*33& 1,)*+ 1 &.0+) /*+'04 0, )'5*; $)
.1& ).*+*,0+* 7**( /0&)?31)*4 ).1) 1 5*56
7+1(*670?(4@ +1/'438 19)'>1)'(2 23?9090+)'90'4
+*9*/)0+ 5?&) 7* /+*&*();
S.*( ).* 23?9090+)'90'4 90(9*()+1)'0( '&
>*+8 .'2.@ '(9+*1&'(2 (?57*+& 0, 23?9090+)'90'4

503*9?3*& 1+* '()*2+1)*4 '()0 ).* 9*33 5*56

/+0&)1231(4'(& -'). /.8&'0302'913 ,?(9)'0(&@
*;2;I
!
J*2?31)'0( 0, /*+'/.*+13 +*&'&)1(9*@ +*(13
73004 ,30-@ 1(4 &04'?5 *3'5'(1)'0(@
!
E8)0/+0)*9)'0( 0, ).* 21&)+'9 5?90&1 78 '(6
9+*1&'(2 ).* ,30- 0, 5?9?& 1(4 '(.'7')'(2
19'4 &*9+*)'0(@
!
K(.1(9*5*() 0, /1'( +*9*/)0+ &*(&')'>')8@
!
L+0(9.04'31)'0(;
!"#% '& '(4?9*4 '( 50(098)*&@ 519+06
7+1(*@ 91?&'(2 (0(&/*9','9 9.1(2*& '( ).* /.86
&'913 /+0/*+)'*& 0, ).* 5*57+1(* P,3?'4')8@ /*+6
5*17'3')8Q; B+1(&5*57+1(0?& 91)'0( )+1(&/0+)
).*( 4*9+*1&*& 1(4 ).* 0>*+133 19)'>1)'0( 91/16
9')8 0, ).* 9*33 '& +*4?9*4;
T3?9090+)'90'4& .1>* 51(8 -18& 0, '()*+,*+6
'(2 '( '(,31551)0+8 /+09*&&*& 1(4 9*33?31+ '56
5?(* +*&/0(&*&; R0+ *:15/3*@ ).*8 '(.'7') ).*
5'2+1)'0( 0, 3*?A098)*& )0 ).* &')* 0, '(,315516
)'0(@ 504?31)* ).* >1+'0?& ,?(9)'0( 0, *,,*9)0+

#
/.12*&@ *(40).*3'13 9*33&@ 1(4 &8(0>'098)*& 78 9*33&@ 1(4 4*9+*1&* ).* /+04?9)'0( 0, '(,315516
'(,31551)0+8 &)'5?3' *:*+)*4@ ,0+ *:15/3*@ 78 )'0( 5*4'1)0+&;
*(40)0:'(& 0+ $M6H; $) *(.1(9*& /+0&)1231(4'(
&8().*&'& 4?+'(2 1( '(,31551)0+8 +*&/0(&*;
E89300:82*(1&* '(.'7')'0( 78 !"#$%& ).*+*6
,0+* .1& 1( 1()'6'(,31551)0+8 *,,*9) 1(4 7309A&
).* EFGH65*4'1)*4 /.8&'0302'913 *,,*9)& 0,
/+0&)1231(4'(&; B.* 1()'6'(,31551)0+8 *,,*9)
'& ).*+1/*?)'91338 ?&*,?3 '( 19?)* 1(4 9.+0('9
N0'() '(,31551)'0(&; $(.'7')'0( 0, EFGH6
5*4'1)*4 *,,*9)& '& ).* 91?&* 0, 50&) &'4* *,6
,*9)& 1&&09'1)*4 -'). ).*&* 4+?2&@ '(93?4'(2
21&)+'9 -133 41512* 1(4 ?39*+ ,0+51)'0(; $(.'6
7')'0( 0, ).* *(D85* 91( 13&0 91?&* +*(13 ,1'3?+*
1(4 73004 /+*&&?+* 4'&0+4*+& '( 9*+)1'( /16
)'*()&;

9" :-4;$;$)'*;$*+&
B.* 1()'6'(,31551)0+8 *,,*9) 0, 23?9090+)'90'4&
/318& 1 A*8 +03* '( ).* )+*1)5*() 0, +.*?51)'9
4'&*1&*&; B.* 19)'0( 0, ).*&* 4+?2& '& 40&*64*6
/*(4*() 1(4 099?+& 1) 4',,*+*() &')*& '( ).* 9*33;

"
O0&) 0, ).*'+ 19)'>')'*& 1+* '(4?9*4 78 13)*+*4
)+1(&9+'/)'0(; #,)*+ 7'(4'(2 )0 1 23?9090+)'90'4
+*9*/)0+ '( ).* 98)0&03@ ).* +*9*/)0+ 4'&&09'1)*&
,+05 .*1) &.09A /+0)*'( P.&/Q 905/3*:*& 1(4
7*905*& 91/173* 0, 7'(4'(2 )0 9*+)1'( &')*& 0,
?@A 2*(05'9 %!# '( ).* 9*33 (?93*?& P).* &069133*4
&'()'*+ (+,-'*,+ +.+)+*/,Q; B.'& 3*14& )0 ).*
Physiological stimulus
#$%&'()$*+,- !%'*.*%0-,11,'$)2 3)45& ,%+ :-4;$;$)'*;$*+&

Inflammatory stimulus
"
IL-1
Phospholipids

NSAIDs Phospholipase A2 Glucocorticoids

COO–

CH3

Arachidonate
COX 1 COX 2
Lipoxygenase

>-*%*;,- /114%$-$52
Prostaglandin H Glucocorticoids Leukotriene A4
(indirect effects)
Prosta-
cyclin
Leukotriene B4 Leukotriene C4, D4
Prostaglandins Thromboxane A2 chemotaxis bronchoconstriction

Peripheral resistance Inflammation: Florid ulcers Impaired blood-

Stomach protection cell formation
Renal function Vasodilation
Bronchial ! Pregnancy,

#
Hyperalgesia Mediators
Bronchodilatation Proteases asthma nursing
2. Contraindications
1. Mechanisms
A. Nonsteroidal anti-inflammatory drugs (NSAIDs)

CH 2 OH Myelopoiesis Lymphocytes
CO
OH MHC class II via redistribution
HO
Fc-receptors IL-2 production
IL-1, IL-6, TNF-" IL-2 effect
O prostaglandin
IL-2

Second CH2OH
messenger Cation CO
hsp 90 HO OH
transport
hsp
90
? Free
radicals O

Membrane
NF!B stability
Adhesion to Permeability of blood
Activation endothelium vessels
capacity Eosinophils Adhesion molecules
Basophils IL-1

"
Neutrophils Prostaglandins
mRNA mRNA
ACE, lipocortin, Phospholipase A2, COX2, Fibroblast proliferation
endonuclease receptor expresion, cytokines Fibronectin, COX 1 prostaglandins
1. Mechanisms 2. Effects on the immune system
B. Glucocorticoids
?@@

#
! :&&5#' ;2(<&(0*+*=/

!" !#$%&'$()*+%$',
!"#$%#&"'(#" )!*+, (-#. (. (/ (/#01"#(2%30#"
#$(# 0/#"&4"&". 50#$ 4%30- (-06 1"#(2%30.17 89
20/60/: #% #$" "/;91" 60$96&%4%3(#" &"6<-#(."=
0# 0/$020#. #$" 0/#&(-"33<3(& &"6<-#0%/ %4 4%3(#" #%
#"#&($96&%4%3(#"= #$"&"29 23%->0/: ?@ 1"#(2%A
30.1= 5$0-$ 0. &"B<0&"6 4%& #$91060/" (/6 C<&A
0/" 20%.9/#$".0.7 *$" 6"-&"(."6 DEF (/6 GEF
.9/#$".0. 3"(6. #% 4</-#0%/(3 6"40-0#. (/6 -"33
6"(#$ )1(0/39 0/ 8 -"33.,7 !*+ (3.% 0/$020#.
-"33 :&%5#$ 0/ %#$"& &(C0639 C&%304"&(#0/: #0.A
.<".= "7:7= $"1(#%C%0"#0- 2%/" 1(&&%5= :%/(6.=
1<-%.(3 30/0/:.= #<1%&.= (/6 C.%&0(#0- .>0/7
H0:$ 6%.". %4 !*+ $(I" ( C&01(&039 -9#%.#(#0-
"44"-#= 5$"&"(. 3%5 6%.". )%/"A404#$ #% %/"A
.+%#%0(+ :&&5#*+*=/
." 45+6(,(+(7%#'
R<34(.(3(;0/" 0. %/" %4 #$" 1%.# .C(&0/:39 (2A
.%&2"6 .<34%/(106" 6"&0I(#0I".7 S# 0. <."6 0/
#$" #&"(#1"/# %4 <3-"&(#0I" -%30#0. (/6 ?&%$/T.
60."(."7 *$" 6&<: 20/6. #% -%33(:"/ (/6 "3(.#0/
402"&. %4 #$" .<2"C0#$"30(3 #0..<" 0/ 1<-%.(3
3".0%/. 0/ #$" 6""C 3(9"&. %4 #$" .1(33 0/#".#0/"7
F 4&(-#0%/ %4 #$" 6&<: 0. -%/I"&#"6 #% #$" (-#0I"
-%1C%/"/#. .<34(C9&060/" (/6 UA(10/%.(30-9A
3(#" )UAFRF, 29 -3"(I(:" %4 (;% 2%/6. 29 0/#".#A
0/(3 2(-#"&0(7 *$" (-#0I" -%1C%/"/#. 0/$020#
0/43(11(#%&9 &".C%/.". 0/ #$" 0/#".#0/(3 5(337
*$" 3(#"& (2.%&C#0%/ %4 .<34(C9&060/" 0. &".C%/A
.023" 4%& .%1" %4 #$" 6&<:T. .06" "44"-#. )60;;0A
/"..= /(<."(= .<34%/(106" 4"I"&= (&#$&(3:0(,7 *$"

#"/#$ %4 #$" 011</%.<CC&"..0I" 6%.", $(I"
(/ (/#0C$3%:0.#0- "44"-# 6<" #% #$" 0/$020#0%/
%4 (6$".0%/ 1%3"-<3". (/6 -9#%>0/".7 FC(&#
4&%1 #$" .06" "44"-#. 0/ #$" &(C0639 C&%304"&(#0/:
#0..<".= $"C(#%#%'0-0#9 (/6 C<31%/(&9 #%'0-0#9
1(9 (3.% %--<&7
!"#$%&'()&*+ 0. ( C(&#0-<3(&39 "44"-#0I" 0/$020A
#%& %4 *A-"33 :&%5#$7 F4#"& "/#"&(3 (2.%&C#0%/=
#$" 6&<: 0. -%/I"&#"6 #% JA1"-(C#%C<&0/"= (
.<34<&%<. (6"/0/" #$(# 0/$020#. C<&0/" 20%A
-%/.#0#<"/#. (&" (-"#93(#"6 (/6 "'-&"#"6 0/ #$"
<&0/"7 *$" .06" "44"-#. (&" 1%.# ."I"&" 0/ .%A
-(33"6 K.3%5A(-"#93(#0/:L C(#0"/#.7
8" 9*+3
M%36 C&"C(&(#0%/. (&" C(&# %4 #$" 60."(."A1%6A
0490/: #$"&(C9 &":01"/ 4%& &$"<1(#%06 (&#$&0#0.7
*$" 1"-$(/0.1 %4 (-#0%/ 0. .#033 </"'C3(0/"67
N/" $9C%#$".0. 0. #$(# 011</%1%6<3(#0%/ %-A
-<&. 6<" #% -$"10-(3 1%6040-(#0%/ %4 C"C#06".

"
.9/#$".0. 29 (-#0/: (. ( K5&%/: "/6 C&%6<-#L
C&"."/#"6 29 !H? 1%3"-<3".7 F/%#$"& #$"%&9
#$(# #&(/.10#. /":(#0I" 4""62(->7 !%&"%I"&= 0#
0. #$(# 1(-&%C$(:". $(I" ( .#(2030;0/: 4</-#0%/
0. 0/-%&C%&(#"6 (. ( 4(3." -%1C%/"/# 0/#%
6<"= C&".<1(239= #% 0/$020#0%/ %4 1"60(#%& (/6
DEF (/6 GEF= #$"&"29 6(1(:0/: #$" 1%3"A
"/;91" &"3"(."7 *$" .06" "44"-#. %4 :%36 )6"&A
-<3".7 *$" (/#0:%<# (:"/# (33%C<&0/%3 0. (/ 0/$0A
1(#0#0.= .#%1(#0#0.= #$&%12%-9#%C"/0(= (/6
20#%& %4 '(/#$0/" %'06(."7 *$" 6&<: #$"&"4%&"
(:&(/<3%-9#%.0., 1(>" 0# /"-"..(&9 #% 1%/0#%&
0/$020#. #$" 1"#(2%30.1 (/6 "440-(-9 %4 JA1"&A
#$" 23%%6 (/6 <&0/" .#(#<. (# &":<3(& 0/#"&I(3.7
-(C#%C<&0/%3= 2<# 0/-&"(.". 0#. #%'0-0#97 M(.#&%A
0/#".#0/(3 60.%&6"&. (/6 &"I"&.023" C(/-9#%C"A
/0( 1(9 %--<& (. .06" "44"-#.7

-" ./0+*12*,12(&%3'
?9-3%C$%.C$(106"= ( -9#%.#(#0- 6&<:= 0. %/" %4
#$" 1%.# C%#"/# 011</%.<CC&"..0I" (:"/#.7
N/-" 0# $(. 2""/ -%/I"&#"6 0/ #$" 30I"& #% #$"
(-#0I" 4%&1= OA$96&%'9-9-3%C$%.C$(106"= 0#
-(/ (3>93(#" (/6 #$<. 0/(-#0I(#" I(&0%<. .#&<-A
#<&". 50#$0/ #$" -"33.7 *$" (3>93(#0%/ %4 2(.".
0/ DEF (/6 GEF 1%3"-<3". 3"(6. #% #$"
-&%..A30/>(:" %4 %CC%.0/: 2(." C(0&. (/6= <3#0A
1(#"39= #% -"33 6"(#$7 *$" 0/$020#0%/ %4 4</-A
#0%/(3 (-#0I0#9 (/6 #$" /<1"&0- &"6<-#0%/ 0/

!
-"33. (44"-#. 8 (/6 * -"33. "B<(3397 *$" 1%.#
.0:/040-(/# .06" "44"-# %4 -9-3%C$%.C$(106" 0.
$"1%&&$(:0- -9.#0#0.= #$" &0.> %4 5$0-$ -(/ 2"
&"6<-"6 29 -%(610/0.#&(#0%/ %4 PA1"&-(C#%A
"#$(/".<34%/0- (-06 )!QREF,7
>?@
 !#$%&'$()*+%$',A ./0+*12*,12(&%3'A 45+6(,(+(7%#'A (#3 9*+3
!
Methotrexate Dihydrofolate reductase Thymidine synthesis

T
Folate FH2 FH4 (tetrahydrofolate)
SH
Feedback
IN N
Azathioprine Purine biosynthesis

N N
A G
Wrong
6-Mercaptopurine Ribose P base

.+%#%0(+ :&&5#*+*=/
C1 1
Methotrexate 5 10
Inhibition of expression
A. Antimetabolites

Cyclophosphamide Immune modulation

Structures

"
Liver
H
OH
Cl CH2 CH2 N
P O Cross-linkage Cell death
Cl CH2 CH2 O

B. Cyclophosphamide

COOH
OH
H
N SO2 N N

Au
Sulfapyridine 5-ASA

? Inhibition

Side effects
T cells NK cells
– Headache

!
– Dizziness – Chemotaxis
– Fever – Inflammation
– Allergic mediators
reaction – Enzymes SH Au HS

C. Sulfasalazine D. Gold
>?B

"
! 8665,0 9/1*61%'&':$

!" #$%&'()'*+, !
!"#$%&'%()* + )& , #"#$)# '-'.)/- '(%/0#-/ 1"
.2- &%)$ 30*40& !"#$%"&#'()*+ ),-#'.*+5 62-(-
)*-&5 U)*#- $"8'2%#".-& ,(- -&'-#),$$" /-'-*9
/-*. %* /- *%:% &"*.2-&)&< , &2,(' /(%' )*
.2- #%*#-*.(,.)%* %3 40,*)*- *0#$-%.)/-& %#9
#0(&5 62- /,8,4- .% $"8'2%#".-& %##0(& 1" /)39
,(- 77 ,8)*% ,#)/& )* .2- 8%$-#0$-5 62- )8809
3-(-*. (%0.-&5 62- /V6G /-3)#)-*#" $-,/& .% , (-9
*%&0''(-&&):- -33-#. %3 #"#$%&'%()* + )& /0- .%
/0#.)%* %3 TB+ ,*/ FB+ &"*.2-&)&5 62-(- )& ,*
.2- )*2)1).)%* %3 #".%;)*- '(%/0#.)%*< -&'-9
,//).)%*,$ $,#; %3 40,*%&)*- M! 9/)'2%&'2,.-9
#),$$" .2,. %3 =>9?< ,. ,* -,($" '2,&- %3 69#-$$ ,#9
30#%&-< @2)#2 )& (-Q0)(-/ 3%( 894$"#%&"$,.)%*
.):,.)%*5 62- 8%$-#0$,( 8-#2,*)&8 %3 .2- /(04
%3 4$"#%'(%.-)*&< &0#2 ,& ,/2-&)%* 8%$-#0$-&5
@,& (-#-*.$" -A'$,)*-/ ,& 3%$$%@&5 !"#$%&'%()*
62- /-3)#)-*#" %3 V6G9#"#$%2"/(%$,&-97 #,0&-&
+ 1)*/& .% .2- #".%'$,&8)# (-#-'.%( #"#$%'2)$)*<
, $,#; %3 .-.(,2"/(%1)%'.-()*5 62)& (-/0#-& .2-
, '(%$)*- )&%8-(,&-5 62- #"#$%&'%()* + ,*/ #"9
*081-( %3 (-/%A (-,#.)%*& )* .2- #-$$< -&'-#),$$"
#$%'2)$)* #%8'$-A )*2)1).& #,$#)*-0()*< @2)#2
.2- 3%(8,.)%* %3 BW5
,#.& ,& .2- '(%.-)*9'2%&'2,.- '2%&'2,.,&-
(-&'%*&)1$- 3%( .2- ,#.):,.)%* %3 .(,*&#()'.)%* #" 304&5,'6+70
3,#.%( BC+6 D*0#$-,( 3,#.%( %3 ,#.):,.-/ 6 #-$$&E5
#&+,+%1& 8665,'&':$

62- ,1&-*#- %3 /-'2%&'2%("$,.)%* )*2)1).& .2-
8)4(,.)%* %3 ,#.):- BC+6 )*.% .2- #-$$ *0#$-0&
,*/< .20&< )*2)1).& .(,*&#()'.)%* %3 .2- =>9?
4-*-5 !"#$%&'%()* + ,$&% )*.-(3-(-& @).2 .2- &)49
*,$ .(,*&/0#.)%* %3 ',.2@," %3 6!F5 =. )*2)1).&
'(%.-)* ;)*,&- !! DGH!!E< .2-(-1" 1$%#;)*4 .2-
)*/0#.)%* %3 *0#$-,( #%8'%*-*.& %3 BC+65
!"#$%&'%()* + )*2)1).& .2- '(%/0#.)%* %3
%.2-( #".%;)*-& .% , &8,$$ /-4(-- D-545< =>97 )*
8,#(%'2,4-& ,*/ =>9I< =>9J< =>9K< ,*/ =CB9"E5
>-3$0*%8)/- )& ,*%.2-( *-@ )880*%&0''(-&9
&,*. .2,. -&'-#),$$" .,(4-.& $"8'2%#".-&5 =.&
8-#2,*)&8 %3 ,#.)%* )& &)8)$,( .% .2,. %3
8"#%'2-*%$,.-5 X" )*2)1).)*4 .2- -*Y"8- /)2"9
/(%%(%.,.- /-2"/(%4-*,&- DTLW9TLE< ). )*.-(9
3-(-& )* .2- -,($" '2,&- %3 /- *%:% '"()8)/)*-
1)%&"*.2-&)&5 62- /(04 -Q0,$$" )*2)1).& X ,*/
6 #-$$&5 F-&.)*4 $"8'2%#".-& 2,:- %*$" , &8,$$
'%%$ %3 '"()8)/)*-&5 =3 %*$" , 3-@ '"()8)/)*-&
#,* 1- &"*.2-&)Y-/ /0- .% .2- )*2)1).)%* %3

"
L-*#-< ). 2,& , '()8,(" )8',#. %* #-$$0$,( )89 TLW9TL /0()*4 ,#.):,.)%*< , (-/0#.)%* %3
80*)."5 TB+ ,*/ FB+ &"*.2-&)& @)$$ %##0(5 62- &"*.29
!'&/"#)+*0 DCHMNOE< , 8,#(%$)/- ,*.)1)%.)#< )& -&)& %3 ,/2-&)%* 8%$-#0$-& @)$$ ,$&% 1- (-/0#-/5
,$&% 0&-/ .% &0''(-&& #-$$0$,( )880*)."5 =.& 8-9
#2,*)&8 %3 ,#.)%* )& :-(" &)8)$,( .% .2,. %3 #"9
#$%&'%()* +5 +3.-( 1)*/)*4 .% , #".%'$,&8)# (-9
#-'.%(< 1234),(),5 %/".6), DCH91'E< .2-
.,#(%$)80&PCH91' #%8'$-A )*2)1).& .2- '2%&9
'2,.,&- #,$#)*-0()* ,*/< .20&< )*/)(-#.$" )*2)9
1).& #".%;)*- '(%/0#.)%*5
7'%'+$&),< ,*%.2-( 8,#(%$)/- ,*.)1)%.)#< )*9
2)1).& =>9?9/-'-*/-*. '(%#-&&-& )* .2- .,(4-.
#-$$ ,3.-( 1)*/)*4 .% , #".%'$,&8)# (-#-'.%(5
62- /(04 .2-(-3%(- )*.-(3-(-& @).2 .2- 69#-$$ ,#9
.):,.)%* &-Q0-*#- &%8-@2,. $,.-( .2,* #"#$%&9
'%()* + ,*/ .,#(%$)80& ,*/< .20&< ,#.& &"*-(4)&9
.)#,$$" @).2 .2-85

-" .$%')/0,'&120
R"#%'2-*%$,.- )& , *-@ )880*%&0''(-&&):-
/(04 .2,. 2,& ,#2)-:-/ 4%%/ (-&0$.& )* .2- .(-,.9
8-*. %3 .(,*&'$,*. (-S-#.)%*5 =. @,& #$)*)#,$$"

!
.-&.-/ )* ',.)-*.& @).2 (2-08,.%)/ ,(.2().)&
,*/ '&%(),&)&5 62- '(%/(04 8"#%'2-*%$,.-98%9
3-.)$ )& Q0)#;$" #%*:-(.-/ .% 8"#%'2-*%$,.-
,3.-( )*.(,:-*%0& ,/8)*)&.(,.)%*5 R"#%'2-*%9
$,.- #,0&-& (-:-(&)1$- )*2)1).)%* %3 )*%&)*-
;<= 8%*%'2%&'2,.- /-2"/(%4-*,&- D=RG9TLE
,*/< .20&< %3 .2- /- *%:% 1)%&"*.2-&)& %3 '0(9
 MHC class II
#$%&'()'*+, !> .$%')/0,'&120> 1,7 304&5,'6+70
!
(Auto-)antigen
TCR
Tacrolimus
(FK506)

Cyclosporin A
FK-
binding IL-1
protein IL-3
Cyclophilin PKC" IL-4
Ca2+

#&+,+%1& 8665,'&':$
IFN-!

Calcineurin IL-8
P
P
Cytokine
NFAT IL-2 effect production
NFAT

Promoter

"
Cytosol
NFAT
NFAT
Rapamycin Tacrolimus
Cyclosporin A
IL-2 gene
A. Cyclosporin A/FK506 Nucleus Effect on cellular immunity

IMP Gln, HCO3, ATP

Myco- NAD+
phenolate IMP-DH
NADH
XMP
Glu + ADP Leflunomide Dihydroorotate
GMP synthase Adhesion
Gln + ATP
DHO-DH FMNH2 molecules
GMP
FMN

Guanosine 5 - GTP- Orotate

diphosphate- cyclo-
fucose hydrolase 1 RNA/DNA
GTP, dGTP synthesis

N-Glycosylation Tetrahydro-
of glyco- DNA/RNA biopterin UMP -Pool

!
proteins synthesis
Antibodies
Adhesion Redox
molecules reactions
NO
formation TTP UTP CTP

B. Mycophenolate C. Leflunomide
;<?

"
! 4556%- 07(85(&$'$91

!" #$%$&'$%(' !%)*+$,*-.

!"# $%&'(%)*'+# ,( -%+.# /'%&*0*0#1 ,( %&*02,3
40#1 ,( % .05#& 16#)0(0)0*7 27 ('10,& ,( % 8 )#--
)#--3$#40%*#4 )7*,*,J0)0*7 =?HGG@ 27 GHQP E0--3
#+ )#--1 %+# ,*"#+ 6,*#&*0%- )7*,*,J0) #((#)*1 ,(
$,&,)-,&%- %&*02,40#1; !"# *%+.#* )#-- )%&: *,
% )#+*%0& 4#.+##: )-#%5# ,+ *!)+ *"# GHO $,-#3
90*" % $7#-,$% )#-- "%1 .%0&#4 .+#%* 10.&0(03
)'-# %&4 %**%)"#4 %&*02,47 ,+ 0&*#+&%-0B# *"#$:
)%&)#: #16#)0%--7 0& 40%.&,1*0) %66-0)%*0,&1;
*"#+#27 %5,040&. 4%$%.#; C#5#+%- $,&,)-,&%-
<,9#5#+: $,&,)-,&%- %&*02,40#1 =>?21@ %+#
%&*02,40#1 "%5# #&*#+#4 *"# )-0&0) 0& *"# -%1*
4#+05#4 (+,$ $0)# =$'+0&#@: %&4 *"#7 +#6+#3
MLR 7#%+1S 83)#--316#)0(0) GHMT %&*02,47 +0*'J3
1#&* % (,+#0.& %&*0.#& 9"#& 0&*+,4')#4 0&*,
0$%2 "%1 2#),$# %& 0$6,+*%&* *,,- (,+ *"#
*"# "'$%& 2,47; A& +#16,&1#: *"# 2,47 6+,3
*+#%*$#&* ,( 83)#-- <,4.E0&U1 -7$6",$%1:
4')#1 %&*02,40#1 *, &#'*+%-0B# *"# >?2; !"01
%&4 *"# %&*03<VI3MW&#' %&*02,47 *+%1*'B'$%2
%&*02,47 +#16,&1# -0$0*1 *"# '1# ,( $,&,)-,&%-
01 1'))#11('--7 '1#4 0& 2+#%1* )%&)#+ *+#%*$#&*;
%&*02,40#1 0& *"#+%6#'*0) %66-0)%*0,&1; C0&)#
?4"#10,& $,-#)'-# 2-,)E%4# 01 %&,*"#+ 9%7
"'$%& $,&,)-,&%- %&*02,40#1 %+# $')"
*, 0&"020* *"# 0&(-%$$%*,+7 6+,)#11 %&4 *"# %)3
$,+# 40((0)'-* *, 6+,4')#: +#1#%+)"#+1 %+# %*3
*05%*0,& ,( 0$$'&# )#--1; >,&,)-,&%- %&*02,3
*#$6*0&. *, +#4')# *"# %&*0.#&0)0*7 ,( $'+0&#
:'*%*&(' 4556%$'$91

40#1 40+#)*#4 %.%0&1* AG?>3N =GHXO@ 6+#5#&*

$,&,)-,&%- %&*02,40#1; D&# %66+,%)" 01 *, !"#
%4"#10,& $,-#)'-#1 (+,$ 20&40&. *, YF?3N
$%&'() *"# $,&,)-,&%- %&*02,40#1 27 -0&E0&.
=GHNN%WGHNQ@ %&4: *"'1: (+,$ %4"#+0&. *, #&3
*"# %&*0.#&316#)0(0) $'+0&# F%2 1#.$#&*
4,*"#-0%- )#--1 %&4 %)*05%*0&. ! )#--1; G-0&0)%-
90*" % "'$%& F) 1#.$#&*; ?&,*"#+ 9%7 *, #&3
*+0%-1 %+# )'++#&*-7 2#0&. )%++0#4 ,'* *, #5%-'%*#
.0&##+ $,&,)-,&%- %&*02,40#1 01 *, 0&),+6,+%*#
*"# #((0)%)7 ,( *"#1# $,&,)-,&%- %&*02,40#1 0&
,&-7 *",1# 6%+*1 ,( *"# $'+0&# F%2 (+%.$#&*
*"# *+#%*$#&* ,( %'*,0$$'&# 401#%1#1;
0$6,+*%&* (,+ %&*0.#& +#),.&0*0,& =),$6-#3
$#&*%+0*734#*#+$0&0&. +#.0,&1: GHI@ 0&*, *"# /" 0$'1&'$%(' !%)*+$,*-.
"'$%& %&*02,47 =GHI .+%(*0&.@;
D&# #J%$6-# ,( % )"0$#+0) %&*02,47 4#10.& Z,-7)-,&%- %&*02,40#1 )%& 0&*#+(#+# 0& 0$$'&#

"
90*" $'+0&# %&4 "'$%& #-#$#&*1 01 *"# %&*03
!KF %&*02,47: 9"0)" ),&101*1 ,( % $'+0&# F%2
(+%.$#&* 90*" "0." %((0&0*7 (,+ "'$%& !KF
%&4 % "'$%& F) (+%.$#&*; A& !KF3ILF) ('10,&
6+,*#0&: *"# F%2 (+%.$#&* 01 +#6-%)#4 90*" +#3
),$20&%&* "'$%& 1,-'2-# !KF +#)#6*,+; !"# +#3
)#6*,+ 01 &,+$%--7 6+#1#&* 0& 1#+'$ %&4 20&41
!KF3!; 8,*" *76#1 ,( #&.0&##+#4 !KF 2-,)E#+1
9#+# 0&5#1*0.%*#4 0& )-0&0)%- 1*'40#1 %&4 (,'&4
*, 2# #((#)*05# (,+ *+#%*$#&* ,( +"#'$%*,04
%+*"+0*01: 61,+0%*0) %+*"+0*01: %&4 %&E7-,10&.
16,&47-0*01; ?&*03!KF %&*02,40#1 0&"020* *"# 0&3
4')*0,& ,( %& 0&(-%$$%*,+7 +#%)*0,& 27 !KF3!:
9"0)" )%& %((#)* *"# 2-,,4 5#11#-1: *"# $0.+%3
*0,& ,( 0$$'&# )#--1: 0&(-%$$%*0,&1 ,( *"# 173
&,50% %&4 )%+*0-%.#: %&4 *"# 2,&# $#*%2,-01$;
D&# 104# #((#)* ,( %&*03!KF3! *"#+%67 01 *"#
6,1102-# %)*05%*0,& ,( -%*#&* *'2#+)'-,,101 =1##
6; MMN@;
?&,*"#+ 0$6,+*%&* )-0&0)%- %66-0)%*0,& (,+
$,&,)-,&%- %&*02,40#1 01 *"# 0&"020*0,& ,(
GHO P )#--1 *, +#4')# *"# 0$$'&# +#16,&1# 0&
%'*,0$$'&# 401#%1#1; ?&*03GHO >?2 %+# 403
+#16,&1#1 0& 1#5#+%- 9%71; !"#7 )%& +#4')# *"#
0$$'&# +#16,&1# 0& 6%*0#&*1 90*" %'*,0$3
$'&# 401#%1#1 27 6+#5#&*0&. ?ZG1 (+,$ )%63
*'+0&. %&4 6+#1#&*0&. %&*0.#&1 *, ! )#--1;
!"#7 )%& %-1, 0$6#4# *"# 6"%.,)7*,101 ,( %&*03
.#&1 27 $%)+,6"%.#1 %&4 0&"020* 83)#-- %)*05%3
*0,&; !"# 0&*#+)#6*0,& ,( 6%*",.#&0) %'*,%&*03
2,40#1 01 % 5#+7 0$6,+*%&* 6,0&* ,( %**%)E ,(
6,-7)-,&%- %&*02,40#1;
0-2)*,- 3(&&*%()*$%
!"# -%*#1* %**#$6*1 *, 0&"020* *"# )#--'-%+ 0$3
$'&# +#16,&1# 0& %'*,0$$'&# 401#%1#1 "%5#
*, 4, 90*" *"# 0&*#+%)*0,&1 ,( ><G $,-#)'-#1
%&4 !GI; ?&*03><G %&*02,40#1 "%5# 2##& 1')3
)#11('--7 '1#4 0& 50*+, %&4 0& %&0$%-1 *, 0&"020*
!3)#-- %)*05%*0,& 27 0&"020*0&. ><G +#),.&0*0,&
%&4W,+ %&*03!GI %&4 %&*03GHO %&*02,40#1;
Z#6*04# 5%))0&%*0,& 0&5,-5#1 *"# '1# ,( 6#63
*04#1 16#)0(0) (,+ *"# !3)#-- )-,&#1 %)*05# 0& %
401#%1# 6+,)#11; !"#1# 6#6*04#1 ),$6#*0*05#-7
4016-%)# *"# 6%*",.#&0) 6#6*04#1 (+,$ *"#
><G $,-#)'-#1; !"#7 "%5# 2##& 1",9& *, +#3

!
;<=
+#)*#4 %.%0&1* *"# #J*+%)#--'-%+ 4,$%0& ,( *"#
GHO $,-#)'-#; D&)# 2,'&4: *"#7 )%& $,4'-%*#
*"# %)*05%*0,& )%6%)0*7 ,( ! )#--1 ,+ 0&4')#
%6,6*,101; G,$6-#$#&* %)*05%*0,& 90*" 1'23
1#/'#&* -7101: 6"%.,)7*,101 ,( *"# *%+.#* )#--1
27 $%)+,6"%.#1: %&4 %&*02,4734#6#&4#&*
4')# *"# -#5#- ,( 401#%1# %)*050*7 0& #J6#+0$#&3
*%- %&0$%-1;
 Abs of single
specificity produced
#$%$&'$%(' (%, 0$'1&'$%(' !%)*+$,*-.

Antigen
!
+ Fusion Murine
part

B cell Myeloma cell

(Nonsecretory)
Human
part

1. Production Hybridoma cell 2. Reduction of antigenicity

TNF-!
Anti-TNF
antibody

:'*%*&(' 4556%$'$91
T cell TNF-!
rhs-TNF-R:
Fc fusion
Blood vessels Migration Synovitis Cartilage/bone protein

– proliferation – activation – proliferation – degradation Joint changes

– enhanced – chemotaxis – activation – activation of RA
adhesion – IL-8 production – pannus formation – faulty repair
a) Inhibition of TNF-! effects by anti-TNF Ab (e.g., in RA)

Shedding
! "
Complement-
mediated lysis
ADCC
phagocytosis
Anti-ICAM-1 Ab

LFA-1
ICAM-1
"
TCR CD4 LFA-1

ICAM-1

Modulation
Apoptosis
Adhesion Co-stimulatory
signal
b) Anti-CD4 antibodies c) Anti-ICAM-1 Ab
A. Monoclonal antibodies

Antigen Antigen B-cell activity Neutralization of Overloading

phagocytosis presentation pathogenic Ab of MPS

Ag
Ag
Fc#R

CR

B. Polyclonal antibodies
Polyclonal
antibodies
Ag

Phagocytosis
!
;<>

"
! !"#$%6

!"#$% &' !"# "$%&'$%( )*$ "+(,,%)%-(&%*. *) #/'01(&*%2 !$&/$%&%, 3#!4 3,/*$&'.'24

()*+%)*,- ./,)+ 0%1*-*+*,-

56 7*$.%.8 ,&%)).',, 7*$.%.8 ,&%)).',, %. *$ ($*0.2 &/' 9*%.&,

3)*$ (& +'(,& 5 /*0$4

:6 !$&/$%&%, %. &/$'' *$ 1*$' 9*%.& "*.-0$$'.& %.;*+;'1'.& *) (& +'(,& &/$'' 9*%.& $'8%*.,
$'8%*., <%&/ ,*)& &%,,0' ,<'++%.8 *$ '))0,%*.

=6 !$&/$%&%, %. &/' 9*%.&, *) &/' /(.2> B*)& &%,,0' ,<'++%.8 *$ '))0,%*. %. (& +'(,& *.' *) &/','
<$%,&? 7"@,? *$ @A@, $'8%*.,

C6 BD11'&$%-(+ ,<'++%.8 "*.-0$$'.& %.;*+;'1'.& *) &/' ,(1' 9*%.& $'8%*., *. E*&/

3($&/$%&%,4 ,%2', *) &/' E*2D

F6 #/'01(&*%2 .*20+', B0E-0&(.'*0, .*20+', *;'$ E*.D 'G-$',-'.-',? 'G&'.,*$

,0$)(-',? *$ %. *&/'$ ($'(, H$*G%1(+ &* &/' 9*%.&,

I6 #/'01(&*%2 )(-&*$ %. ,'$01 J'&'-&%*. *) (E.*$1(++D /%8/ K0(.&%&%', *) ,'$01

788%-0*9

$/'01(&*%2 )(-&*$,

L6 #(2%*+*8%-(+ -/(.8', *) J'&'-&%*. *) &DH%-(+ -/(.8',? ,0-/ (, '$*,%*., (.2

$/'01(&*%2 ($&/$%&%, 2'-(+-%)%-(&%*. H$*G%1(+ &* &/' 9*%.&,

" !"#$% 2' MBBN "+(,,%)%-(&%*. *) BH*.2D+($&/$*H(&/D

A.)+(11(&*$D ,H%.(+ H(%.

!"
BD.*;%&%,
(,D11'&$%- *$
H$'2*1%.(.&+D %. &/' +*<'$ +%1E,
"-0 ,-% ,) 3,)% ,1 +/% 1,$$,4*-5'
@*,%&%;' )(1%+D /%,&*$D
@,*$%(,%,
A.)+(11(&*$D E*<'+ 2%,'(,',
O$'&/$%&%,? -'$;%-%&%,? *$ (-0&' 2%($$/'( <%&/%. 5 1*.&/ E')*$' ($&/$%&%,
P0&&*-Q H(%. (+&'$.(&%.8 E'&<''. $%8/& (.2 +')& 8+0&'(+ ($'(,
M.&/',*H(&/D
B(-$*%+%%&%,

!
2:2
!"#$% &' !"#$"%&'()* !"#$+,-$(. $" /0(%1)#$& 2$.().(.
()%*+,+*+-.
=>*$%+* "*+;8
!
2,%+'(3.#*)"-(- 24! 5-.24!67
$-("#$&)' )"#$8("$& -(#(*1$")"#.
$" -.24! )"- ..24!
! B$"8'(3.#*)"-(- 24! 5..24!67
)"#$8("$& -(#(*1$")"#. *(')#(-
#, @%*$"(. )"- @F*$1$-$"(.
3+8-</%8
!
!"#$8("$& -(#(*1$")"#. ," 9K7
9L)7 9L+7 9M7 9N ,* &,"8',3
1(*)#(- A$#0 9L)39L+7 9M39N
=>*$%"1 )1<-%+/8
! BO )"#$8("
!"#$8("$& -(#(*1$")"# &,1@'(P(.
A$#0 .1)'' "%&'()* /4! 5."/4!6
!
RK3/4S
!"#$8("$& -(#(*1$")"# &,1@'(P(.
A$#0 RK3/4!
!
BB3!5/,6
!"#$8("$& -(#(*1$")"#.
L @*,#($".X :K E2)7 IL E2)
!
BB3[\C)
!"#$8("$& -(#(*1$")"# *(')#(-
#, ) NM E2) @*,#($"7 &,1@'(P(.
A$#0 /4!
! SQ4! 5@*,'$?(*)#$"8 &(''
"%&'()* )"#$8("6
!"#$8("$& -(#(*1$")"# *(')#(-
#, ) MM E2) @*,#($"
B&' =; 5#,@,$.,1(*).( ]6
!
!
^,3K 50$.#$-F'3.F"#0(#).(6
!
Q("#*,1(*(
5E$"(#,&0,*( )"#$8("6
!"#$%8
"
(-"+/+/0 )"--%1/ :/*+;%/*% <, ;+8%"8%
234567 *%$$89
9,1,8("(,%.7 2(#(&#)+'( $" :;<=; > ,? @)#$("#. A$#0
&$*&%')* BCD 5-$)8",.#$& 1)*E(* ,? BCD6
9,1,8("(,%.7 2(#(&#)+'( $" ,G(* HI > ,? @)#$("#. A$#0
&$*&%')* BCDJ )'., ,+.(*G(- $" ,#0(* -$.().(.7
(G(" ","*0(%1)#,$- &,"-$#$,".
9,1,8("(,%.7 2(#(&#)+'( $" M;<=; > ,? @)#$("#. A$#0
&$*&%')* BCD7 $" KI<L; > ,? @)#$("#. A$#0 /!7 )"-
$" %@ #, HI > ,? @)#$("#. A$#0 -*%83$"3
-%&(- BCD
?))%/;+@
Q,)*.('F 8*)"%')* 2(#(&#)+'( $" LI<MI > ,? @)#$("#. A$#0
BCDJ -$.().(3.@(&$?$& 1)*E(*
Q,)*.('F 8*)"%')* 9$80 #$#(*. -(#(&#)+'( $" HI > ,? @)#$("#.
A$#0 OQT2 )"- $" MI<NI > ,? @)#$("#.
A$#0 BCDJ ',A #$#(*. )*( -(#(&#(- $"
@)#$("#. A$#0 @*,8*(..$G( .F.#(1$&
.&'(*,.$.7 -$.&,$- BCD7 )"- BU,
.F"-*,1(
V8*("W.
#
Y$"('F 8*)"%')* Z 2(#(&#)+'( $" M;<N; > ,? @)#$("#.
&F#,@').1 A$#0 BCD )"- $" :;<=; > ,? @)#$("#.
A$#0 BU,
V8*("W. .F"-*,1(J .$8"$?$&)"# $"
"(,")#)' BCD )..,&$)#(- A$#0 &,"8("$#)'
0()*# +',&E
Y$"('F 8*)"%')* Z 2(#(&#)+'( $" KI > ,? @)#$("#. A$#0
&F#,@').1 BCD )"- $" N;<:; > ,? @)#$("#. A$#0
BU,
V8*("W. .F"-*,1(J .$8"$?$&)"# $"
"(,")#)' BCD $" )..,&$)#$," A$#0
&,"8("$#)' 0()*# +',&E
4%&'()* 2(#(&#)+'( $" M > ,? @)#$("#. A$#0 BCD
?'%,*(.&("&( ,?
G)*$)+'( $"#(".$#F
4%&'(,')* )"- 2(#(&#)+'( $" M; > ,? @)#$("#. A$#0
"
0,1,8("(,%. @*,8*(..$G( .F.#(1$& .&'(*,.$.
_*)"%')* $" 2(#(&#)+'( $" I > ,? @)#$("#. A$#0
&F#,@').1 -(*1)#,1F,.$#$. )"- $" M; > ,? #0,.(
A$#0 @,'F1F,.$#$.
B@,##(- 2(#(&#)+'( $" =; > ,? @)#$("#. A$#0 #0( 7A&
#
'$1$#(- ?,*1 ,? .&'(*,-(*1)
! !"#$%)

!"#$% &' !"#$"%"&'$&( )% *+,)'$,"-)."(/ "$ ,0( 1"'#$)/"/ )% *+,)"22+$( 1"/('/(/

())*+,"-%. .,)%")%
(/-*0 345 67!8 3+$%9*0 62*0 3;*
<=9%1>) ?@%/:"0 A9,:"92 (1-,0
"1-,#*.2 .%9:" ),-,) )21.9*: -*,. B")+/$,-,) C@*)C@*0
"9-@9,-,) $,C,.
)21.9*:%
*3* 444 444 444 4 444 4 4 4
./13* 444 5 5 5 5 5 5 5
!6 44 5 5 5 5 5 5 5
78593: 4 444 4 4 5 5 5 5
9"-)/)2'; : 44 5 5 5 5 5 5 5
:<3* 4 5 5 5 5 5 5 5
9) 44 4 4 5 444 4 5 5
=' 44 4 4 5 444 4 5 5
9*>> 44 44 5 5 4 44 5 5
(CC%1.,D

!&;?@ 5 5 444 5 5 5 5 5
<($,A)2(A( 5 5 444 5 5 5 5 5
B)58 5 5 44 5 5 5 5
:65!&; 5 5 4 4 5 5 5 5

"
<'A.");"C"$ 444 4 4 5 4 4 5 444
*3<* 5 5 5 5 5 5 444 5
90(+2',)". %'&,)A 44 4 4 4 444 444 4 5

!
EF&
!"#$% &' !"# "$%&'$%( )*$ "+(,,%)%-(&%*. *) /01 2,3*$&'.'45
!"#$%0
!
()*+%)*,- .%/*-*+*,-

6(+($ $(,3 7+(& *$ $(%,'4 $(,3 *. 8*&3 -3''9, &3(& ,9%:, &3' 8$%4;' *)
&3' .*,'

<%,-*%4 $(,3 1$=&3'>(&*?, $(%,'4 ,:*&, @%&3 9'$(&*&%- ,-(+', (.4 (&$*:3%-
,-($,A :$%>($%+= (& ,%&', 'B:*,'4 &* +%;3&

C3*&*,'.,%&%D%&= #(,3 &3(& $(:%4+= 4'D'+*:, ()&'$ 'B:*,?$' &* ,?.+%;3&

2*$ -*$$',:*.4%.; )(>%+= 3%,&*$=5

E$(+ ?+-'$, C(%.+',, *$(+ *$ .(,*:3($=.;'(+ ?+-'$, *8,'$D'4 8= &3'

(&&'.4%.; :3=,%-%(.

!$&3$%&%, F*.'$*,%D' ($&3$%&%, %. >*$' &3(. &@* :'$%:3'$(+ G*%.&,

2&'.4'$.',,A ,@'++%.;A '))?,%*.5

/'$*,%&%, <*-?>'.&'4 *--?$$'.-' *) :+'?$%&%, *$ :'$%-($4%&%,

122%-3*4
#'.(+ 4%,*$4'$ C'$,%,&'.& :$*&'%.?$%( *) !HIJ ;K4(= *$ -=+%.4$?$%(
23=(+%.%-A '$=&3$*-=&%-A ;$(.?+(&'45

F'?$*+*;%-(+ 4%,*$4'$ "*.D?+,%*., *$ :,=-3*,', %. &3' (8,'.-' *) >'&(8*+%- *$

M'>(&*+*;%-(+ 4%,*$4'$

N>>?.*+*;%-(+ 4%,*$4'$
4$?;L$'+(&'4 -(?,',

N>>?.*3'>*+=&%- (.'>%( 2$'&%-?+*-=&*,%,A :*,%&%D' "**>8,O

&',& !" +'?9*:'.%( *) "PHHHK>Q !" +=>:3*:'.%( *) "RJHHK>>Q
!" &3$*>8*-=&*:'.%( *) "RHH HHHK>>Q

C*,%&%D' 01 -'++ &',& !" 4'&'-&%*. *) 4,<F! (.&%8*4%', !"

"
4'&'-&%*. *) /> (.&%8*4%', !" )(+,'S:*,%&%D' ,=:3%+%, $'(-&%*.

!.&%.?-+'($ (.&%8*4%', !8.*$>(++= 3%;3 !F! &%&'$ %. :(&%'.& .*& &(9%.; (.= 4$?;,
&3(& -*?+4 +'(4 &* T4$?;L%.4?-'4 /01U

#$% &'()*+,-%!)& !" &%"',* .%+%/+'!- !0 0!)" !" (!"% !0 +$%&% 11 /"'+%"', '- , 2,+'%-+ .)"'-3 , 3'4%-
!5&%"4,+'!- 2%"'!. '& /*,&&'0'%. ,& .',3-!&+'/ !0 6789

!
56&

"
! !"#$%)

!"#$% &' !"#$%& '(&& )%*(+(,(-+ -* ./0,%1(2 3#024&(,(0

(")*+$,-,) ,./0$/,.1 $"21% /%))%$)

5(#+, 2%&& 6,%1$-7#&8 #7,%7(,(0 57#+4&-1#,-40 #7,%7(,(0 -* ,"% #-7,# #+9 (,0 1#:-7 ;7#+2"%0<
$7%9(&%2,(-+ *-7 ,"% %=,7#27#+(#& ;7#+2"%0 -* ,"% 2#7-,(9 #7,%7/>
?%1$-7#& #7,%7/ (0 2-11-+&/ #**%2,%9 6#@%A !BC /%#708>
!-11-+&/ #00-2(#,%9 D(," $-&/1/#&@(# 7"%41#,(2#>

?#E#/#04F0 #7,%7(,(0 57#+4&-1#,-40 (+*&#11#,(-+ -* ,"% #-7,# #+9 (,0 1#:-7

;7#+2"%0 6#@%A !BC /%#708>

(")*+$,-,) ,./0$/,.1 3%4,+35),6%4 /%))%$)

G-&/#7,%7(,(0 +-9-0# H%27-,(I(+@ (+*&#11#,(-+ -* ,"% 1%9(41J0(I%9 -7 01#&&

#7,%7(%0 D(,"-4, @&-1%74&-+%$"7(,(0 #+9 D(,"-4, K#024&(,(0 -*
,"% #7,%7(-&%0L 2#$(&&#7(%0L #+9 K%+4&%0>

M#D#0#E(F0 9(0%#0% N7,%7(,(0 -* ,"% &#7@%L 1%9(41J0(I%9L #+9 01#&& #7,%7(%0<

2-11-+&/ #00-2(#,%9 D(," 142-24,#+%-40 &/1$" +-9%
788%.4,9

0/+97-1%> ?"% 2-7-+#7/ #7,%7(%0 #7% -*,%+ #**%2,%9>

O+K-&K%1%+, -* ,"% #-7,# #+9 K%(+0 1#/ #&0- ;% -;0%7K%9
6404#&&/ (+ 2"(&97%+8>

(")*+$,-,) ,./0$/,.1 )3"$$ /%))%$)

" P%@%+%7F0 @7#+4&-1#,-0(0

!"47@Q.,7#400 0/+97-1%
57#+4&-1#,-40 (+*&#11#,(-+ -* ,"% 7%0$(7#,-7/ ,7#2, #+9
+%27-,(I(+@ K#024&(,(0 -* ,"% 01#&& ,- 1%9(41J0(I%9 ;&--9
K%00%&0> H%27-,(I(+@ @&-1%74&-+%$"7(,(0>

R-0(+-$"(&(# #+9 @7#+4&-1#,-40 (+*&#11#,(-+ -* ,"%

7%0$(7#,-7/ ,7#2, D(," +%27-,(I(+@ (+*&#11#,(-+ -* ,"% 01#&& ,-
1%9(41J0(I%9 ;&--9 K%00%&0< #00-2(#,%9 D(," #0,"1# #+9 %-J
0(+-$"(&(#>

S(27-02-$(2 $-&/#+@((,(0 H%27-,(I(+@ (+*&#11#,(-+ -* ,"% 01#&& K%00%&0 D(,"-4, -7

D(," -+&/ 1(+(1#& (114+% 9%$-,0> H%27-,(I(+@ #7,%7((,(0 -* ,"%
01#&& #+9 1%9(41J0(I%9 #7,%7(%0 1#/ ;% $7%0%+,> H%27-,(I(+@
@&-1%74&-+%$"7(,(0L $4&1-+#7/ 2#$(&&#7(,(0>

.2"-
T+&%(+Q'%+-2" $47$47# .1#&& K%00%& K#024&(,(0 D(," (+ 0(,4 (114+% 9%$-0(,0 2-+,#(+(+@
1#(+&/ O@N> !"#7#2,%7(I%9 ;/ (+K-&K%1%+, -* ,"% 0E(+L
@#0,7-(+,%0,(+#& ,7#2,L #+9 @&-1%74&( (+ 2-+:4+2,(-+ D(,"
#7,"7#&@(# #+9U-7 #7,"7(,(0>

R00%+,(#& 27/-@&-;4&(+%1(2 .1#&& K%00%& K#024&(,(0 #00-2(#,%9 D(," 27/-@&-;4&(+ (114+%

K#024&(,(0 9%$-0(,0 (+ 0(,4 #+9 D(," 27/-@&-;4&(+0 (+ 0%741> 5&-1%74&#7
(+K-&K%1%+, (0 2-11-+>

!
!4,#+%-40 &%4E-2/,-2&#0,(2 O0-&#,%9 &%4E-2/,-2&#0,(2 #+@((,(0 -* ,"% 0E(+ D(,"-4, 0/0,%1(2
#+@((,(0 K#024&(,(0 -7 @&-1%74&-+%$"7(,(0>

:&&
!"#$% &' !"#"$"%&" '()*$(+*$, -(./"0
!"#$%/
"
()*+%*,-)*"$ .*-,/ 01 .*-,/

1$,+2$*&,+" 0"345"%+(+4*% $(+" 617!8 9(."0: ;<= 55 6> 28? @<>= 55 6A 28

B"5(."0: C<>> 55 6> 28? C<AD 55 6A 28

2%3%4%*5% +"$.%/ 3)4 #$))6

'"/E*&,+"0 FG;<>DGD!>D;H!. FG;<>DGD IH.

J2$*5)*&,+"0 >@D<;@D!>D;H. >@D<;@D IH.
K"5*L.*)4% 6K)8 9(."0: >;<>= LH3. =G><>>GA 55*.H.
B"5(."0: >A<>C LH3. MGF<NGN 55*.H.
1$,+2$*&,+"0 9(."0: FG@<CGN!>DCH!.
B"5(."0: FGD<@GA!>DCH!.

7-33%4%*,-"$ 5%$$ 5).*,

I$(%/.*&,+"0
!
7"L5"%+"3 %"/+$*O24.0 @M " >DP

>::%*6-?
! 7+() %"/+$*O24.0 @ " ;P
!
1*04%*O24.0 ; " AP
!
Q(0*O24.0 !>P
',5O2*&,+"0 ;D " >DP

#
9*%*&,+"0 C " FP
R.(05( &"..0 !DG>P

7-/,4-#.,-)* )3 $89:;)58,% /.#:):.$",-)*/

J &"..0: STF# ST=< &(G FMP C>D<>FDDH!.

ST=# STF< &(G ;>P FDD<N;DH!.
"# &(G ><@P AC<CDH!.
STF< ST=< !>P
Q &"..0 !ADP ACD<CDDH!.

<$%5,4):;)4%/-/

U.)/54% @F<C@P DG@F<DGC@

$>VL.*)/.4%0 A<@P DGDA<DGD@
$AVL.*)/.4%0 M<>DP DGDM<DG>D
%VL.*)/.4%0 N<>AP DGDN<DG>A

=$"/9" :4),%-*/ CGC<=G@ LH3. CC<=@ LH.

R$*+"4%? +*+(. AD<;D 5LH3. ADD<;DD 5LH.
U.)/54% ;GC<@GD LH3. ;C<@D LH.
$>VU%+4+$,O04% ND<ADD 5LH3. DGN<AGD LH.
$AV9(&$*L.*)/.4% >;D<;DD 5LH3. >G;<;GD LH.

"
%AV94&$*L.*)/.4% 6%A 58 =<AF 5LH3. DG=<AGF 5LH.
9,*L.*)/.4% !MD !LH. !MD !LH.
B"$$4+4% ;D<;DD !3H3. ;D<;DD !3H3.
J$(%0#"$$4% ADD<;CD 53H3. AGD<;GC LH3.
K(O+*L.*)4% MD<;=D 5LH3. DGM<;G= LH.
S"$/.*O.(054% >@<CD 5LH3. DG>@<DGC LH.
SV$"(&+4W" O$*+"4% 6S!R8 !DG= 5LH3. !DGDD= LH. @A&
! !"#$%/

!!"#$% &' "#$#%#&'# ()*+%),+%- .)/0#12 '+&,3&0#45

()*+%*,-)*"$ .*-,/ 01 .*-,/

122.*)3$)#.$-*/

678 9:;<:: =7>4/ :?@;<?A 7>/

!"# $%&'()$$*$
678B A9;CDB =7>4/ :?A9;C?DB 7>/
678D <?9;ED =7>4/ :?:<9;:?ED 7>/
67F 9::;BG:: =7>4/ 9;BG 7>/
!"+ $%&'()$$*$
67FB <DD;BD@D =7>4/ <?DD;BD?@D 7>/
67FD BB9;9<9 =7>4/ B?B9;9?<9 7>/
67FC <B;BD@ =7>4/ :?<B;B?D@ 7>/
67F< !D@B =7>4/ !D?@B 7>/
67F 3& 0%3&# B: =7>/ B: =7>/
67H <:;DC: =7>4/ :?<;D?C 7>/
67I !D< =7>4/ ,- !:?D< 7>/ ,-
B:;BD: 0&3,1>=/ B:;BD: 0&3,1>=/
:;;%*<-=

JBK BE: !7>=/

JB 3&L3*3,+% G:;B<: M G:;B<: M
JC '+=N/#=#&, AA;BD: =7>4/ :?AA;B?D 7>/
J< '+=N/#=#&, D:;A: =7>4/ :?D;:?A 7>/
6(OD %#'#N,+% D::;B::: 0&3,1>=/

"
6(OE !9: &7>/

4*562%/

8JI BA;E: 0&3,1>/

8/P)/3&# NL+1NL),)1# G:;BE: 0&3,1>/
J%#),3&# P3&)1# !JQ5 !E: 0&3,1>/

()"3.$",-)*

RL%+=*+N/)1,3& ,3=# !K03'P5 9:;BC: M :?@;B?BA 6S"7

T)%,3)/ ,L%+=*+N/)1,3& ,3=# !TRR5 DC;CA 1
U3*%3&+7#& D::;<:: =7>4/ A?EE;BB?9G !=+/>/

!.2)8 2"89%8/

"BOU#,+N%+,#3& !8UT5 !B: !7>/ !B: !7>/

JI8 !A !7>/ !A !7>/
J8 BDA !CA V>=/
J8 BAOC !DE V>=/
J8 B@O@ !C9 V>=/
J8 9DO< !G?: V>=/
J8 B@O@ !C9 V>=/

!
J8 9DO< !G?: V>=/
76S" W 3&,#%&),3+&)/ &+%=)/3X#4 %),3+ W N),3#&, N/)1=) !Y03'P5>N++/ N/)1=) !Y03'P5

>?@
!!"#$% &' "#$#%#&'# ()*+%),+%- .)/0#12 '+&,3&0#45
!"#$%/
!
()*+%*,-)*"$ .*-,/ 01 .*-,/

(%2%#2)/3-*"$ 4$.-5 6(078

6#// '+0&, !789: !9/

;/*0<3& 77=:8 <>94/ 77?=:8? <>94/
@>; !?AB <>94/ !B <>9/
@>C ?AD=EAB <>94/ D=EB <>9/
@>F ?A?D=?AE8 <>94/ ?AD=EA8 <>9/

()2,-/)$

F+%&3&> 7G7=H?? &<+/9/ 7G7=H?? &<+/9/

IJ#&3&> HEAH=KGG &<+/9/ HEAH=KGG &<+/9/

9*,-#)5-%/

;&,3*+43#12 10'L )1 )&,3&0'/#)% )&,3*+43#1 )&4 )&,3MNO; )&,3*+43#12 )%# &+, /31,#4 L#%# *#')01#

933%*5-:
+$ ,L# >%#), 4#>%## +$ <#)10%#<#&, J)%3),3+&1 $%+< +&# ,#1, 1-1,#< ,+ )&+,L#%A PL# %#$#%#&'#
J)/0#1 <01, *# Q%+J34#4 *- ,L# %#1Q+&13*/# /)*+%),+%-A

"

!
;<=

"
! !"#$%2

!"#$% &' !" #$%&'()*+,-&

!"#"$%"#&% &#'()"*(+, -!.)/ 0&1+ (' 2",,()%+ '"
")'&(# & 34&#'('&'(5+ &,,+,,0+#' "6 $+%% 2"24%&7
'("#, (# '8+ )%""*9 '" ,":' '8+09 &#* '" $%&,,(6;
'8+0 &$$":*(#< '" '8+(: ,4:6&$+ &#'(<+#,= >8+ 5&:7
("4, #&0+, 6": '8+ 0"#"$%"#&% &#'()"*(+, &#*
'8+(: &#'(<+#, ?+:+ 2:"$+,,+* ); '8+ @AB7CDCE
E'&#*&:*(F&'("# G"00(''++ "# H+41"$;'+ I(66+:7
+#'(&'("# .#'(<+#, &#* $"02(%+* '" 6":0 '8+ ,(07
2%(6(+* (#'+:#&'("#&% '+:0(#"%"<;= !"#"$%"#&%
&#'()"*(+, ?('8 5(:'4&%%; (*+#'($&% ,2+$(6($('; 6":
& <(5+# 0+0):&#+ &#'(<+# ?+:+ <:"42+* '"7
<+'8+: &#* *+6(#+* 4,(#< $%4,'+: "6 *(66+:+#'(&'("#
-GI/ #40)+:,= >8+ 6"%%"?(#< '&)%+ 2:"5(*+, &#
"5+:5(+? "6 '8+ 0"#"$%"#&% &#'()"*(+, &#* '8+(:
&#'(<+#,= >8+ #+? GI $%4,'+:, &#* ,4)$%4,'+:,
2:+,+#'+* &' '8+ J'8 C#'+:#&'("#&% @":1,8"2 (#
A&::"<&'+9 D#('+* K(#<*"09 (# LMMM -NAHI.JO/9
?8($8 8&5+ :+$+#'%; )++# 24)%(,8+* -H+41"$;'+
>;2(#< PCC/9 &:+ &%," (#$%4*+*=

() *+,#%- ./0%- 1%234*"/35*675$%8+$%69*/34%* (%$$+$"- -%"8/3:3/;

!".*/ 3-&4&'+*+5$' %$)&(,)& 6$- %7($0*(+&-5*) )58524 ><7%$(7+&4/ ?@!/ "!

!".0/ ><7%$(7+&4/ "!
!".(1 ><7%$(7+&4/ ?@!/ "!/ A
9<<%*13=

!".2 !$'4+5+,+59&)7 &:8-&44&2/ 5'+&-*(+5$' ;5+< #=> (&))4 B/ > (&))4

!"C >../ >8DE/ 4<&&8 &-7+<-$(7+& -&(&8+$-/ -&(&8+$- > (&))4/ #= (&))4
6$- !"FG/ !"DG/ !"DH
!"CI !"C &85+$8& $' *(+59*+&2 > (&))4 > (&))4/ #= (&))4
!"J !"J ($%8)&: > (&))4

"
!"F >F/ B@! ()*44 KK/ @KL -&(&8+$- > (&))4/ %$'$(7+&4
!"D >8MN/ !"NC -&(&8+$- > (&))4/ A (&))4
!"M >.C > (&))4/ A (&))4
!"N KOB P( -&(&8+$- > (&))4/ #= (&))4
!"G >G/ B@! ()*44 KQ48&(565( -&(&8+$- > (&))4/ #= (&))4
!"G0 >G/ B@! ()*44 KQ48&(565( -&(&8+$- > (&))4
!"H 8CF 8-&QA/ B/ 3)+/ R$
!".E #&,+-*) &'2$8&8+52*4&/ O8.EE/ ($%%$' S?? *'Q (S??/ O&-%5'*) (&'+&- A (&))4/
+5O&' T!S??SU O-*',)$(7+&4
!"..* ?&,V$(7+& 6,'(+5$' *'+5O&' . T?PSQ.U ?&,V$(7+&4
!"..0 !J05 -&(&8+$- T!IJU/ B*(Q./ B$Q. B/ W/ #=
!"..( !J05 -&(&8+$- T!IJU/ !J2OI/ !IF B/ W/ #=/ A
!";.C X'V'$;' 6,'(+5$' B/ W/ 3)+
!".J S%5'$8&8+52*4& #/ O8.DE/ ($-$'*95-,4QI B$'$(7+&4/ O-*',)$(7+&4
!".F ?3YZ?A3 -&(&8+$-/ O8DD B/ W/ "!/ A
!".D ?&;54 T?&Q:U/ JQPS?/ :Q<*8+&'/ W/ B/ I&&2[Y+&-'0&-O (&))4
)*(+$Q!Q6,($8&'+*+$4& KKK/ YYRS
!".D4 Y5*)7)Q?&;54 T4?&Q:U/ !"MC& )5O*'2 ?&,V$(7+&4/ R!
!".D, Y,)6*+&2 !".D
!".M P(IKKK* 6$- KOW/ O8 DE[MD #=/ W/ %*(-$8<*O&4
!".M0 P(IKKK0 6$- KOW T;5+< W3K *'(<$-U W-*',)$(7+&4
!";.N ?*(+$47)(&-*%52& W/ B/ 8)*+&)&+4
!".G !CQK'+&O-5' (<*5' ;5+< !"..*/ 0/ ( ?&,V$(7+&4

!
!".H AO8HD/ Y)O 6*%5)7 A (&))4
!"CE A./ A8JD/ !*C\ (<*''&)4 A (&))4
!"C. !J2QI T!"CU/ O8.FE/ RALQI/ !"CJI B*+,-& A (&))4/ P"!
!"CC AO8.JD/ !"FDIE -&(&8+$- A (&))4
!"CJ ?$;Q*665'5+7 P(QKOR -&(&8+$-/ P("IKK/ B*+,-& A/ B/ P"!/ R$
>?@ W8DE[FD/ !"C. -&(&8+$-
!!"#$% &' "# $%&'()*+,-.'/ )%(,0(-'12
!"#$%2
!
() *+,#%- ./0%- 1%234*"/35*675$%8+$%69*/34%* (%$$+$"- -%"8/3:3/;

"#34 5'+,67,+8*' +(,09'( !5:;2 <%&%*%9-' = )'**7/ 9.+(-*%)>,'7

"#3? @A63 .')'B,%. ! )<+0(/ C+) +(,09'( ;),0DE C/ =/ F
"#3G #0B'B,01>*B'B,01+7' @H/ 9BI3J/ C+I ;),0DE C/ =/ FK
"#3L "#LJ .')'B,%./ C$MN6*0O' B.%,'0( C )'**7/ ,<>&%)>,'7/ $P/ =
"#3Q CB44/ "#QJ .')'B,%./ "#QG .')'B,%. C )'**7/ +),0DE =
"#3R "I6@(,'9.0( )<+0(/ B*+,'*', 9B@@+ A'-O%)>,'7
"#SJ P06I +(,09'(/ C$MN6*0O' B.%,'0( ;),0DE = )'**7/ C )'**7T
N''1U:,'.(8'.9 )'**7
"#SI KV";F6I/ B*+,'*', 9B@@+/ '(1%)+& K*+,'*',7/ F/ W/ =/ C
"#S3 M)N@@ X%. @9W/ 9B4J F/ W/ =/ V%
"#SS F>R/ -(O(%Y( X-(),0%( F/ &>'*%01 B.')-.7%.7
"#S4 F>IJ 5'&+,%B%0',0) B.')-.7%.7/
V%
"#S? "S8Z"48 .')'B,%. !"NI2 V.>E/ W/ F/ = !C/ $P/ M#"2
"#SG K*+,'*', 9B@H !9B@@@82/ ,<.%&8%7B%(10( F/ K*,/ V"
.')'B,%./ )%**+9'( ,>B' @Z@@@ .')'B,%.

9<<%*13=
"#SL 9B4JU4? = )'**7/ !C2/ &>'*%01 )'**7
"#SQ CIJ/ 9B4? !$;# 9*>)%<>1.%*+7' +(1 ;#K K*+7&+ )'**7/ '+.*> = +(1 C/
.08%7>*)>)*+7' +),0D0,>2 +),0D+,'1 C )'**7
"#SR 9BQJ = )'**7/ $P/ V"/ F/ #"

"
"#4J 9B?J/ "#4JA6N/ X.%& C$MN X+&0*> =/ F/ #"/ 8+7+* V"
"#4JA 9BSR/ CN;K6I/ "#4J *09+(1 C )'**7
"#4I N')'B,%. X%. X08.0(%9'( +(1 D[M K*,/ &'9+O+.>%)>,'7
"#43+ K*+,'*', 9B@\ K*,/ &'9+O+.>%)>,'7
"#438 K*+,'*', 9B@86! K*,/ &'9+O+.>%)>,'7
"#43) K*+,'*', 9B@86" K*,/ &'9+O+.>%)>,'7
"#431 K*+,'*', WKH K*+,'*',7
"#4S A'-O%70+*0(/ 9BR?/ 70+*%B<%.0(/ 9BII?/ A'-O%)>,'7/ '])'B, .'7,0(9 =
*'-O%)>,' 70+*%9*>)%B.%,'0(
"#44 K9B6I/ 9BQJUR?/ <>+*-.%(0) +)016N/ 5";F C/ =/ W/ F/ '.>,<.%)>,'7
"#44N N'7,.0),'1 "#44 V.>,<.%)>,'7
"#4? C3JJ/ *'-O%)>,' )%&&%( +(,09'( !A";2/ ;** <'&+,%B%0',0) )'**7
,>.%70(' B<%7B<+,+7'
"#4?N^ N'7,.0),'1 C3JJ/ 9BIQJ/ "#336N C 7-87',7/ =67-87',7/ F
"#4?N; N'7,.0),'1 C3JJ/ 9B33J/ A"; 07%X%.& C 7-87',7/ =/ F
"#4?N= N'7,.0),'1 C3JJ/ A"; 07%X%.& C 7-87',7/ =/ W/ F
"#4G F'&8.+(' )%X+),%. B.%,'0( !F"K2/ A'-O%)>,'7
9B4?ULJ/ &'+7*'7 D0.-7 .')'B,%.
"#4L @(,'9.0(6+77%)0+,'1 B.%,'0(/ ^;S/ I#Q ;** )'**7
"#4Q 9B4I/ B-,+,0D' "#344 .')'B,%. A'-O%)>,'7
"#4R+ HA; !I )<+0( !HA;6I2T *+&0(0( +(1 )%**+9'( ;),0D+,'1 C/ =T F
.')'B,%.
"#4R8 HA; !3 )<+0( !HA;632T B*+,'*', WK@+T *+&0(0( K*+,'*',7/ )-*,-.'1 C )'**7

!
+(1 )%**+9'( .')'B,%.
"#4R) HA; !S )<+0( !HA;6S2T *+&0(0(/ )%**+9'(/ = )'**7
+(1 X08.%('),0( .')'B,%.
"#4R1 HA; !4 )<+0( !HA;642T X08.%('),0( +(1 H";F .'6 F/ C/ =/ ,<.%&8%)>,'7
)'B,%.
"#4R' HA; !? )<+0( !HA;6?2/ X08.%('),0( N F'&%.> C/ F/ K*,
"#4RX HA; !G )<+0( !HA;6G2/ *+&0(0( N K*,/ C >?@

"
! !"#$%2

!!"#$% &' "# $%&'()*+,-.'/ )%(,0(-'12

() *+,#%- ./0%- 1%234*"/35*675$%8+$%69*/34%* (%$$+$"- -%"8/3:3/;

"#34 5(,'.)'**-*+. +16'70%( &%*')-*' 8 !5"9:;82/ $-&'.%-7/ B-, (%, %( C"

"#<<+="#<> !?@9;<2 .')'A,%.
"#3< ! "6+0( %D E0,.%('),0( .')'A,%. !F$G2 !H*,2/ C"/ D0B.%B*+7,7
"#3I "+&A+,6;</ JAI<KI> ?'-L%)M,'7
"#38 :C:;38 N(*M %( *'-L%)M,'7/ B-, (%,
%( A*+,'*',7
"#3O 5(,'.)'**-*+. +16'70%( &%*')-*' < !5"9:;<2/ $-&'.%-7
"#<<+="#<> !?@9;<2 .')'A,%./ :9";< *0J+(1
"#33 #')+M;+))'*'.+,0(J D+),%. !#9@2 $-&'.%-7
"#3P $QR</ 07%D%.& %D ('-.+* )'**-*+. +16'70%( $Q
&%*')-*' !$"9:2
"#3S R$Q</ JA<<4/ -(L(%T( D-(),0%( $Q/ U/ V 7-B7',7/ B.+0(
"#3> ?M&A6%)M,' D-(),0%(;+77%)0+,'1 +(,0J'( 8 ?'-L%)M,'7/ 'A0,6'*0-&
!?@9;82/ "#I .')'A,%.
"#3W JA<>KI4/ ?M;P 70&0*+.0,M/ 6%&%*%J%-7 $-&'.%-7
.'7,.0),0%( D+),%. I4 !RG@;I42/ "#I .')'A,%./
9<<%*13=

A.%,'),0(
"#P4+ X+(J*0%701' X#8 V )'**7/ A*+,'*',7
"#P4B W;!;+)',M*;X#8 V )'**7/ A*+,'*',7
"#P4) S;!;+)',M*;X#8 V )'**7/ A*+,'*',7
"#P< "I;5(,'J.0( )6+0( !JA555+2 H*+,'*',7/ &'J+L+.M%)M,'7

"
"#PIC C;7'*'),0(/ C?9:;< 9),0EY C"
"#PI? ?;7'*'),0(/ ?9:;</ ?'-;>/ VZ</ :C?<O $-&'.%-7
"#PIH H;7'*'),0(/ J&A<O4/ H9#XC: 9),0EY C"/ H*,
"#P8 H*, 38 L#+ +),0E+,0%( +(,0J'(/ ?5:H 9),0EY H*,[ :/ !X/ V/ U2
"#PO @)G5 D%. 5JX/ 60J6;+DD0(0,M @)G D%. 5JX :%(%)M,'7
"#P3 F5:I +(,0J'(/ )'.+&01' 1%1')+7+))6+.01' O) X.+(-*%)M,'7/ !&%(%)M,'72
"#PP+ U0*0+.M J*M)%A.%,'0( !UXH2 X.+(-*%)M,'7
"#PP+B)' 9B ,% UXH/ $"9W3/ $"9W4 X.+(-*%)M,'7
"#PP+)1 9B ,% UXH/ $"9W4/ "X:< X.+(-*%)M,'7
"#PP+)1' 9B ,% UXH/ $"9W4/ "X:</ "C9 X.+(-*%)M,'7
"#PP+)' 9B ,% UXH/ $"9W4/ "C9 X.+(-*%)M,'7
"#PP+1' 9B ,% UXH/ "X:</ "C9 X.+(-*%)M,'7
"#PP+' 9B ,% UXH/ "C9 X.+(-*%)M,'7
"#PPB "#PS/ A<44/ "X:P/ (%(7A')0D0) ).%77;.'+),0(J X.+(-*%)M,'7
+(,0J'( !$"92 W3
"#PPB' 9B ,% $"9W3/ "C9 X.+(-*%)M,'7
"#PP) $"9W4 X.+(-*%)M,'7
"#PP)' 9B ,% $"9W4/ "C9 X.+(-*%)M,'7
"#PP1 "X:< X.+(-*%)M,'7
"#PP1' 9B ,% "X:</ "C9 X.+(-*%)M,'7
"#PP' "+.)0(%'&B.M%(0) +(,0J'( !"C92 "%*%( 'A0,6'*0+* )'**7
"#PS $%T "#PPB \
"#P> JA<<4/ &+).%70+*0( :/ :#/ ('-,.%A60*7/ B+7%A60*7

!
"#PW 9),0E+,0%( 0(1-)'. &%*')-*' !95:2/ C9</ :?G/ C+.*M +),0EY V )'**7/ U )'**7/
?'-I8 &+).%A6+J'7/ $Q
"#S4 "#IS .')'A,%./ Q0;IO V/ U;CUF/ A.';U??/
G''1K],'.(B'.J )'**7
"#S< V.+(7D'..0( .')'A,%./ VW +(,0J'( 9),0EY V/ U/ A.%*0D'.+,0(J
>?> )'**7
!!"#$% &' "# $%&'()*+,-.'/ )%(,0(-'12
!"#$%2
!
() *+,#%- ./0%- 1%234*"/35*675$%8+$%69*/34%* (%$$+$"- -%"8/3:3/;

"#34 56784/ "#9 .')':,%. ; )'**</ (%, :*+<&+ )'**<

"#3= >),%89! 8(-)*'%,01+<' !'),%89! 8$?2 ; )'**</ ? )'**<
"#3@ AB" )*+<< CC8<:')0D0) )E+:'.%(' 0(F+.0+(, )E+0( ; )'**</ &%(%)6,'<
"#39 5+),%<+&0('</ :'.E+:< + "#44 *0G+(1 A+,-.' ; )'**</ ? <-7<',<
"#3H !84/H8<0+*+,'1 *+),%<+&0('< ; )'**</ ? )'**</ >"
"#33 I*%7%,.0+%<6*)'.+&01' !I7=2/ ;-.J0,,K< I'.&0(+* ; )'**</ ;-.J0,,K<
*6&:E%&+ +(,0G'( !;5L2 *6&:E%&+ )'**<
"#3M! &78N/ CG8! ; )'**<
"#3M" ;4M/ CG8" ; )'**<
"#OP ;3Q;;NR "#4O +(1 "?5L8@ .')':,%. ; <-7<',
"#ON ?+.G', %D +(,0:.%*0D'.+,0F' +(,07%16 !?LSL8N2/ A=O 56&:E%)6,'<
"#O4 T4/ @UM/ "==/ CL@ A/ L),0FV ;/ ?/ 5I5
"#O= B;N9 5B"/ #"/ '.6,E.%)6,'<
"#WO@ :39/ 4I3/ -(J(%W( D-(),0%( ;/ ?/ A/ :*+,'*',<
"#O9 C5?Q5CT D+&0*6 #'(1.0,0) )'**<
"#OH UX$8N/ ;X8H=/ ;384R "#4O +(1 "?5L8@ *0G+(1 ; )'**</ &%(%)6,'</ #"

9<<%*13=
"#O3 X.%J0(+<' :*+<&0(%G'( +),0F+,%. .')':,%. !-SLT2 A%(%)6,'</ G.+(-*%)6,'</
'(1%,E'*0+* )'**<
"#OO "9+ .')':,%. !"9+T2/ ITNP I.+(-*%)6,'</ &%(%)6,'</
<&%%,E &-<)*' )'**<

"
"#OM CGL U) .')':,%. I/ A/ ;/ ?
"#MP ?E68N S.')-.<%. )'**</ 7.+0(
"#MN !48A+).%G*%7-*0( .')':,%. !!4AT2 A%(%)6,'<
"#M4 :3P/ YCAN9/ -(J(%W( D-(),0%( I.+(-*%)6,'</ &%(%)6,'</ >"
"#M= :N4P/ ITNN/ -(J(%W( D-(),0%( A/ I/ >"
"#M@ ZS@= $Z )'**</ ? )'**<
"#M9 LS[8N/ U+< L),0FV ? )'**</ AS
"#MH ?L"?C5> !?8)'** +),0F+,0%( 0().'+<'1 *+,' ? )'**</ $Z )'**<
'\:.'<<0%(2
"#M3 :3@QOPQOM/ ?$UT D+&0*6/ ITN/ 70(1< "#99 I/ A/ ?/ ;
"#MO @U4 ?/ ;/ $Z/ :*+,'*',<
"#MM >4/ AC"4 $-&'.%-<
"#MMT T'<,.0),'1 "#MM $-&'.%-<
"#NPP :N9P $-&'.%-<
"#NPN :N@P I/ A/ ?/ #"
"#NP4 C(,'.)'**-*+. +1E'<0%( &%*')-*'84 !C"LA842 $-&'.%-</ 0()*-10(G >"< +(1
&%(%)6,'<
"#NP= BA5N/ !>"3 0(,'G.0( C(,.+':0,E'*0+* *6&:E%)6,'<
%D ,E' 0(,'<,0('</ E+0.6 )'**<
"#NP@ "@8C(,'G.0( )E+0( ?E6V
"#NP9 >(1%G*0(R ?IU8"N +(1 8"= .')':,%. >"/ +),0FV A
"#NPH Y"LA8N/ C$"LANNP/ Y5L8@ .')':,%. L),0FV '(1%,E'*0+* )'**<
"#NP3+ 5LASN L),0FV >"/ :*+,'*',</ ?
"#NP37
"#NPO
"#NPM
"#NNP
"#NNN
5LAS4
ISC8G:OP !W0,E ISC +()E%.2
!B+< ISC +()E%.2
AS5/ ?S[ T
STTNQ$'),0(N
L),0FV >"/ :*+,'*',</ ?
>.6V/ )0.)-*+,0(G *6&:E%)6,'<
>"/ ? )'**</ :*+,'*',<
S*+,'*',<
A6'*%01 )'**<
!
>?@

"
! !"#$%2

!!"#$% &' "# $%&'()*+,-.'/ )%(,0(-'12

() *+,#%- ./0%- 1%234*"/35*675$%8+$%69*/34%* (%$$+$"- -%"8/3:3/;

"#334 5664 78'*%01 )'**9

"#33: ;<"=6 .')'>,%. ;.+(-*%)8,'9/ &%(%)8,'9
"#33? "%*%(8<9,0&-*+,0(@ A+),%.<3 .')'>,%. !"B=<362/ 7< 7%(%)8,'9/ &+).%>C+@'9
"B=6
"#33D ;7<"B= .')'>,%. !;7<"B=62 7%(%)8,'9/ @.+(-*%)8,'9
"#33E B,'.( )'** A+),%. .')'>,%./ )<F0, 7+9, )'**9/ &8'*%01 >.')-.9%.9
"#33G A%. H=$<!/ " .')'>,%. $-&'.%-9
"#33I H(,'.A'.%(<# .')'>,%. !H=$<#<62 7/ ;/ J/ $K
"#34L+ ?? F#+ M$= ,8>' H .')'>,%. !M$=6H2 $-&'.%-9
"#34LN E? F#+ M$= ,8>' HH .')'>,%. !M$=6HH2 $-&'.%-9
"#343+ H(,'.*'-F0(<3 ,8>' H .')'>,%. !HO36H2 M/ ,C8&%)8,'9
"#P343N H(,'.*'-F0(<3 ,8>' HH .')'>,%. !HO36HH2 ;/ 7/ J/ &+).%>C+@'9
"#344 HO<46 " )C+0( Q),0RS M )'**9/ )-*,-.'1 $K
)'**9/ &%(%)8,'9
"#34T @>EL/ HO<T6 ! )C+0( 78'*%01 >.')-.9%.9
"#34: HO<:6 ! )C+0(/ HO<3T6 ! )C+0( 7+,-.' JUM )'**9/ 7/ C'&+<
9<<%*13=

,%>%0',0) >.')-.9%.9
"#34? @>DL/ HO<? .')'>,%. 78'*%01 >.')-.9%.9
"#34D HO<D6 ! )C+0( Q),0RS J/ >*+9&+)8,'9/
'(1%,C'*0+* )'**9
"#34E HO<E6 ! )C+0( O8&>C%01 >.')-.9%.9/

"
>.%<J )'**9
"#P34G @>?GVDE/ HO<G .')'>,%. ;/ M/ 7/ F'.+,0(%)8,'9
"#34I !"# $%%&'()*+ ,)%),-)* .", /012 ,)3)4#", 5
"#3TL @>3TL/ HO<D6 " )C+0( $-&'.%-9
"#P3T3 @>I?V34L/ ,.+(91-)0(@ " )C+0( %A HO<T6/ 7/ ;/ W%
HO<?6/ +(1 ;7<"B=6
"#3T4 # "C+0( %A HO<46/ HO<:6/ HO<E6/ HO<I6/ +(1 M )'**9/ J )'**9/ *8&>C%01
HO<3?6 >.')-.9%. )'**9
"#3TT Q"3TT B,'&U>.%@'(0,%. )'**9
"#3T: XY:L/ M$=6 A+&0*8 Q),0RS M )'**9
"#3T? =*,TU=*F4/ ,8.%90(' F0(+9' H@ 9-NA+&0*8 W+.*8 *8&>C%01 >.')-.9%.9
"#P3TD @>3GL/ >.%,%<%()%@'(' )<.%(/ &+).%>C+@'< $-&'.%-9
9,0&-*+,0(@ >.%,'0( .')'>,%.
"#P3TE @>TL/ :V3JJ/ M$=6 A+&0*8 M )'**9
"#3TG B8(1')+(<3/ C'>+.+( 9-*A+,' >.%,'%@*8)+(/ J )'**9
'Z,.+)'**-*+. &+,.0Z .')'>,%.
"#3TI @>4LIV44G/ -(F(%P( A-(),0%( J )'**9/ A%**0)-*+. #"9
"#3:L+ 5#;=6 ! )C+0( $-&'.%-9
"13:LN 5#;=6 " )C+0( W"/ 9,.%&+/ &'9+(@0-&
"#3:3 MC.%&N%&%1-*0( W"/ 9&%%,C &-9)*' )'**9
"#3:4 M099-' A+),%./ 0(0,0+,'9 )*%,,0(@/ N0(19 A+),%. W"/ '>0,C'*0-&/ &%(%)8,'9/
[HH+ F'.+,0(%)8,'9
"#3:T Q(@0%,'(90(<)%(R'.,0(@ '(\8&' !Q"W2/ W(1%,C'*0+* )'**9/ '>0,C'*0-&/

!
>'>,018* 10>'>,01+9' &+).%>C+@'9
"13:: [W<)+1C'.0( W(1%,C'*0+* )'**9
"#P3:? >@4?VILV33L/ >+('(1%,C'*0+* &+.F'./ 5
+*9% %( N+9'&'(, &'&N.+('
"#3:D 7]"3G/ B<'(1% W"
>?@
!!"#$% &' "# $%&'()*+,-.'/ )%(,0(-'12
!"#$%2
!
() *+,#%- ./0%- 1%234*"/35*675$%8+$%69*/34%* (%$$+$"- -%"8/3:3/;

"#345 $'-.%,6'*0(/ 7+8090(/ :";</ =>>?@A$/ >B ="8/ &C'*%01 +(1 *C&D6%01
D.')-.8%. )'**8
"#34E F?:?G!/ #=?G3/ D6%8D6%,C.%80(' $-&'.%-8H *%8, 0( 7.'+8,/
D6%8D6+,+8' 7*+11'./ +(1 6'D+,%)'**-*+.
)+.)0(%&+ )'**8
"#3IJ A9 8-7K+&0*C/ 8-.K+)' *C&D6%)C,' +),0L+,0%( &%G O )'**8/ : )'**8/ ,6C&%)C,'8
*')-*' !;MN>2
"#3I3 ?=:NGP/ ,',.+8D+( ?*,/ ="8/ 'D0,6'*0-&/
9.+(-*%)C,'8
"#3IQ ":MNG4/ A9 8-7K+&0*CH "#EJ +(1 "#EB *09+(1 N),0LR : )'**8
"#3IP "#PJ *09+(1/ :$< K+&0*C : )'**8
"#3I4 "#4J *09+(1/ 9DPS/ :$< K+&0*C N),0LR "#4T : )'**8
"#3II ?%*0% L0.-8 .')'D,%. !?U@2/ A9 8-7K+&0*C $-&'.%-8/ 'R9R/ >/ >"/
:6CR/ ('-.%(8 0( ";<
"#3IB+ =V< 8-7K+&0*C/ N#N>E !+ 1080(,'9.0( +(1 >/ V/ >"
&',+**%D.%,'+8'2

9<<%*13=
"#3IB7 :N"=WN#N>35 N16'80%( 8,.-),-.'8
"#3I5 O%(' &+..%X 8,.%&+* +(,09'( !O;:G32 O%(' &+..%X 8,.%&+* )'**8/
V/ >/ ="/ <#"
"#3IE YA@ K+&0*C $Y )'**8

"
"#3IS+ $YVQN $Y )'**8
"#3BJ OZII : )'**8
"#3B3 $Y@?3N/ "G*'),0( 8-7K+&0*C $Y )'**8/ : )'**8
"#3BQ ?G8'*'),0( 9*C)%D.%,'0( *09+(1G3 !?;VMG32/ >/ V/ :/ !O2
V#BQ? *09+(1
"#3BQ@ ?=$I $Y )'**8
"#3BP >3PJ/ 8)+L'(9'. @AWAA/ -([(%X( K-(),0%( !>%(%)C,'8/ &+).%D6+9'82
"#3B4 >V"GQ4/ &-)0(G*0[' 6%&%10&'. >/ V/ : !O2
"#3BI N#Q ?*,/ :/ $Y/ :6CR
"#3BB NM"N>/ "#B *09+(1/ A9 8-7K+&0*C ="/ >
"#3B5+ #08)%010( 1%&+0( @ !##@32 N16'80%( 8,.-),-.'8/ ="
"#3BE @FN>> N16'80%( 8,.-),-.'8/ 7.'+8,
)+()'. )'**8
"#3BS ;0+*%+16'80( N16'80%( 8,.-),-.'8/ 8-78',
%K &+).%D6+9'8
"#35J ;09*')GI N16'80%( 8,.-),-.'8/
('-,.%D60*8
"#353 M3 N16'80%( 8,.-),-.'8/
(-&'.%-8
"#35Q+ ;A@?# N16'80%( 8,.-),-.'8/
(-&'.%-8
"#35P O*%%1 9.%-D F ,CD' Q "+.7%6C1.+,' 8,.-),-.'8
"#354 M'X08 C "+.7%6C1.+,' 8,.-),-.'8

!
"#35I :( "+.7%6C1.+,' 8,.-),-.'8
"#35I8 ;0+*C*G:( "+.7%6C1.+,' 8,.-),-.'8
"#35B :< "+.7%6C1.+,' 8,.-),-.'8
"#355 $O3 >C'*%01 )'**8
"#35E <+8 *09+(1 N),0LR :
"#35S+ UD.'GO =+.*C O
>?@

"
! !"#$%2

!!"#$% &' "# $%&'()*+,-.'/ )%(,0(-'12

() *+,#%- ./0%- 1%234*"/35*675$%8+$%69*/34%* (%$$+$"- -%"8/3:3/;

"#3456 7+&61+ 8 9
"#3:; <=3;8 9
"#3:> "?"<@> $-&'.%-A
"#3:B "?"<@B $-&'.%-A
"#358 ""<8 $-&'.%-A
"#C354 ""<4 $-&'.%-A
"#D;; E?D $%(*0('+F' &%*')-*'A
"#D;3 G=" < G"
"#D;D6 H0'D !H')2 G"
"#D;>) $==>I=#$=> JK'*%01 )'**A
"#D;B J+).%LM+F' A)+N'(F'. < JK'*%01 )'**A
"#D;8 #G"D;8 #"
"#D;O J+).%LM+F' &+((%A' < J+).%LM+F'A/ G"
"#D;4 7+(F'.0( #"
"#D;: #"@7PJ= #"
"#D;5 #"@QRS$ #"
9<<%*13=

"#CD3; R7@3;< $-&'.%-A

"#D3D R7@3D< P),0NT "#BU/ "#:U H
"#D3>+3 R7@3>@<!3 9/ J/ G"/ V06.%6*+A,A
"#D3>+D R7@3>@<!D 9/ J/ G"/ V06.%6*+A,A
"#CD34 R7@34< P),0NT &'&%.K H )'**A

"
"#DD; R(A-*0(< $-&'.%-A
"#DD3 RSW@3< $-&'.%-A
"#DDD J+((%A' O@LM%ALM+,'IRSW@D < $-&'.%-A
"#DD> 7PS@> P),0NT H/ $X
"#DDB "@S*-,+&K*,.+(AV'.+A' $-&'.%-A
"#DD8 7'-3> $-&'.%-A
"#DDO #$PJ@3 !=HP32 H A-6A',/ $X/ L*+,'*',A/ J
"#DD4 JY"T3 $-&'.%-A
"#DD: J'*+(%,.+(AV'..0( $-&'.%-A/ M-&+(
&'*+(%&+A
"#DD5 7K5 7K&LM%)K,'A
"#D>; =.0%( L.%,'0( $-&'.%-A
"#D>3 HP77P@3IP38 $-&'.%-A
"#D>D ZGQ= < $-&'.%-A
"#D>> 9+(1 > G.K,M.%01 )'**A
"#D>B WK@F*K)%L.%,'0( !#P<"2 G.K,M.%01 )'**A
"#D>8+ S*K)%LM%.0( P G.K,M.%01 )'**A
"#D>86 S*K)%LM%.0( 9 G.K,M.%01 )'**A
"#D>8+6 S*K)%LM%.0( P9 G.K,M.%01 )'**A
"#D>O S*K)%LM%.0( "I# G.K,M.%01 )'**A
"#D>O< S*K)%LM%.0( " G.K,M.%01 )'**A
"#D>: X'** G.K,M.%01 )'**A
"#D>5 9@"PJ G.K,M.%01 )'**A

!
"#DB;"G <M>;"G G.K,M.%01 )'**A
"#DB;# <M>;# G.K,M.%01 )'**A
"#DB;#"G <M>;#I"G ).%AA@.'+),0N' G.K,M.%01 )'**A
"#DB3 <MPF G.K,M.%01 )'**A
"#DBD R"PJ@B G.K,M.%01 )'**A
>?@ "#DB> J#<@3 Q,'&IL.%F'(0,%. )'**A
!!"#$% &' "# $%&'()*+,-.'/ )%(,0(-'12
!"#$%2
!
() *+,#%- ./0%- 1%234*"/35*675$%8+$%69*/34%* (%$$+$"- -%"8/3:3/;

"#344 354 $6 )'**7

"#348 933:;34:/ $9<= = )'**7
"#34> <(+?*+7,0) *@&?A%&+ B0(+7' $-&'.%-7
"#34C D',+ )A+0( =/ $6

!"# $% &''(")*&$*%+,- !"#$%& ' ("#$%(#)*+ !,, ' ("-#) ./0123$* .)-4)0$(+ 5 ' 5 ")..6+ 78 ' )9*3#2).$(. ")..6+ 73 ' )36$9312$. :;(9-.3"/#)6+
7;/& ' );/#2;3"/#)6+ <=8 ' >3..$"-.(; *)9*;$#$" ")..6+ =8 ' *)9*;$#$" ")..6+ ? ' :;(9-.3"/#)6+ , ' .$:(9*+ ,?, ' .(;:) :;(9-.(; ./0123"/#)6+
,@8 ' ,(9:);2(96 ")..6+ A ' 0393"/#)6+ AB ' 0(";312(:)6+ CD ' CD ")..6+ B.# ' 1.(#).)#6+ E ' ;)")1#3;+ F ' F ")..6+ F2/& ' #2/03"/#)6&
G> 93# 61)"$>$)*+ #2) >-9"#$39 3> #2) (9#$:)9 $6 -9493H9&

9<<%*13=
"

!
>??
! !"#$%3

!"#$% &' !"#$ %&'"($)*$ +,$"-.*/# )*0 +1/&"-.*/# .* %&&2*"3"4,

5/, $" )66(/7.)$."*#8 99 : )&.*" );.0#< );$.7= : );$.7)$/0< >+ : 0/*0(.$.; ;/33#

()*+,-.% /*0%1 2%3-4."*-+.3 5%.% $+673 8*176*71%

%?@A ?,&'1";,$/ );$.7)$.*4 B);$"(< CDAC@DCA< FG" &"3/;23/# G.$1 #3.41$

/*0"4/*"2# ',("4/*< 3/2-";,$/
/*0"4/*"2# &/0.)$"(< &"*"*2;3/)(
;/33 B);$"(< ;)$)6"3.*
CDAE@DCA 1"&"3"4,8 %?@A! HCIA 99J
)*0 .* %?@A" HCKL 99J= M"$1
6.*0 $" $1/ #)&/ (/;/'$"(=
%?@A (/;/'$"( )*$)4"*.#$ H%?@
AN)J )3#" 6.*0# $" .$ )*0
;)*;/3# $1/ /BB/;$ "B %?@A=

%?@C F@;/33 4("G$1 B);$"( HF;OPJ QDCK@DCI AEE 99< AR ->9

9::%.2-;

%?@E !23$.@;"3"*, #$.&23)$.*4 B);$"( H!@+SPJ< RDCE@DEA ARC 99< AR ->)

&)#$ ;/33 4("G$1 B);$"( H!+OPJ< /"#.*"@

"
'1.3@+SP HT@+SPJ< 1/&)$"'"./$.; ;/33
4("G$1 B);$"( HU+OPJ< 62(#$@'("&"$.*4
);$.7.$, HMV9J

%?@Q M@;/33 #$.&23)$.*4 B);$"( A HMSP@AJ RDEA O3"623)( #$(2;$2(/ G.$1

) 1,0("'1"6.; *2;3/2#<
ACL 99< AR ->)

%?@R T"#.*"'1.3 0.BB/(/*$.)$."* B);$"(W;"3"*, RDCE@DEA >.#23B.0/@6"2*0

#$.&23)$."* B);$"( HT>PWT@+SPJ< M@;/33 1"&"0.&/(< AAR 99< AE ->)
4("G$1 B);$"( %% HM+OP%%J< M@;/33 0.BB/(@
/*$.)$."* B);$"( B"( %4! HM+>P#J< F@;/33
(/'3);.*4 B);$"( HFNPJ

%?@K %*$/(B/("*@"C< M@;/33 #$.&23)$.*4 B);$"( C I'CA@'AQ AXE 99< CK ->)

HMSP@CJ< '3)#&);,$"&) 4("G$1 B);$"(<
1/')$";,$/ 0.BB/(/*$.)$."* B);$"( HUSPJ<
&"*";,$/ 4()*23";,$/ .*02;/( $,'/ C
H!O%@CJ

!
%?@I ?,&'1"'"./$.* A H?V@AJ< '(/@M@;/33 XDCA@DAE ARC 99< CYZCX ->)
4("G$1 B);$"(

<=>
 !"#$%3
!
T+ : T*0"$1/3.)3 ;/33#< %? : .*$/(3/2-.*< ->) : -.3"0)3$"*< M! : 6"*/ &)(("G

8+716% !"14%* 6%$$3 ?-+$+4-6"$ "6*-@-*) A%6%:*+1

!"*";,$/#< F ;/33#< M ;/33#< 9;$.7)$."* "B 3,&'1"@ F,'/ % (/;/'$"(8 +>ACA)<

&);("'1)4/#< /*0"$1/3.)3 ;/33#< ;,$/# )*0 &);("@ XY ->)< E .&&2*"43"623.*@3.-/
>+< )#$(";,$/#< "(4)*#8 1/')$"@ '1)4/#< .*;(/)#/# ;/33 0"&).*#= F,'/ %% (/;/'$"(8
[5 ;/33#< M ;/33#< ;,$/#< 6"*/ )01/#."*< B/7/(< +>ACA6< KY ->)< E .&&2*"@
T+< B.6("63)#$# G/.41$ 3"##< 1,'"$/*@ 43"623.*@3.-/ 0"&).*#\ #"3263/
#."*< );2$/@'1)#/ (/@ (/;/'$"( ;)* 6.*0 %?@A"
);$."*

F ;/33# F ;/33#< [5 ;/33#< V("3.B/()$."* )*0 F1(// ;1).*#8 ! ;1).* H'RRJ<

M ;/33#< &"*"@ 0.BB/(/*$.)$."* "B F F9+< +>CR\ " ;1).* H'IRJ<
;,$/#< &);("@ )*0 M ;/33#< );$.7)$."* +>ACC\ $ ;1).* H'KQJ< ;"&&"*
'1)4/#< "3.4"@ "B &"*";,$/# $ ;1).* $"4/$1/( G.$1 %?@QN<
0/*0(";,$/# %?@IN< %?@LN< %?@AEN< )*0 %?@ARN\
!W$ "( "W$ 1/$/("0.&/(# B"(&
(/;/'$"(# "B .*$/(&/0.)$/

9::%.2-;
)BB.*.$,\ !W"W$ 1/$/("$(.&/(#
B"(& 1.41@)BB.*.$, (/;/'$"(#

9;$.7= F ;/33#< 933 6"*/ &)(("G O("G$1 B);$"( B"( FG" #262*.$#8 %?EN! H+>ACEJ

"
&)#$ ;/33#< '(/;2(#"( ;/33# 6"*/ &)(("G '(/;2(@ )*0 ) " ;1).* B"(& ) 1.41@
/"#.*"'1.3 #"( ;/33#< M ;/33#< )BB.*.$, %?@E (/;/'$"(= F1/
4()*23";,$/# &"*";,$/# " ;1).* .# #1)(/0 G.$1 %?@RN
)*0 O!@+SPN

!)#$ ;/33#< F ;/33#< F ;/33#< M ;/33#< %#"$,'/ #G.$;1 6, M FG" ;1).*#8

6"*/ &)(("G &"*";,$/#< ;/33#< #/;(/$."* "B %4OQ ! ;1).* : 'AQY H+>ACQJ<
#$("&)3 ;/33# /*0"$1/3.)3 ;/33#< H%4OAJ )*0 %4T 6, 1.41@)BB.*.$, 6.*0.*4 "B %?@Q\
B.6("63)#$# M ;/33# $ ;1).* H'KQJ< ;"&&"* $
;1).*\ .*;(/)#/# $1/ )BB.*.$,
B"( %?@Q

!)#$ ;/33#< F ;/33#< T"#.*"'1.3 %*02;/# /"#.*"'1.3 FG" ;1).*#8

/"#.*"'1.3 4()*2@ 4()*23";,$/# 0.BB/(/*$.)$."*< M@;/33 ! ;1).* : H+>ACRJ 3"G@)BB.*.$,
3";,$/# 4("G$1 )*0 0.BB/(/*@ 6.*0.*4 "B %?@R\
$.)$."* H.* &.;/ "*3,J " ;1).* : #1)(/0 G.$1 %?@EN
)*0 O!@+SPN

F ;/33#< M ;/33#< M ;/33#< '3)#&)@ M ;/33 4("G$1 )*0 FG" ;1).*#

&);("'1)4/#< ;,$/#< F ;/33#< 0.BB/(/*$.)$."*< F ;/33 ! ;1).* : H+>ACKJ 3"G@)BB.*.$,
6"*/ &)(("G 1/')$";,$/#< '("3.B/()$."*< );2$/@ 6.*0.*4 "B %?@K\
#$("&)3 ;/33#< 6"*/ &)(("G '1)#/ (/);$."* " ;1).* H4'AEYJ )##";.)$/0
B.6("63)#$#< T+ ;/33# G.$1 ! ;1).*W%?@K ;"&'3/]

M! ;/33#< $1,&.;
#$("&)3 ;/33#<
#'3/*.; ;/33#
F ;/33#<
M ;/33#
V("3.B/()$."* )*0
&)$2()$."* "B F@ )*0
M@;/33 '("4/*.$"( ;/33#
FG" ;1).*#8
! ;1).* : H+>ACIJ< 6.*0.*4
"B %?@I\
$ ;1).*8 #1)(/0 G.$1 %?@QN<
%?@LN< %?@AEN )*0 %?@ARN
!
<=&
! !"#$%3

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

()*+,-.% /*0%1 2%3-4."*-+.3 5%.% $+673 8*176*71%

&89: !"" #$"%&'()"*

&89; <=>4 '*$% 5022 3)#?%@90+@*+5/+3 DEFGHG GIJ KK4 FILF; .M*
*5%/A/%-4 B95022 3)#?%@ C*5%#) &&&

&89G> ,-%#./+0 $-+%@0$/$ /+@/N/%#)- C*5%#) G GJ> KK4 FDL=> .M*

!,O&P7

&89GG K6/(#30+0$/$ /+@/N/%#)- C*5%#) G;EGFHF9 GQ; KK4 IF .M*

9::%.2-;

GFH=

" &89GI R*%1)*2 ./220) 5022 $%/'12*%#)- C*5%#)

!RSOP74 5-%#%#T/5 2-'(@#5-%0 '*%1)*9
%/#+ C*5%#) !,8"P7
U V0%0)#6/'0) ?/%@ %?#
5@*/+$ !(FD *+6 (=>74
G;J KKWF>J KK *+6
F>LFF .M*WFDL== .M*4
)0$(05%/A02-

&89GF <J>> DEFG GGI KK4 ;WGQ .M*

&89G= V/3@ '#20512*) ?0/3@% X95022 3)#?%@ U =:F KK4 J> .M*
C*5%#) !V"Y9X,ZP7

&89GD B95022 3)#?%@ C*5%#) =EFG O/'/2*)/%- ?/%@ /+%0)201./+9I4

GG= KK4 G= .M*

!
<=>
&89GJ 8-'(@#5-%0 5@0'#*%%)*5%*+% C*5%#)
!8,P7
U GF> KK4 => .M*
!()051)$#)[ JFI KK7
 !"#$%3
!
8+716% !"14%* 6%$$3 ?-+$+4-6"$ "6*-@-*) A%6%:*+1

BVI 5022$ V#63./+\$ 5022$4 &+5)0*$0$ %@0 ()#2/C9 &89; )050(%#) 5*+ *$$#5/*%0
B 5022$4 '*$% 5022$4 0)*%/#+ #C B 5022$ *+6 ?/%@ %@0 5#''#+ ! 5@*/+
'03*.*)-#5-%0$4 N*$#(@/2$
0)-%@)#5-%0
()051)$#) 5022$

BV> *+6 BVI 5022$4 X 5022$4 %@-'#9 K5%/A*%/#+ *+6 ()#9 ^+0 5@*/+4 @#'#2#3- %#
*5%/AH ,M=] *+6 5-%0$4 BVG 5022$4 2/C0)*%/#+ #C X 5022$4 &PR9! *+6 &PR9"# )050(%#)
,M:] B 5022$4 '#+#5-%0$4 RS %@-'#5-%0$4 '*$%
'#+#5-%0$4 5022$ 5022$
'*5)#(@*30$4
M,

P/N)#N2*$%$4 X" V0'*%#(#/0%/5 Z)#?%@ C*5%#) C#)

9::%.2-;
$%)#'*2 5022$ ()051)$#) 5022$4 @0'*%#(#/0%/5
(2*$'*5-%#'* ()051)$#) 5022$4
5022$4 *6/(#5-%0$ /+@/N/%/#+ #C *6/(#9
5-%0$

M,4 '#+#5-%0$4
'*5)#(@*30$4
X 5022$
B 5022$4 RS 5022$ &PR9! ()#615%/#+ /+
B 5022$ *+6 RS 5022$_
*5%/A*%/#+ *+6 6/CC0)9
0+%/*%/#+ #C BVG B 5022$
^+0 2*)30 )050(%#)_
$%)15%1)*22- $/'/2*) %# %@0
Z9,OP )050(%#)
"
K5%/AH B 5022$ X 5022$4 '#+#9 X 5022 ()#2/C0)*%/#+ U
5-%0$ *+6 6/CC0)0+%/*%/#+4
&3` $05)0%/#+

B 5022$4 K5%/AH X 5022$ O%/'12*%0$ %@0 ^+0 $/+320 )050(%#) %-(0

X 5022$ ()#2/C0)*%/#+ #C
*5%/AH X 5022$4
/+@/N/%$ /''1+#9
32#N12/+ $-+%@0$/$

<0)/(@0)*2 B 5022$4 2-'(@#9 B95022 3)#?%@ C*5%#) B?# )050(%#) 5@*/+$[

'#+#+1520*) ./+09*5%/A*%06 # 5@*/+ *+6 ! 5@*/+4 $@*)06
5022$ !<X",74 ./220) 5022$ ?/%@ &89I )050(%#)_ #+0 A*)/*N20
(2*50+%*4 $.020%*2 " 5@*/+
'1$520$4 ./6+0-4
21+34 @0*)%

,M:] B 5022$ `#$/+#(@/2 3)*+19

2#5-%0$4 ,M=]
B 5022$4
'#+#5-%0$
,@0'#%*T/$ U

!
<=B

"
! !"#$%3

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

()*+,-.% /*0%1 2%3-4."*-+.3 5%.% $+673 8*176*71%

&89:; ,-%#%#</5 =92-'(>#5-%09*$$#5/*%06 A :BC ??4 CD .E*

*+%/30+ !,=8?9@7

&89:@ &+%0)F0)#+9!9/+615/+3 F*5%#) !&G&H7 A :I; ??4 :@ .E*4

$/'/2*) %# &89:"

&89:J :KBCLC
!&89:D
>#'#2#37

&89CD :KBCLC :;LM .E?4 :IC ??

!&89:D
>#'#2#37
9::%.2-;

&89C:
!52#$02-
)02*%06
%# &89C

" *+6 &89:I7

&89CC
!&89:D
>#'#2#37
=95022960)/N06 /+615/O20 F*5%#) !&89=&H7 :CK:I :ML@ .E4 :P; ???

&89CB :CK:BL:B

&89CP "02*+#'* 6/FF0)0+%/*%/#+9*$$#5/*%06 :KBC CB .E*

!&89:D 30+0 ; !"E?9;7Q '#O9I4 &89:;H
>#'#2#37

&89CI RHCD
!'0'O0)
#F %>0
&89:; F*'/2-7

!
<=<
&89CM
!&89:D
>#'#2#37
?S:II :CK:I
 !"#$%3
!
8+716% !"14%* 6%$$3 >-+$+4-6"$ "6*-?-*) @%6%:*+1

,EPT = 5022$ R%)#'*2 5022$4 F/9 U)#/+F2*''*%#)- V# >#'#2#3- %# #%>0)

O)#O2*$%$ 0FF05% 2/.0 %>*% #F =VH )050(%#)$
*+6 2-'(>#%#</+

S1(FF0) 5022$4 = 5022$4 VS 5022$ &+615%/#+ #F &HV9! W+0 (*)% #F %>0 )050(%#) /$
.0)*%/+#5-%0$4 $>*)06 X/%> &89: )050(%#)
#$%0#52*$%$

"#+#5-%0$ U)#615%/#+ #F &89M4

=VH9#Q /+6150$ *(#(9
%#$/$ *+6 )0*5%/N0
#<-30+ $(05/0$

S0)*%/+#5-%0$ S0)*%/+#5-%0$ U2*-$ * )#20 /+

!*1%#5)/+0 0(/60)'*2 F1+5%/#+
F*5%#)74 *+6 ($#)/*$/$4 /+6150$

9::%.2-;
'#+#5-%0$ ()#2/F0)*%/#+

= 5022$4 VS 5022$4 =95022 5#9$%/'12*%/#+4 &89C:Z *+6 $>*)0$ 5#''#+

Y 5022$ VS 5022 0<(*+$/#+4 5-%#./+0 )050(%#) ! 5>*/+ X/%>
Y95022 ()#2/F0)*%/#+4 &89C4 P4 ;4 J4 *+6 :I

= 5022$
*+6 /''1+#32#O12/+
()#615%/#+

&+615%/#+ #F *51%0
(>*$0 )0*5%*+%$ /+
2/N0) *+6 (*+5)0*$
&89CCZ4 &89:DZ" "
?5%/NL 60+6)/%/5 "0'#)- = 5022$ R05)0%/#+ #F &89:; &89CBZ4 &89:CZ":Q >0%0)#6/'0)$
5022$ 5#'(#$06 #F &89:C(PD $1O1+/%
*+6 +#N02 $1O1+/% )02*%06 %#
&89:C(BI4 %0)'06 (:J

G)#X%>9 =1'#) $1(()0$$#) &89CCZ:[&89CDZCQ

*))0$%06 *+6 30+04 $%/'12*%0$ &8CDZ:[&89CDZC
%0)'/+*22- =95022 3)#X%> *+6
6/FF0)0+%/*%06 /+>/O/%$ *+3/#30+0$/$4
'02*+#'* 5022$4 /+6150$ 0+6#%>02/*2
*5%/NL '#+#5-%0$ 5022$ %# ()#6150 &89C4
*+6 = 5022$ =GH9"4 *+6 ",U9:

Y#+0 '*))#X U)#'#%0$ * =\C92/.0 =>-'/5 $>*)06 *+%/30+9:

$%)#'* 5022$ )0$(#+$0 !=R?9:7

= 5022$
!
<=A

"
! !"#$%3

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

()*+,-.% /*0%1 2%3-4."*-+.3 5%.% $+673 8*176*71%

&89:! &+%0);0)#+:!4 %-(0 & /+%0);0)#+4 201.#: = !:&+%0);0)#+$ *)0 * ;*'/2-

5-%0 /+%0);0)#+4 <1;;- 5#*% /+%0);0)#+ #; ()#%0/+$ >/%? *% 20*$%
@A 30+0$4 /+%0);0)#+:!BC
BDD EE4 BDF@G .H*4
/+%0);0)#+:!@C BG@ EE4 I .H*

&89:" &+%0);0)#+:"4 %-(0 & /+%0);0)#+4 ;/<)#<2*$% =(@@ BDD EE4 @J .H*
/+%0);0)#+

&89:# &+%0);0)#+:#4 /''1+0 /+%0);0)#+ #) B@L@AMB BAN EE4 AJFGJ .H*4

%-(0 && /+%0);0)#+4 K:5022 /+%0);0)#+ '#+#'0)$ #; @JF@O .H*
;#)' 6/'0)$ #) '12%/'0)$
9::%.2-;

K98:! K1'#) +05)#$/$ ;*5%#)4 5*5?05%/+4 D(@BMN BOG EE4 O@ .H* !()/'*)/2-
+05)#$/+4 ?0'#))?*3/5 ;*5%#)4 ;)#' BGMA .H* 1+/%$7
'*5)#(?*30 5-%#%#P/+

" K98:" K1'#) +05)#$/$ ;*5%#)4 2-'(?#%#P/+4

5-%#%#P/+
D(@B NO Q ?#'#2#3- %# K98:!4
BGB EE4 @O .H*

KR8:! K)*+$;#)'/+3 3)#>%? ;*5%#):!4 @ OJ EE4 D .H*4 ?/3? 603)00 #;

$*)5#'* 3)#>%? ;*5%#) ?#'#2#3- %# &38

KR8:" K)*+$;#)'/+3 3)#>%? ;*5%#):"4 6/;;0): B=LBN K?)00 )02*%06 ()#%0/+$4

0+%/*%/#+ /+?/</%/+3 ;*5%#) BLAB KR8:"&4 :&&4 *+6 :&&&4 *22 >/%?
BAL@A BB@ EE *+6 @O .H*

SR8 S(/60)'*2 3)#>%? ;*5%#)4 ":1)#3*$%)#+ A4 L@O T)#%0#2-%/5 520*U*30 ()#615%

#; * '0'<)*+0 ()#%0/+4
ON EE4 D .H*

R:,V8 R)*+12#5-%0 5#2#+-:$%/'12*%/+3 ;*5%#) BG4 L@B:@@ BG EE4 @B .H*

!
<=>
 !"#$%3
!
8+716% !"14%* 6%$$3 ?-+$+4-6"$ "6*-@-*) A%6%:*+1

W-'(?#5-%0$4 "#$% 5022$ /+ %?0 &+%0);0)#+:! /+6150$ E% 20*$% @ 6/;;0)0+% )050(%#)$4

'#+#5-%0$4 <#6- U/)*2 )0$/$%*+504 /+: #+0 #; >?/5? </+6$ >/%? /+%0):
'*5)#(?*30$ ?/</%$ 5022 ()#2/;0)*: ;0)#+:! *+6 /+%0);0)#+:"M
%/#+4 *+6 )0312*%0$ X#'#2#3/0$ %# /+%0);0)#+:#
52*$$ & "X, 0P()0$$/#+ *+6 &W:BJ )050(%#)

8/<)#<2*$%$ *+6 Y/)%1*22- *22 5022$ V/'/2*) %# /+%0);0)#+:! ,#''#+ )050(%#) $?*)06 >/%?
0(/%?02/*2 5022$ #; %?0 <#6- /+%0);0)#+:!

,HZ[ *+6 ,HA[ X0'*%#(#/0%/5 E5%/U*%/#+4 3)#>%? K># 5?*/+$4 #+0 !,HBB=7 >/%?
K 5022$4 9\ 5022$ 5022$4 0(/%?02/*2 *+6 6/;;0)0+%/*%/#+ #; ?/3?:*;;/+/%- </+6/+3 #; &89:#^
*+6 0+6#%?02/*2 K *+6 ] 5022$4 '*5)#: " 5?*/+C *550$$#)- 5?*/+ ;#)
5022$4 +1'0)#1$ (?*30$4 9\ 5022$4 S,: $/3+*2 %)*+$615%/#+
%1'#) 5022$ 0+?*+506 *+%/U/)*2 0;:
;05% #; &89:! *+6 &89:"

9::%.2-;
E5%/UM '#+#5-%0$ Y/)%1*22- *22 5022$ T)#/+;2*''*%#)- K-(0 & )050(%#) !,HB@JE74
*+6 '*5)#: #; %?0 <#6- 5-%#./+0$4 3)#>%? K-(0 && )050(%#) !,HB@J]7M
(?*30$4 H,4 ;*5%#)4 *+6 6/;;0)0+: ]#%? </+6 K98:! *+6 K98:"^
] 2-'(?#5-%0$4 %/*%/#+ ;*5%#) ;#) '*+- $#21<20 )050(%#)$ 60%05%*<20 /+
K 5022$4 5022$M ,-%#%#P/5 ;#) $0)1' *+6 1)/+0
;/<)#<2*$%$

E5%/UM K *+6
] 5022$
Y/)%1*22- *22 5022$
#; %?0 <#6-
'*+- %)*+$;#)'06
5022$

R)#>%? *+6 6/;;0)0+:

%/*%/#+ #; +1'0)#1$
5022$
_050(%#) $?*)06 >/%? K98:! "
"#+#5-%0$4 Y/)%1*22- *22 5022$ R)#>%? *+6 6/;;0)0+: _050(%#) $?*)06 >/%? SR8
.0)*%/+#5-%0$4 #; %?0 <#6- %/*%/#+ #; +1'0)#1$ !.+#>+ *$ 5:0)<]7
U*)/#1$ %/$$10$ 5022$

Y/)%1*22- *22 +1: Y/)%1*22- *22 5022$ &+?/</%/#+ #; 5022 K?)00 )050(%#)$ #; U*)/*<20
520*) 5022$4 '*+- #; %?0 <#6- 3)#>%?4 `%/$$10 '#6: *5%/U/%-
%1'#) 5022$ 02/+3a

E22 05%#60)'*2 Y/)%1*22- *22 5022$ S(/%?02/*2 5022 3)#>%?4 _050(%#) $?*)06 >/%? KR8:!
5022$4 '#+#5-%0$4 #; %?0 <#6- >#1+6 ?0*2/+3
)0+*2 5022$4
32*+6$

"*5)#(?*30$4 R)*+12#5-%0$ R)#>%?4 6/;;0)0+%/*: K># )050(%#) ;#)'$ ?*U/+3

;/<)#<2*$%$4 *+6 '-02#/6 %/#+ *+6 *5%/U*%/#+ 6/;;0)0+50$ /+ %?0/) /+%)*5-%#:
0+6#%?02/*2 5022$4 ()051)$#) 5022$4 ;*5%#) ;#) 3)*+12#: (2*$'/5 $03'0+%$
]" $%)#'*2 5022$ S,4 %?)#'<#:
5-%0$ *+6 ()0:
51)$#) 5022$
5-%0$ *+6 '-02#/6
()051)$#) 5022$^ ()#2/;:
0)*%/#+ *+6 '/3)*%/#+
#; 0+6#%?02/*2 5022$ !
<=B

"
! !"#$%3

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

()*+,-.% /*0%1 2%3-4."*-+.3 5%.% $+673 8*176*71%

8"9,:; 8)*+12#5-%0<'*5)#(=*30 ?4 @AB@CA BAD EE4 AA .F*

5#2#+-9$%/'12*%/+3 >*5%#)4 ,:;9!

"9,:; "*5)#(=*30 5#2#+-9$%/'12*%/+3 >*5%#)4 ?4 @CCGB AAH4 HIJ4 ?AA EE4 H?KLI
,:;9& .F*M
=#'#6/'0) $%)15%1)04
C 'NOE $(05/0$ 0P/$%

:,; :%0' 5022 >*5%#)4 '*$% 5022 3)#Q%= >*5%#)4 BA4 @AA9AH T)#%0#2-%/5 520*U*30 ()#615%
./% 2/3*+6 !RS74 $%002 >*5%#) !:S;7 #> %)*+$'0'V)*+#1$ ()#9
=>>%.2-?

%0/+$4 AAA EE *+6 AHW EE4

CJ .F*

;2%CS >'$92/.09%-)#$/+0 ./+*$0 C4 >2.9A BL@BCGC9 AC? EE

!>0%*2 2/U0) ./+*$09A7 BCGC

"
XTY X)-%=)#(#/0%/+ D(%0)9@AA BJJ EE4 CJ .F*

ZTY Z=)#'V#(#/0%/+ C@AD CAA EE4 JI .F*

,=0'#./+0$

Z=0 +*'0 [5=0'#./+0$\ 60)/U0$ >)#' 5=0'#%*5%/5 5-%#./+0$ V02#+3/+3 %# * $1(0)>*'/2- #>
$'*22()#/+>2*''*%#)- *5%/U*%/#+9/+615/V20 '#205120$ %=*% ()#'#%0 5=0'#%*P/$ !'/3)*%/#+7 #>
6/>>0)0+% 5022 %-(0$G Z=0- =*U0 * '#20512*) Q0/3=% #> WKBI .F* *+6 $=#Q * =/3= 603)00 #>
=#'#2#3-M %=0- *22 =*U0 * +1'V0) #> 5#+$0)U06 5-$%0/+ )0$/610$G ZQ# 2*)30 >*'/2/0$ *)0 60>/+06]
%=0 9: 60%;+,-.%3 *)0 0+5#606 >#) V- 30+0$ #+ 52#$02- )02*%06 2#5/ 5*2206 :,^_ !$'*22 /+615/V20
5-%#./+0 $1V>*'/2- '0'V0) _7 #+ 5=)#'#$#'0 H@BA9ABG Z=0 5=0'#./+0$ #> %=/$ >*'/2- =*U0 %Q#

!
@AB
5-$%0/+0 )0$/610$ !,7 $0(*)*%06 V- * $/+320 *'/+# *5/6 !`74 $# %=0- *)0 5*2206 (<( 60%;+,-.%3G
!
 !"#$%3
!
8+716% !"14%* 6%$$3 C-+$+4-6"$ "6*-D-*) E%6%>*+1

Z 5022$4 8)*+12#5-%0$4 8)#Q%= >*5%#) >#) ZQ# 5=*/+$] *+ ! 5=*/+ !,FBBJ7

'*5)#(=*30$4 '#+#5-%0$4 =0'*%#(#/0%/5 ()09 #> 2#Q9*>>/+/%- V/+6/+3 *+6
>/V)#V2*$%$4 ()051)$#) 5022$4 51)$#) 5022$4 6/>>0)0+9 * " 5=*/+ !$=*)06 Q/%= &S9C *+6
0+6#%=02/*2 5022$ X,4 >/V)#V2*$%$4 %/*%/#+ *+6 *5%/U*%/#+ &S9? )050(%#)$7 V/+6 Q/%= *+
S*+30)=*+$ 5022$4 >*5%#) >#) 3)*+12#9 ! 5=*/+ %# >#)' * =/3=9*>>/+/%-
60+6)/%/5 5022$ 5-%0$ *+6 '#+#5-%0$4 )050(%#)
3)#Q%= >*5%#) >#) X,

S-'(=#5-%0$4 "*5)#(=*30$ 8)#Q%=4 6/>>0)0+%/*9 "9,:; !,FBB?7 /$ 5#606 V- %=0

'#+#5-%0$4 *+6 ()051)$#) %/#+ *+6 *5%/U*%/#+ #> 59!"# ()#%#9#+5#30+0
>/V)#V2*$%$4 5022$ '*5)#(=*30$ *+6
0(/%=02/*2 *+6 ()051)$#) 5022$
0+6#%=02/*2 5022$

:%)#'*2 5022$4 a/)%1*22- *22 8)#Q%= >*5%#) >#) Z=0 ()#%#9#+5#30+0 59./% /$
V)*/+4 2/U0)4 =0'*%#(#/0%/5 =0'*%#(#/0%/5 5022$ %=0 )050(%#) >#) :,; !,FBBD7

=>>%.2-?
./6+0-4 21+34 ()051)$#) 5022$
>/V)#V2*$%$4 0P50(% _ 5022$
#U#5-%0$

Z95022 2/+0$ b0'*%#(#/0%/5 :%0' 5022 '#V/2/c*%/#+ ;2%CN4 LLC EE4 ? /''1+#9
()051)$#) 5022$ /+ %=0 (0)/(=0)*2
V2##64 0P U/U# 0P(*+9
$/#+ #> $%0' 5022$4 0P
U/U# *+6 /+ U/U# 0P9
(*+$/#+ #> F,4 /+ U/%)#
*+%/%1'#) *5%/U/%-
32#V12/+92/.0 0P%)*502212*)
6#'*/+$

"
S/U0)4 X)-%=)#/6 F/>>0)0+%/*%/#+ *+6 Y+0 5=*/+4 HWH EE
./6+0- ()051)$#) 5022$4 3)#Q%= >*5%#) >#)
0+6#%=02/*2 5022$ 0)-%=)#5-%0 ()051)$#)
*+6 V2##6 U0$$02$

S/U0)4 ./6+0-4 "03*.*)-#5-%0$ F/>>0)0+%/*%/#+ *+6 Y+0 ! 5=*/+M %=0 " 5=*/+
$.020%*2 '1$520$ 3)#Q%= >*5%#) >#) /$ $=*)06 Q/%= &S9C4 &S9?4 *+6
'03*.*)-#5-%0$ 8"9,:; )050(%#)$

Z=/$ /$ /+ 5#+%)*$% %# %=0 $05#+6 2*)30 >*'/2-4 %=0 FG: 60%;+,-.%34 Q=/5= =*U0 %=0 >/)$%
%Q# 5-$%0/+ )0$/610$ *6d*50+% !(( 60%;+,-.%37 *+6 *)0 0+5#606 #+ 5=)#'#$#'0 BD@BB9CA
!%=0 :,^E 2#51$7G Y%=0) 5=0'#./+0$ *)0 5=*)*5%0)/c06 V- %=0 ()0$0+50 #> * $/+320 6/$12>/60 V)/630
*+6 * 5-%#(2*$'/5 , %0)'/+1$ %=*% /$ +00606 >#) $/3+*2/+3 H( 60%;+,-.%3IJ Q=/20 $#'0 *)0
5=*)*5%0)/c06 V- %=0 ()0$0+50 #> %=)00 *'/+# *5/6 )0$/610$ V0%Q00+ %=0 %Q# 5-$%0/+ )0$/610$
!(<K( 60%;+,-.% #) L1"6*"$,-.%7G Y+2- * >0Q '0'V0)$ #> %=0$0 %Q# 3)#1($ =*U0 V00+ /60+%/>/06
$# >*)G

!
@AG

"
! !"#$%0

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

8-$%0'*%/5 "#$% 9)0:10+% ;%<0) 60$/3+*%/#+$ =0+0 2#51$4

+*'0 +*'0 30+0 $-'>#2

()( (*%+,-./%0' !1, (203%./% 4(5 6,$%78$%0 "9% :.;.<%< #2 =/,3*%9 =+./, =7.< 4)5

,?,@A =B;! =)#C%<D)02*%06 #+5#30+0 ! !=B;!74 J:AKD:AG4

'02*+#'* 3)#C%< $%/'12*%#)- *5%/E/%- ! $'*22 /+615/>20
!"=8F!74 +01%)#(</2D*5%/E*%/+3 (0(D 5-%#./+0 $1>D
%/60DG !HFIDG7 9*'/2- '0'>0) LA
!8,MLA7

,?,@K =B;" =)#C%<D)02*%06 #+5#30+0 " !=B;"74 J:AKD:AG4

'02*+#'* 3)#C%< $%/'12*%#)- *5%/E/%- " 8,MLK
!"=8F"74 '*5)#(<*30 /+92*''*%#)-
()#%0/+DKD! !"&IDKD!7
=>>%/<.?

,?,@G =B;# =)#C%<D)02*%06 #+5#30+0 # !=B;#74 J:AKD:AG4

'02*+#'* 3)#C%< $%/'12*%#)- *5%/E/%- 8,MLG
# !"=8F#74 '*5)#(<*30 /+92*''*%#)-
()#%0/+DKD" !"&IDKD"7

" ,?,@J INJ I2*%020% 9*5%#)DJ !INJ74 ;+5#$%*%/+ F J:AKD:AG4

8,MLJ

,?,@O PHFDQR P(/%<02/*2 5022D60)/E06 +01%)#(</2 J:AKD:AG4

*%%)*5%*+%DQR !PHFDQR7 8,MLO

,?,@S =,IDK =)*+12#5-%0 5<0'#%*5%/5 (0(%/60DK J:AKD:AG4

!=,IDK74 @I8D/+61506 ,?, !@&?7 8,MLS

,?,@Q HFIDK H01%)#(</2D*5%/E*%/+3 ()#%0/+DK J:AKD:AG4

!HFIDK74 5#++05%/E0 %/$$10 *5%/E*%/+3 8,MLQ
()#%0/+DG !,TFIDG74 2#C *99/+/%- (2*%020%
9*5%#)DJ !@FDINJ74 (2*%020% >*$/5 ()#%0/+
!ILI74 "D%<)#'>#32#>12/+

!
@AA
 !"#$%0
!
8%)15%1)0 8#1)50 T*)30% 5022$ L/#2#3/5*2 *5%/E/%- B050(%#)

QG FF4 QUV .W* F5%/EU '#+#D H01%)#(</2$4 H01%)#(</2 5<0'#%*X/$ ,?,BK !

5-%0$4 9/>)#D 0+6#%<02/*2 *+6 603)*+12*%/#+Y ,?,BA
>2*$%$4 5022$ 3)#C%< #9
0+6#%<02/*2 5022$4 9/>)#>2*$%$4 '02*+#'*4
0(/%<02/*2 5022$4 *+6 #2/3#60+6)#5-%0 ()0D
$-+#E/*2 5022$ 51)$#) 5022$

QG FF4 QUV .W* F5%/EU '#+#D H01%)#(</2$4 H01%)#(</2 5<0'#%*X/$ ,?,BK

5-%0$4 9/>)#D 0+6#%<02/*2 *+6 603)*+12*%/#+Y
>2*$%$4 5022$ 3)#C%< #9
0+6#%<02/*2 5022$4 9/>)#>2*$%$4 '02*+#'*4
0(/%<02/*2 5022$4 *+6 #2/3#60+6)#5-%0 ()0D
$-+#E/*2 5022$ 51)$#) 5022$

=>>%/<.?
QG FF4 QUV .W* F5%/EU '#+#D H01%)#(</2$4 H01%)#(</2 5<0'#%*X/$ ,?,BK
5-%0$4 9/>)#D 0+6#%<02/*2 *+6 603)*+12*%/#+Y
>2*$%$4 5022$ 3)#C%< #9
0+6#%<02/*2 5022$4 9/>)#>2*$%$4 '02*+#'*4

QZ FF4 QUR .W*

0(/%<02/*2 5022$4
$-+#E/*2 5022$

"03*.*)-#5-%0$
*+6 (2*%020%$4
'*$% 5022$4 0+D
"#+#5-%0$4
+01%)#(</2$
*+6 #2/3#60+6)#5-%0 ()0D
51)$#) 5022$

,<0'#%*X/$ #9 '#+#5-%0$4
*5%/E*%/#+ *+6 603)*+12*D
%/#+ #9 +01%)#(</2$4 /+</D
[+.+#C+
!5<#+6)#/%/+D
$129*%0 ()#D
"
6#%<02/*2 5022$ #9 >/%$ *+3/#30+0$/$ %0#32-5*+ #9
1'>/2/5*2 E0/+$ +01%)#(</2$7

QR FF4 RUJ .W* P(/%<02/*2 5022$ H01%)#(</2$ ,<0'#%*X/$ *+6 *5%/E*%/#+ ,?,BK
#9 +01%)#(</2$

QO FF4 R .W* N/>)#>2*$%$4 H01%)#(</2$ ,<0'#%*X/$ #9 +01%)#(</2$ ,?,BA4

0(/%<02/*2 5022$ ,?,BK

SV\RO FF4 "*5)#(<*30$4 "#+#5-%0$4 ,<0'#%*X/$ #9 9/>)#>2*$%$4 ,?,BK

S\QUO .W* (2*%020%$4 +01%)#(</2$4 +01%)#(</2$4 *+6 '#+#D
!6/990)0+% %)1+D 0(/%<02/*2 5022$4 9/>)#>2*$%$ 5-%0$Y '/%#30+/5 9#) 9/>)#D
5*%06 9#)'$ 0+6#%<02/*2 5022$ >2*$%$Y )020*$0$ <-*21)#+/5
60)/E06 9)#' *5/64 32-5#$*'/+#32-5*+$4
* ()051)$#)] (2*$'/+#30+ *5%/E*%#)4
201.#5-%0D60D *+6 I=PKY </$%*'/+0 )0D
)/E06 3)#C%< 20*$0 >- >*$#(</2$
9*5%#) !@W=N7U
W020%/#+ #9 K FF
9)#' HFIDK 3/E0$
#)/3/+ %# %<)#'D
>#5/6/+DA7
!
@A&

"
! !"#$%(

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

8-$%0'*%/5 "#$% 9)0:10+% ;%<0) 60$/3+*%/#+$ =0+0 2#51$4

+*'0 +*'0 30+0 $-'>#2

,?,@A &@BA C01%)#(</2 *%%)*5%*+%D*5%/E*%/+3 K:FLB:FM4

()#%0/+BF !CGHBF74 +01%)#(</2B*5%/B 8,NOA
E*%/+3 9*5%#) !CGI74 201.#5-%0 *6<0$/#+
/+</>/%#) !@G&74 3)*+12#5-%0 5<0'#B
%*5%/5 ()#%0/+ !=,H74 0+6#%<02/*2 5022
+01%)#(</2B*5%/E*%/+3 (0(%/60 !JCGHB!7

,?,@P "/3 "#+#./+0 /+61506 >- &ICB" !'/374 K:LFSLF4

5-%#./+0 )0$(#+$/E0 30+0BFQ 8,NOP
!,R=BFQ7
)**%+,-.

,?,@FQ &HBFQ &+%0)90)#+B/+615/>20 ()#%0/+BFQ #) /'B K:LFSLF4

'1+0 ()#%0/+BFQ !&HBFQ74 5-%#./+0 )0B 8,NOFQ
$(#+$/E0 30+0BL !,R=BL7

" ,?,@FF &BTG, &+%0)90)#+B/+615/>20 TB5022 # 5<0'#*%B

%)*5%*+% !&BTG,74 /+%0)90)#+B"B/+615/>20
()#%0/+BP !&HBP7
K:LFSLF4
8,NOFF

,?,@FL 8UIBF#D! 8%)#'*2 5022B60)/E06 9*5%#)BF !8UIBF74 FQ:FFSF4

()0BOB5022 3)#V%< $%/'12*%/+3 9*5%#) 8,NOFL
!HO8I7

,?,@FM O@,DO,GBF OB2-'(<#5-%0 5<0'#*%%)*5%*+% !O@,74 K:LF4

OB5022 *%%)*5%/+3 5<0'#./+0BF !O,GBF74 8,NOFM
G+3/0

,?,@FK ORGW ,?, 5<0'#./+0 /+ >)0*$% *+6 ./6+0- X:MF4

!ORGW74 OB5022 *+6 '#+#5-%0B*5%/E*%/+3 8,NOFK
5<0'#./+0 !O"G,74 >#20./+0

!
/&0
 !"#$%(
!
8%)15%1)0 8#1)50 T*)30% 5022$ O/#2#3/5*2 *5%/E/%- R050(%#)

YL GG4 A .U*4 G5%/ES 0+6#%<02/*2 G22 /''1+0 ,<0'#%*Z/$ #9 *22 '/3)*B ,?,RF4
()#50$$06 5022$ *+6 '#+#B 5022$4 0)-B %#)- /''1+0 5022$4 *5%/E*B ,?,RL
9)#' * 2*)30) 5-%0$4 9/>)#>2*$%$4 %<)#5-%0$4 %/#+ #9 +01%)#(</2$4
()051)$#) #9 .0)*%/+#5-%0$4 0+6#%<02/*2 /+</>/%$ </$%*'/+0 )020*$0
PP GGS @#+30) '02*+#5-%0$4 5022$4 $#'0 >- >*$#(</2$4 &3J ()#615B
*+6 $<#)%0) <0(*%#5-%0$4 0(/%<02/*2 %/#+ >- O 5022$4 ()#'#%0$
9#)'$ 0Z/$% 5<#+6)#5-%0$4 5022$ *+3/#30+0$/$
*+6 * +1'>0) #9
%1'#) 5022 2/+0$

FQM GG4 "*5)#(<*30$4 G5%/ES >)#+B ,<0'#%*Z/$ #9 '#+#5-%0$4 ,?,RM

FFSY .U* +01%)#(</2$4 5</*2 0(/%<0B '#612*%0$ 5022 3)#V%<
0+6#%<02/*2 5022$4 2/1' *+6 *5%/E*%/#+ 61)/+3
%1'#) 5022$4 /+92*''*%/#+
1(#+ &ICB"

)**%+,-.
$%/'12*%/#+

PA GG @-'(<#5-%0$4 @-'(<#B R0312*%0$ %<0 3)#V%< #9 ,?,RM

'#+#5-%0$4 5-%0$4 '#+#B /''*%1)0 <0'*%#(#/0%/5
*5%/ES .0)*%/+#B 5-%0$4 +01B ()#30+/%#) 5022$4 /+</>/%$

YM GG4 ASM .U*

5-%0$4 0+6#%<0B
2/*2 5022$4 +01B
%)#(</2$

G5%/ES *$%)#B
5-%0$4 *5%/ES
%)#(</2$4 0+B
6#%<02/*2
5022$

&@BLB*5%/E*%06
T 5022$
*+3/#30+0$/$4 /+6150$
()#2/90)*%/#+ #9 '0$*+3/*2
5022$

H#%0+% 5<0'#*%%)*5%*+%
9#) &@BLB*5%/E*%06 T 5022$
,?,RM
"
'#+#5-%0$

AP *+6 PM GG [>/:1/%#1$ "*/+2- ,<0'#%*Z/$ #9 '#+#B ,?,RK4

!K *66/%/#+*2 0Z()0$$/#+ 2-'(<#5-%0$ +1520*) 5022$ /+5216/+3 O" ()0BOB5022B
GG /+ 8UIBF!74 !+#% #+ >2##6 *+6 '#+#B ()#30+/%#) 5022$ 60)/E06
ML .U* 5022$7 5-%0$ 5<0'#./+0
)050(%#)
!HOB,RW7

FQP GG4 I#22/520$ #9 %<0 ,022$ 0Z()0$B G5%/E*%0$ *+6 ()#'#%0$ ,?,RX4 >2)BF
FMSL .UG4 $(200+4 2-'(< $/+3 O1)./%% 5<0'#%*Z/$ #9 O 2-'(<#B
8\&OFM +#60$4 H0-0)]$ 2-'(<#'* 5-%0$
(*%5<0$ )050(%#)BF
!>2)BF7

AA GG [>/:1/%#1$2- G5%/ES '#+#B 80205%/E02- *%%)*5%$ *5%/ES [+.+#V+

0Z()0$$06 /+ 5-%0$ '#+#5-%0$ /+ /+92*'06
+#)'*2 %/$$104
()#61506 >-
9/>)#>2*$%$4 .0)B
*%/+#5-%0$4 2*'/B
+* ()#()/* 5022$
%/$$10$

!
/&1

"
! !"#$%/

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

8-$%0'*%/5 "#$% 9)0:10+% ;%<0) 60$/3+*%/#+$ =0+0 2#51$4

+*'0 +*'0 30+0 $-'>#2

,?,@AB D0/)6 5<0'#./+0 @1+3./+0 "1)/+0 5<)G BGBAGB4

!$# 9*) /60+%/C !DE,FE7 8,HIAB
9/06 #+2- /+
'/507

( ()%*+,-.%/

?,@A @-'(<#%*5%/+ 8/+320 , '#%/9CA! !8,"CA!74 *5%/J*%/#+ A:MN

!@%+4 @(%+7 /+61506 KC,022 60)/J06 *+6 5<0'#./+0
)02*%06 !LKL,7

?,@M 8,"CA" 8/+320 , '#%/9CA" !8,"CA"7 A:MN

233%.4-5

(01( ()%*+,-.%/

,?N,@A O)*5%*2./+0 !OP4 AR:AN

OPQ7

"
(( ()%*+,-.%/

,,@A &CNST UBSS4 K,LCN !'1)/+0 <#'#2#310 AV:AAGM4

#9 &CNST7 8,HLA

,,@M ",UCAW",LO "#+#5-%0 5<0'#*%%)*5%*+% ()#%0/+CA AV:AAGMC:MAGA4

!",UCA74 '#+#5-%0 5<0'#*%%)*5%*+% ZE 30+0 *% 8,HLM
*+6 *5%/J*%/+3 9*5%#) !",LO74 32/#'*
5022C60)/J06 5<0'#%*5%/5 9*5%#) !=X,O74
%1'#) +05)#$/$ 9*5%#)C$%/'12*%06 30+0
$0:10+50CY

,,@N "&UCAC!W@XVY! "*5)#(<*30 /+92*''*%#)- ()#%0/+CAC! AV:AAGM4

!"&UCAC!74 =SW=A $[/%5< 30+0 !=;8CAT7 8,HLN

!
6&6
 !"#$%/
!
8%)15%1)0 8#1)50 K*)30% 5022$ I/#2#3/5*2 *5%/J/%- \050(%#)

AV .X* F/3<2- 0]C "1)/+0 I" &+</>/%$ %<0 3)#[%< #9 <0'*C

()0$$06 /+ '1)C 5022$ %#(#/0%/5 0)-%<)#/6 ()051)$#)
/+0 21+34 90%*2 5022$4 ()#'#%0$ '/3)*%/#+ #9
2/J0)4 -#2. $*5 >#+0 '*))#[ 5022$

TN LL4 L5%/JG ()#CK 5022$4 K 5022$4 ,<0'#%*5%/5 9*5%#) 9#) ?,\A

M 6/990)0+% %<-'#5-%0$4 QP 5022$4 2-'(<#5-%0$4 QP 5022$4
$%)15%1)*2 ,XY^ K 5022$ I 5022$4 *+6 +01%)#(</2$
5#+9#)'*%/#+$ +01%)#(</2$

;+2- M LL 8/'/2*) %# ?,@A_ 8/'/2*) %# 8/'/2*) %# ?,@A_ ?,\A

6/990) 9)#' ?,@A_
?,@A

233%.4-5
NTV LL4 E+6#%<02/*2 5022$4 "#+#5-%0$4 "0'>)*+0C>#1+6 ,?N,\A
* 5<0'#./+0C 0(/%<02/*2 5022$4 K 5022$4 9)*5%*2./+0 /+6150$
2/.0 6#'*/+
(2*506 *%#(
* '15/+ $%*2.
*+6 * %)*+$C
'0'>)*+0
6#'*/+
+01)#+$ QP 5022$ >/+6/+3 *+6 *6<0$/#+
#9 ,?N,\AC(#$/%/J0 5022$G
8#21>20 9)*5%*2./+0
/+6150$ *5%/J*%/#+ *+6
'/3)*%/#+ #9 ,?N,\AC
(#$/%/J0 5022$
"
VM LL4 L5%/JG "#+#5-%0$ ,<0'#%*]/$ *+6 *5%/J*%/#+ ,,\Y
AB`AR .X* K 2-'(<#5-%0$ #9 '#+#5-%0$

VR LL4 "#+#5-%0$ *+6 "#+#5-%0$4 ,<0'#%*]/$ #+ '#+#C ,,\M

R`V .X* 1+C '*5)#(<*30$4 K 5022$4 >*$#C 5-%0$4 *5%/J*%/+3 09905% #+
32-5#$-2*%064 9/>)#>2*$%$4 0+C (</24 *+6 '#+#5-%0$ *+6 >*$#(</2$
1( %# NS .X* 6#%<02/*2 5022$4 0#$/+#(</2 !/+6150$ </$%*'/+0 )0C
32-5#$-2*%06 .0)*%/+#5-%0$4 3)*+12#5-%0$ 20*$07
$'##%< '1$520
5022$4 *$%)#5-%0$4
*+6 J*)/#1$ %1C
'#) 5022$ 2/+0$

RT LL4 "#+#5-%0$ *+6 =)*+12#5-%0$4 &+</>/%$ <0'*%#(#/0$/$4 ,,\A4 ,,\B

VGY .X* '*5)#(<*30$
!1(#+ $%/'12*%/#+
[/%< >*5%0)/*2
0+6#%#]/+$74
'0'#)- K 5022$
!1(#+ *5%/J*%/#+7
K 5022$4
<0'*%#(#/C
0%/5 ()0C
51)$#) 5022$
/+6150$ KC5022 '/3)*%/#+4
0+<*+50$ *6<0)0+50 #9
'#+#5-%0$ %# 0+6#%<02/*2
5022$ !
6&1

"
! !"#$%*

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

8-$%0'*%/5 "#$% 9)0:10+% ;%<0) 60$/3+*%/#+$ =0+0 2#51$4

+*'0 +*'0 30+0 $-'>#2

,,?@ "&ABCB! &''1+0 *5%/D*%/#+ 30+0BE !F,GBE74 CH:CCIE4

'*5)#(<*30 /+92*''*%#)- ()#%0/+BCB! 8,JF@
!"&ABCB!7

,,?K LFMGN8 (0312*%06 1(#+ "5%/D*%/#+4 )#)'*2 CH:CCIE4

!B5022 %O()0$$064 *+6 *05)0%06 8,JFK
!LFMGN874 $'*22 /+615/>20
$05)0%06 5<0'#./+0B602%* !8&8B602%*74
0#$/+#(</2 5<0'#%*5%/5 (#2/(0(%/60BC
!N#,ABC7
+,,%)-./

,,?P ,CQ4 '*5)#(<*30 /+92*''*%#)- R+.+#S+4

!#+2- ()#%0/+B)02*%06 ()#%0/+BC !"LABC7 8,JFP
'1)/+07

,,?H ",ABT "#+#5-%0 5<0'#*%%)*5%*+% ()#%0/+BT CH:CCIE !52#$0 %#

!",ABT74 '*$% 5022 *5%/D*%/#+B)02*%06 %<0 0)>VE 2#51$74

" ,,?U ",ABE

5<0'#./+0 !"FL,74 M,EU

"#+#5-%0 5<0'#*%%)*5%*+% ()#%0/+BE

!",ABE7
8,JFH

CH:CCIE4
8,JFU

,,?W !#+2- R+.+#S+ "*5)#(<*30 /+92*''*%#)- "1)/+0 5<)#'#B

'1)/+07 ()#%0/+BCB" !"&ABCB"74 ,,XCU $#'0 CC4
8,JFW

,,?CQ !#+2- R+.+#S+ ND0+%1*22- )02*%06 %# <1'*+ ,,?CKY 8,JFCQ

'1)/+07

,,?CC N#%*O/+ CH:ECICBCH:ECIE4

8,JFCC

!
0&1
,,?CE "1)/+0 ",ABK "#+#5-%0 5<0'#%*5%/5 ()#%0/+BK
!",ABK7
"1)/+0
5<)#'#$#'0 CC4
8,JFCE
 !"#$%*
!
8%)15%1)0 8#1)50 G*)30% 5022$ V/#2#3/5*2 *5%/D/%- L050(%#)

Z/3<2- "#+#5-%0$ *+6 =)*+12#5-%0$4 A)#'#%0$ 3)#S%< #9 ,,LK

<#'#2#3#1$ '*5)#(<*30$ G 5022$4 <0'*%#(#/0%/5 ()051)$#)
%# "&ABCB# !1(#+ $%/'12*%/#+ <0'*%#B 5022$4 *5%/D*%/#+ #9 ./220)
S/%< >*5%0)/*2 (#/0%/5 ()0B 5022$4 /+6150$ *6<0$/#+ #9
0+6#%#O/+$74 51)$#) 5022$ G 5022$ %# 0+6#%<02/*2 5022$
'0'#)- G 5022$
!1(#+ *5%/D*%/#+7

U .[* G 5022$ !/+61506 G 5022$4 0#$/+#B L05)1/%$ 5022$ %# /+92*'B ,,LC4 ,,LT4
>- GMXB# *+6 (</2$4 >*$#B '*%#)- $/%0$4 /+6150$ ,,LK
&?BC#7 (</2$4 '#+#B )020*$0 #9 3)*+120$ >-
5-%0$4 $-+#D/*2 0#$/+#(</2$4 ()#'#%0$
9/>)#>2*$%$ *5%/D*%/#+ #9 ./220) 5022$

+,,%)-./
Z#'#2#310 Z0'*%#(#/0%/5 "#+#5-%0$4 &+D#2D06 /+ '#+#5-%0 R+.+#S+
%# "&ABCB$Y 5022$4 9/>)#>2*$%$ G 5022$ *+6 '*5)#(<*30 '/3)*B
%/#+ 1(#+ /+\1)-

WH FF4 N(/%<02/*2 *+6 "#+#5-%0$4 ,<0'#%*O/$ #9 '#+#5-%0$4 ,,LC4 ,,LE4

U]CU .[*

HP FF4
0+6#%<02/*2 5022$4
>2##6 '#+#B
+1520*) 5022$
1(#+ *5%/D*%/#+

X/>)#>2*$%$4
G 5022$4 0#$/B
+#(</2 3)*+B
12#5-%0$

"#+#5-%0$4
0#$/+#(</2$^ /+6150$
()#%0*$0 $05)0%/#+ >-
'*5)#(<*30$

,<0'#%*O/$ #9 '#+#5-%0$
,,LT4
,,LCQY

,,LC4
"
U]CU .[* 0+6#%<02/*2 5022$4 G 5022$4 ,,LEV4 ,,LK
0(/%<02/*2 5022$4 0#$/+#(</2
>2##6 '#+#B 3)*+12#5-%0$
+1520*) 5022$

CQQ FF "1)/+0 '*5)#B Z0'*%#(#/B 81(()0$$/#+ #9 5#2#+- 9#)B R+.+#S+

(<*30$ 0%/5 5022$ /+ '*%/#+ /+ $%/'12*%06 >#+0
%<0 >#+0 '*))#S4 /+6150$ 5*25/1'
'*))#S4 )020*$0 /+ +01%)#(</2$4 *5%/B
G 5022$ D*%0$ *+6 )05)1/%$ G 5022$

R+.+#S+

WH FF N(/%<02/*2 5022$4 N#$/+#(</2$ ,<0'#%*O/$ #9 0#$/+#B ,,LT

'*5)#(<*30$4 (</2$4 *5%/D*%/#+ *+6
G 5022$4 9/>)#B 5*25/1' )020*$0

UE FF4 WIT .[*

>2*$%$

?-'(< +#60$4
$%)#+32- 1()031B
2*%06 /+ *5%/DI
'#+#5-%0$
"#+#5-%0$4
'*5)#B
(<*30$
8%)#+3 5<0'#*%%)*5%*+%
9#) '#+#5-%0$4 '*5)#B
(<*30$
,,LE
!
0&2

"
! !"#$%(

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

8-$%0'*%/5 "#$% 9)0:10+% ;%<0) 60$/3+*%/#+$ =0+0 2#51$4

+*'0 +*'0 30+0 $-'>#2

,,?@A ",BCD "#+#5-%0 5<0'#%*5%/5 ()#%0/+CD @E:@@FG4

!",BCD7 8,HI@A

,,?@D J,,C@ J0'#9/2%)*%0 ,, 5<0'#./+0C@ @E:@@FG4

!J,,C@74 '*5)#(<*30 5#2#+- /+</>/%#)- 8,HI@D
9*5%#) !"C,&K7
)**%+,-.

,,?@L "&BC@C! "*5)#(<*30 /+92*''*%#)- ()#%0/+CL @E:@@FG4

!"&BCL74 <0'#9/2%)*%0 ,,C5<0'#./+0CG 8,HI@L
!J,,CG74 M,,CA4 201.#%*5%/+C@

" ,,?@N ?O, ?/P0)C0Q()0$$06 5<0'#./+0 !?O,74

'#+#%*5%/+C@4 +0R ,, 5<0'#./+0CD
!M,,CD74 <0'#9/2%)*%0 ,,C5<0'#./+0CD
!J,,CD7
@E:@@FG4
8,HI@N

,,?@E SIT, S<-'1$ *+6 *5%/P*%/#+C)0312*%06 @N:@A4

5-%#./+0 !SIT,74 IU,VCG 8,HI@E

,,?@W V,C,X@ B12'#+*)- *+6 *5%/P*%/#+C)0312*%06 @E:@@FG4

5<0'#./+0 !BIT,74 *2%0)+*%/P0 8,HI@W
*5%/P*%06 '*5)#(<*30 *$$#5/*%06
,,C5<0'#./+0 !I"I,C@74 60+6)/%/5
5022C60)/P06 5<0'#./+0C@ !V,C,X@7

!
/&0
,,?@Y "&BCAC"ZO?, OU&C@C2/3*+6 5<0'#./+0 !O?,74 0Q#61$CA Y(@A4
8,HI@Y
 !"#$%(
!
8%)15%1)0 8#1)50 S*)30% 5022$ U/#2#3/5*2 *5%/P/%- T050(%#)

EL II O(/%<02/*2 *+6 "#+#5-%0$4 B#%0+% 5<0'#*%%)*5%*+% ,,TG4 ,,TA

0+6#%<02/*2 5022$ S 5022$ 9#) '#+#5-%0$ *+6
!1(#+ SMKC# *+6 S 2-'(<#5-%0$F
&?C@ $%/'12*C
%/#+74 '*5)#C
(<*30$

ED II4 WFN .V* 8(200+4 2/P0)4 "#+#5-%0$4 \0*.2- 5<0'#%*5%/5 #+ ,,T@

$.020%*2 *+6 '-02#/6 ()#C '#+#5-%0$4 /+615%/#+ #9
<0*)% '1$5204 30+/%#)$ ()#2/90)*%/#+ #+ ,VAD]
31%4 *+6 >#+0 '-02#/6 5022$4 /+</>/%$
'*))#R[ ()0$0+% 5#2#+- 9#)'*%/#+ /+61506
*$ $#21>20 ()#C >- "C,8K
%0/+ /+ %<0 >2##6

)**%+,-.
YG II4 ?01.#5-%0$ /+ "#+#5-%0$4 I%%)*5%$ '#+#5-%0$4 V,4 ,,T@4 ,,TA
N 5#+$0)P06 2/P0)4 /+%0$%/+04 /''*%1)0 2-'(<#5-%0$4 0#$/+#(</2$[
5-$%0/+ 21+3 V,4 S *+6 U /+</>/%$ 5#2#+- 9#)'*%/#+
)0$/610$ 5022$4 0#$/+#C >- ()#30+/%#) 5022$
/+$%0*6 #9 D4 (</2$
$/'/2*)/%- %#
'1)/+0 ,@^

@^^ II4
@@FG .V*4
* @G^ II
J0(*%#5-%0$4
*5%/PF '#+#C
5-%0$ !1()0312*C
"#+#5-%0$4
2-'(<#5-%0$4
V,
B)#'#%0$ 5022 *6<0$/#+4
)05)1/%$ *+%/30+ ()0$0+%C
/+3 5022$ %# %)*+$905%06
,,T@4 ,,TG4
,,TL4 ,,TW
"
()#(0(%/60 %/#+ >- &?C@^74 %1'#) 5022$
0Q/$%$ $#'0 MX 5022$4
$! S 5022$

YD II4 W .V* S<-'#5-%0$4 S 5022$ I%%)*5%$ ()06#'/+*+%2- ,,TD4 ,,TW

&?C@AC*5%/P*%06 SJGC6/990)0+%/*%06 S 5022$
'*5)#(<*30$4
>)#+5</*2
0(/%<02/*2 5022$4
.0)*%/+#5-%0$

NY II4 EFW .V* V, /+ 30)'/+*2 T0$%/+3 ,<0'#*%%)*5%*+% 9#) _+.+#R+

50+%0)$ *+6 S 5022$ S 5022$ %# *+%/30+ ()0$0+C
SC5022 *)0*$ #9 %*%/#+ $/%0$
2-'(< +#60$4
*2P0#2*) '*5)#C
(<*30$4 *5%/PF

YW II
'#+#5-%0$

S<-'1$4 2-'(<
+#60$4 '*5)#C
(<*30$
S 5022$4 U 5022$ ,<0'#*%%)*5%*+% 9#)
,VAD] 5022$4 *5%/PF S *+6
U 5022$
,,TE
!
/&1

"
! !"#$%(

!!"#$% &' "#$% &'(#)%*+% ,-%#./+0$ /+ &''1+#2#3-4 5#+%/+1067

8-$%0'*%/5 "#$% 9)0:10+% ;%<0) 60$/3+*%/#+$ =0+0 2#51$4

+*'0 +*'0 30+0 $-'>#2

,,?@A "&BCDC!E?FG, ?/H0) *+6 *5%/H*%/#+ )0312*%06 @:DDC:DK4

5<0'#./+0 !?FG,74 0I#61$CJ 8,LF@A

,,?@J M,./+0E8?, ,<0'#./+0 N/%< M 5-$%0/+0$ !M,./+074 O(JD4

$05#+6*)- 2-'(<#/6C%/$$10 5<0'#./+0 8,LF@J
!8?,74 0I#61$C@

,,?@@ "P, "*5)#(<*30C60)/H06 5<0'#./+0 JM:JD4

!"P,74 $%/'12*%06 QC5022 5<0'#C 8,LF@@
*%%)*5%*+% ()#%0/+CJ !8Q,BCJ74 P,ERC,S
)**%+,-.

,,?@D "B&TCJ "-02#/6 ()#30+/%#) /+</>/%#)- 9*5%#)CJ JK:JJV@4

!"B&TCJ74 5<0'#./+0C"CU 8,LF@D

" ,,?@W "B&TC@E0#%*I/+C@ "-02#/6 ()#30+/%#) /+</>/%#)- 9*5%#)C@

!"B&TC@74 5<0'#./+0C"CM
K:JJV@D4
8,LF@W

,,?@X QY,S Q<-'1$C0I()0$$06 5<0'#./+0 !QY,S7 JO(JDV@4

8,LF@X

,,?@M Y#%*I/+CD "*5)#(<*30 /+92*''*%#)- ()#%0/+CWC! K:JJV@D4

!"&BCWC!74 %<-'/5 $%)#'* 5<0'#./+0CJ 8,LF@M
!Q8,CJ7

,,?@K ,QF,SE&?, ,1%*+0#1$ QC5022C*%%)*5%/+3 5<0'#./+0 O(JD4

!,QF,S74 &?CJJG!C2#51$ 5<0'#./+0 !&?,74 8,LF@K
F?B4 $./+./+04 0$./+04 "&?,

!
/&0
,,?@U "Y, "15#$*C*$$#5/*%06 0(/%<02/*2 5<0'#C
./+0 !"Y,7
X4
8,LF@U
 !"#$%(
!
8%)15%1)0 8#1)50 Q*)30% 5022$ R/#2#3/5*2 *5%/H/%- G050(%#)

OM FF ?/H0)4 9/>)#C &''*%1)0 ,<0'#*%%)*5%*+% 9#) ,,GM

>2*$%$4 ?B8C P,4 Q 5022$ 2-'(<#5-%0$4 N0*.
$%/'12*%06 5<0'#*%%)*5%*+% 9#)
201.#5-%0$ 3)*+12#5-%0$

JJJ FF4 <*$ Z/3< 0+6#%<02/*2 Q<-'#5-%0$4 &+6150$ *6<0$/#+ *+6 ,,GK
* DA FF 5*)>#I-C H0+120$ #9 *5%/HV Q 5022$ '/3)*%/#+ #9 Q 5022$4
%0)'/+*2 6#C 2-'(<#/6 #)C (*)%/512*)2- +*/H0 Q 5022$
'*/+ N/%< 3*+$4 2-'(<*%/5
@ *66/%/#+*2 0+6#%<02/1' #9
5-$%0/+ )0$/610$ 6/990)0+% #)3*+$

MO FF4 UVJ .P* "*5)#(<*30$4 F5%/HV G05)1/%'0+% #9 *5%/HV ,,GW

P,4 R 5022$ Q 2-'(<#C Q 5022$ 9#) /+%0)*5%/#+
5-%0$ *+6 N/%< *+%/30+C()0$0+%/+3

)**%+,-.
'#+#5-%0$ 5022$

OO FF [*)/0%- #9 "#+#5-%0$4 ,<0'#*%%)*5%*+% 9#) ,,GJ

%/$$10$ P,4 )0$%/+3 '#+#5-%0$4 P,4 )0$%/+3
Q 5022$ Q 5022$4 #$%0#52*$% ()051)C

OD FF4
JAVM .P*
F5%/HV '#+#C
5-%0$
G0$%/+3 Q 5022$4
0#$/+#(</2$4
$#)$\ /+</>/%/#+ #9 5#2#+-
9#)'*%/#+ >- '-02#/6
()051)$#)$

,<0'#%*I/$ #9 )0$%/+3
Q 5022$4 0#$/+#(</2$4 *+6
,,GD
"
>*$#(</2$4 >*$#(</2$\ )020*$0 #9 </$C
<0'*%#(#/C %*'/+0 *+6 201.#%)/0+0\
0%/5 ()051)$#) /+</>/%/#+ #9 5#2#+- 9#)C
5022$ '*%/#+ /+ $%0' 5022$

J@K FF Q<-'/5 P,4 &+%0$%/+*2 ,<0'#%*%%)*5%*+% 9#) ,,GO

$'*22 /+%0$%/+0 /+%)*C &3FC$05)0%/+3 5022$
0(/%<02/*2 5022$ 0(/%<02/*2
2-'(<#5-%0$

KJ FF Y+6#%<02/*2 5022$4 Y#$/+#(</2$ F5%/H*%/#+ #9 9/>)#>2*$%$ ,,GD

0(/%<02/*2 5022$ #9 *+6 0#$/+#(</2$4 5<0'#C
6/990)0+% %/$$10$ %*I/$ #9 0#$/+#(</2$ *+6
>*$#(</2$

OX FF4 S0)*%/+#5-%0$ "0'#)- 80205%/H02- *%%)*5%$ $./+C ,,GJA

JAVO .P* Q 5022$ *$$#5/*%06 Q 5022$

JAU FF4
J@VD .P*
Y(/%<02/*2 5022$
!(*)%/512*)2-
'15#$*7
G0$%/+3 ,PW
*+6 ,PU
Q 5022$4
0#$/+#(</2$
F%%)*5%$ )0$%/+3 Q 5022$4
0#$/+#(</2$
,,GJA4 ,,GD
!
/&&

"
! ;/+33(*&

!"#$$%&'

!""#$#%& '(%)*(%#+$ !"# $%&'#()# $% (*#'(+# (%,$-./0 (11$%$,0 ,"(, .&&2') /2'$%+ ( )#&.%/('0
$332%# '#)4.%)#5

!""#$#%& 6#()2'# .1 -$%/$%+ ),'#%+," -#,7##% (% (%,$+#%$& /#,#'3$%(%, 8#4$,.4#9

(%/ ( -$%/$%+ )$,# .% (% (%,$-./0 84('(,.4#95

!,*-%+.- !"# '#+$.% .1 (% (%,$+#% .' (%,$+#% 1'(+3#%, ,"(, $%,#'(&,) 7$," (% 6:;
3.<#&2<#5

!//-/- =<,#'%(,$*# 1.'3 .1 ( 4(',$&2<(' +#%# <.&2) 7$,"$% ( +$*#% )4#&$#)5

!//-*,& >'$+$%(<<0 /#1$%#/ () ,"# (<,#'#/ '#(&,$.% ),(,# ,"(, .&&2') 24.% )#&?
.%/('0 &.%,(&, 7$," (% (%,$+#%@ ,./(0 (% (<<#'+0 $) +#%#'(<<0 &.%)$/#'#/
,. -# ( ,04# A .' ,04# AB "04#')#%)$,$*$,0 '#(&,$.%5
!..-$5#2

!//+,-$-#0 =<<.+#%#$& *('$(,$.% /#%.,#) ,"# +#%#,$& /$11#'#%&#) -#,7##% 3#3-#')

.1 ,"# )(3# )4#&$#)5

!//+%&.- C'.,#$% 4'./2&, .1 (% (<<#<# '#&.+%$D#/ () (% (%,$+#% -0 (%.,"#' 3#3-#'

.1 ,"# )(3# )4#&$#)5

" !$(.1&/(%+2#$3

!$(.1&/(2#3
;.34<#3#%, 4#4,$/#) 8;E( (%/ ;F(9 ,"(, $%/2&# ,"# /#+'(%2<(,$.% .1
3(), &#<<) (%/ ,"# &.%,'(&,$.% .1 )3..," 32)&<#)5

=%,$+#%?)4#&$1$&G 4'$3('$<0 A+H?3#/$(,#/ $332%# '#)4.%)# ()).&$(,#/

7$," *()./$<(,(,$.% (%/ &.%,'(&,$.% .1 )3..," 32)&<#) 8(%/ .1 ,"#
-'.%&"$9@ ,"# .2,&.3# 3(0 -# 1(,(<5

!$%#4+5& 6!47 6.<#&2<# 1.'3#/ $% '#)4.%)# ,. &.%,(&, 7$," (% (%,$+#% (%/ 7"$&" &(%
)4#&$1$&(<<0 -$%/ ,. ,"(, (%,$+#%5

!$%#,-$ 6!,7 =%0 )2-),(%&# ,"(, &(% ,'$++#' ( )4#&$1$& $332%# '#)4.%)# .' '#(&, 7$,"
&.34.%#%,) .1 (% (<'#(/0 .%+.$%+ $332%# '#)4.%)# 8#5+5G &'.))?'#(&,
7$," (%,$-./$#)95 !"# 3($% )2-),(%&#) ,"(, (&, () (%,$+#%) ('# 4'.,#$%)
(%/ .,"#' )2-),(%&#) 7$," "$+" 3.<#&2<(' 7#$+",)5 I.3# <.7?3.<#&2<('?
7#$+", )2-),(%&#) ,"(, &(%%., ,'$++#' (% $332%# '#)4.%)# (<.%# ('# (-<#
,. ,'$++#' (% $332%# '#)4.%)# -0 -$%/$%+ ,. #%/.+#%.2) 4'.,#$%)
8"(4,#%J&(''$#' &.34<#K9G ,"2) '#%/#'$%+ ,"#3 12<<?1<#/+#/ (%,$+#%)5

!$%#,-$ .*+0-33#$, !"# ,'(%)1.'3(,$.% .1 (% (%,$+#% ,. ( 1.'3 '#&.+%$D(-<# -0 <034".&0,#)5

!$%#,-$8.*-3-$%#$, ;#<<) )2&" () 3(&'.4"(+#)G /#%/'$,$& &#<<)G L(%+#'"(%) &#<<) ,"(, #K4'#))
0-// 6!9:7 (%,$+#%)G #5+5G 1'.3 3$&'..'+(%$)3) -.2%/ ,. ,"#$' )2'1(&#G (%/ 4'#)#%,

!
,"#3 (<.%+ 7$," 6:; 4'./2&,) ,. ! <034".&0,#)5 !"$) 4'.&#)) .1 3(M$%+
,"# (%,$+#%) N4(<(,(-<#O $) #))#%,$(< 1.' (% #11#&,$*# $332%# '#)4.%)#5

!.+.%+3#3 C'.+'(33#/ &#<< /#(," 8)2$&$/#95

<==
!%+.#(
;/+33(*&

!"# &<$%$&(< 3(%$1#),(,$.%) .1 ,04# A "04#')#%)$,$*$,0G $%&<2/$%+ #&D#3(G

!
(),"3(G (%/ '"$%$,$)5

!)%+/+,+)3 >'$+$%(,$%+ 1'.3 ,"# )(3# $%/$*$/2(<5

!>#5#%& !"# 12%&,$.%(< -$%/$%+ 4.,#%,$(< .1 (% (%,$-./0 ,. $,) (%,$+#%@ /#4#%/#%,

.% ,"# (11$%$,0 -#,7##% #4$,.4#) (%/ 4('(,.4#) () 7#<< () ,"# *(<#%&#) .1
(%,$-./0 (%/ (%,$+#%5

?)*3( +" @(4*#0#)3 L034".#4$,"#<$.$/ .'+(% .% ,"# &<.(&( .1 -$'/)@ )$,# .1 P?&#<< 3(,2'(,$.%
$% -$'/)5

:AB:C ;.34.%#%,) .1 ,"# &<())$&(< (%/ <0,$& &.34<#3#%, 4(,"7(0) .1 ,"#

&.34<#3#%, )0),#3 7"$&" 3#/$(,# $%1<(33(,.'0 '#(&,$.%)G ,"# .4).?
%$D(,$.% .1 4(',$&<#)G (%/ ,"# <0)$) .1 &#<< 3#3-'(%#)5

:(**#-* =% $332%.+#%$& 3.<#&2<# 8.' 4(', .1 ( 3.<#&2<#9 '#&.+%$D#/ -0 ! &#<<)

/2'$%+ (% $332%# '#)4.%)#5

!..-$5#2
:D I## '()*%+, -" .#""+,+$%#/%#-$5

:DE I## '-01(+0+$%/,#%&2.+%+,0#$#$3 ,+3#-$5

:-// 0&0/- C'.&#)) .1 &#<< /$*$)$.%G 7"$&" &(% -# /$*$/#/ $%,. 1.2' 4"()#)Q RSG IG RT

:-// /#$-

:@F
(%/ 65 UV= $) &.4$#/ /2'$%+ ,"# I 4"()#G 7"#'#() &#<< /$*$)$.% .&&2') $%
,"# 6 4"()# 83$,.)$) 4"()#95

;#<<) ,"(, &(% -# -'#/ $% *$,'. $% ( /#1$%#/ &#<< &2<,2'#5 ;#<< <$%#) 2)2(<<0
&.%,($% )#*#'(< $%/$*$/2(< &#<< &<.%#)5

I## '-(-$&2"-,0#$3 )$#%5

"
:1-'+G#$-3#3 A%&'#()#/ 8%.%/$'#&,$.%(<9 3$+'(,$.% (&,$*$,0 .1 &#<<)5

:1-'+%(2#3 U$'#&,$.%(< 3.*#3#%, .1 &#<<) (<.%+ ( &.%&#%,'(,$.% +'(/$#%, .1 &#',($%

&"#3.,(&,$& 1(&,.')5

:1#'-*#3' !"# 4'#)#%&# .1 &#<<) 1'.3 +#%#,$&(<<0 /$11#'#%, $%/$*$/2(<) $% ( +$*#%

$%/$*$/2(<5

:/+$- = 1(3$<0 .1 &#<<) .' .'+(%$)3) 7$," (% $/#%,$&(< +#%#,$& &.%1$+2'(,$.%5

:/)3%-* +" 5#""-*-$8 A%,#'%(,$.%(<<0 ),(%/('/$D#/ %.3#%&<(,2'# 1.' (%,$+#%) .% &#<< )2'1(&#)5
%#(%#+$ 6:D7 ;#<< 4.42<(,$.%) &(% -# /$11#'#%,$(,#/ 2)$%+ 3.%.&<.%(< (%,$-./$#)
/$'#&,#/ (+($%), ,"#)# (%,$+#%$& /#,#'3$%(%,)5

:+/+$&8"+*'#$, )$#% !#'3 1.' -.%# 3(''.7 ),#3 &#<<) ,"(, -#&.3# 3(,2'# -<../ &#<<) (1,#'

!
6:@F7 12',"#' /$11#'#%,$(,$.%5

:+/+$&83%#')/(%#$, 8R'.7," 1(&,.')95 C.<04#4,$/#) 4'./2&#/G 1.' #K(34<#G -0 ! <034".&0,#)

"(0%+* 6:H@7 ,"(, ),$32<(,# ,"# 4'.<$1#'(,$.% (%/ /$11#'#%,$(,$.% .1 "#3(,.4.$#,$& ),#3
&#<<)5

<=A

"
! ;/+33(*&

:+'./-'-$%(*#%&8
5-%-*'#$#$, *-,#+$
:04#'*('$(-<# '#+$.% .1 (%,$-./$#) .' !?&#<< '#&#4,.')5 ;.%,(&, 7$," ,"#
(%,$+#% $) #),(-<$)"#/ *$( ,"# ;UW5
6:DE7

:+$I),(%- W#(+#%, 1.'3#/ -0 ,"# &.*(<#%, -$%/$%+ .1 ,7. 3.<#&2<#)G #5+5G 1<2.'#)?
&#$% -.2%/ ,. (% $332%# 3.<#&2<#5

:&%+G#$- ;.33.% %(3# 1.' ).<2-<# 3.<#&2<#) ,"(, 3#/$(,# &#<<J&#<< $%,#'(&,$.%)5

D-$5*#%#0 0-//3 =%,$+#%?4'#)#%,$%+ &#<<) ,"(, .&&2' $% ,"# )M$% () L(%+#'"(%)X &#<<)G $%
,"# <034" %./#) () 1.<<$&2<(' .' $%,#'/$+$,(,$%+ &#<<)G (%/ $% ,"# -<../ (%/
<034" () *#$<#/ &#<<)5

D-3-%+.- C(', .1 ,"# 6:; 3.<#&2<# ,"(, -$%/) 7$," (% (%,$+#% .' 4'.&#))#/
(%,$+#%5

J""-0%+* 0-//3 Y2%&,$.%(< /#)$+%(,$.% 1.' <034".&0,#) (%/ 4"(+.&0,#) ,"(, #K#', ,"#
(&,2(< #%/ #11#&,) .1 (% $332%# '#)4.%)#5
!..-$5#2

J$1($0-'-$% HK,#%)$.% .1 ,"# )2'*$*(< ,$3# .1 ( ,'(%)4<(%, -0 (%,$-./$#) ,"(, (,,(&"

,. (%/ 3()M (<<.(%,$+#%) .1 ,"# /.%.' ,$))2#5

J.#%+.- =% $%/$*$/2(< /#,#'3$%(%, .1 (% (%,$+#% ,. 7"$&" ,"# 4('(,.4# .1 ,"#

(%,$-./0 -$%/)5

" J2+$

@*('-K+*G *-,#+$3

;-$+'-
= 4'.,#$%?&./$%+ +#%# )#+3#%,5

C.',$.%) .1 ,"# B '#+$.%) .1 (%,$-./$#) ,"(, <$# -#,7##% ,"# "04#'*('$(-<#

'#+$.%)5

!"# #%,$'# +#%#,$& 3(,#'$(< .1 ( &#<<5

L(./+%&.- = )#, .1 +#%#,$& /#,#'3$%(%,) .% ( )$%+<# &"'.3.).3#5

L(.%-$ = )3(<< 3.<#&2<# ,"(, &(% ())23# ,"# 12%&,$.% .1 (% #4$,.4# -2, &(%%.,
#*.M# (% (%,$-./0 '#)4.%)# 7$,".2, ())$),(%&#5

L-%-*+/+,+)3 P#<.%+$%+ ,. (%.,"#' )4#&$#)5

L-%-*+$)0/-(* EM! !"# 1'(&,$.% .1 ( %2&<#(' WV= 3.<#&2<# &.%,($%$%+ ,"# 4'$3('0 UV=
61$EM!7 ,'(%)&'$4, -#1.'# $, $) 4'.&#))#/ 1.' 1.'3(,$.% .1 3#))#%+#' WV=5

L#,1 *-3.+$5-* C#',($%) ,. ( )4#&$1$& (%,$+#% .1 (% $%/$*$/2(< 8.' &2<,2'#/ -'##/9 ,"(,
'#)4.%/) 7$," ( ),'.%+ $332%# '#)4.%)#5

L#3%+0+'.(%#4#/#%& !"# 4'.4#',0 .1 ,'(%)4<(%, (&&#4,(%&# (3.%+ /$11#'#%, $%/$*$/2(<)5

!
L+'+/+,+)3 P#<.%+$%+ ,. ,"# )(3# )4#&$#)5

L&4*#5+'( A% *$,'. "0-'$/$D#/ <$%#) 1'.3 ,7. &#<< ,04#) 82)2(<<0 <034".&0,#)9G .%#
.1 7"$&" .'$+$%(,#) 1'.3 ( ,23.'5

<=N
O5#+%+.-
;/+33(*&

= )$%+<# (%,$+#%$& /#,#'3$%(%, .% ,"# *('$(-<# /.3($% .1 (% (%,$-./05

!
O5#+%&.- !"# .*#'(<< )#, .1 (% (%,$-./0X) $/$.,.4#) ,"(, (<). "(*# (%,$+#%$&
4'.4#',$#)5 =%,$?$/$.,04$& (%,$-./$#) ,"(, ('# $/#%,$&(< ,. ,"# #4$,.4# .1
,"# .'$+$%(< (%,$+#% &(% ,"#'#1.'# -# +#%#'(,#/5

O'')$- 0+'./-2 C'./2&, .1 (% (%,$+#%J(%,$-./0 '#(&,$.%@ $, 3(0 (<). &.%,($% &.34.%#%,)

.1 ,"# &.34<#3#%, )0),#35

O$%-*"-*+$3 6O@M37 A%,#'1#'.%) ('# )0%,"#)$D#/ -0 ( %23-#' .1 /$11#'#%, &#<< ,04#)G #)4#&$(<<0
! <034".&0,#)5 !"#0 4<(0 (% $34.',(%, '.<# $% ,"# N%.%)4#&$1$&O /#1#%)#
(+($%), *$'(< $%1#&,$.%) (%/ ('# $%*.<*#/ $% ,"# <0)$) .1 $%1#&,#/ &#<<)G
,"#'#-0 $%/2&$%+ ,"# $%,#''24,$.% .1 *$'(< '#4<$&(,$.%5

O$%-*/-)G#$3 6OP37 R'.24 .1 3.<#&2<#) ,"(, ,'(%)3$, )$+%(<) -#,7##% &#<<) .1 ,"# $332%#
)0),#35 6.'# ,"(% SZ $%,#'<#2M$%) "(*# -##% &"('(&,#'$D#/ ). 1('5 L('+#'
(3.2%,) &(% -# 3(%21(&,2'#/ -0 +#%#,$& #%+$%##'$%+5 ;.%)#[2#%,<0G ,"#
,"#'(4#2,$& 2)# .1 $%,#'<#2M$%) $) %.7 1#()$-<#5

O$%*+$ R#%# )#+3#%, -#,7##% ,7. #K.%) ,"(, /.#) %., &./# ( 4'.,#$%5

!..-$5#2
O3+/+,+)3 ;"('(&,#'$D#/ -0 (% $/#%,$&(< +#%#,$& &.%),$,2,$.%5

O3+%&.- >1 ,"# )#*#'(< 4.))$-<# *('$(%,) .1 )4#&$1$& 4'.,#$%) .' 4#4,$/#)G ,"#

"
*('$(%,) (%&".'#/ $).,04$&(<<0 $% ,"# +#%.3# ('# $/#%,$&(< 7$," (<<
$%/$*$/2(<) .1 ( )4#&$#) 8#5+5G $332%.+<.-2<$% &<())#)9

Q#$#$3 = +'.24 .1 *().(&,$*# 3#/$(,.' )2-),(%&#) '#<#()#/ 7"#% ,$))2# $)

/(3(+#/5

P#,($5 = 3.<#&2<# ,"(, &(% 3#/$(,# ( -$%/$%+ .' ( <$%M(+#5

P#$G(,- L$%M(+# /$)#[2$<$-'$23 #K$),) $1 ,"# &.$%&$/#%&# .1 ,7. +#%#) $% (

5#3-R)#/#4*#)' 4.42<(,$.% $) 3.'# 1'#[2#%, ,"(% 7.2</ -# #K4#&,#/ -()#/ .% ,"#
4'./2&, .1 ,"#$' $%/$*$/2(< +#%# 1'#[2#%&$#)5

P+0)3 !"# 4.)$,$.% .1 ( )4#&$1$& +#%# .% ( &"'.3.).3#5

P+K *-3.+$5-* =% $%/$*$/2(< .' (%$3(< -'##/ 7$," 7#(M '#(&,$*$,0 ,. .%# .' 3.'#
/#1$%#/ (%,$+#%)5

P&'.1+G#$-8 \4.% $%&2-(,$.% 7$," $%,#'<#2M$%)G <034".$/ 4'#&2').' &#<<) &(%

(0%#>(%-5 G#//-* 0-//3 /$11#'#%,$(,# $%,. 3(,2'# #11#&,.' &#<<) 7$," ( "$+" &0,.,.K$& 4.,#%,$(<G
6P!Q 0-//37 #5+5G (+($%), ,23.' &#<<)5

!N8S#0*+,/+4)/#$ C.<04#4,$/# &.%),$,2#%, .1 &<()) A 3.<#&2<#) 8<$+", &"($%95

S#,*(%#+$8#$1#4#%#+$
"(0%+* 6SO@7

S#%+,-$
C#4,$/#) '#<#()#/ -0 <034".&0,#) ,"(, <$3$, ,"# 3$+'(,$.% .1 3(&'.?
4"(+#)5

I2-),(%&# ,"(, $%/2&#) ,"# ,'(%)1.'3(,$.% (%/ /$*$)$.% .1 &#<<)

83($%<0 <034".&0,#)95
!
<=<

"
! ;/+33(*&

S+$+$)0/-(*
.1(,+0&%#0 3&3%-'
!"# &.%&#4, .1 ,"# 6CI () ( 3.'4".<.+$&(< (%/ 12%&,$.%(< 2%$, "()
'#4<(&#/ ,"# 1.'3#' ,#'3G N'#,$&2<.#%/.,"#<$(< )0),#3O 8WHI95 !"$)
6S9H7 &0,.+#%#,$&(<<0 2%$1.'3 &#<< &.34<#K &(% /$11#'#%,$(,# $%,. 4'.3.?
%.&0,#)G "$),$.&0,#)G ]2411#' &#<<) 8),#<<(,# &#<<)9G 42<3.%('0 (<*#.<('
3(&'.4"(+#)G )$%2) #%/.,"#<$(< &#<<) .1 ,"# )4<##%G <034" %./# 3(&'.?
4"(+#)G )$%2) #%/.,"#<$(< &#<<) .1 ,"# -.%# 3(''.7G 4#'$,.%#(< 3(&'.?
4"(+#)G .' .),#.&<(),)5

T.3+$#U(%#+$ C"(+.&0,.)$) .1 (% (%,$+#% $) 1(&$<$,(,#/ -0 ,"# /#4.)$,$.% .1 .4).%$%) .%

,"# (%,$+#% 8#5+5G (%,$-./0 (%/ ;E-95

9(*(%+.- !"(, 4(', .1 (% (%,$-./0 3.<#&2<# -0 7"$&" &.%,(&, 7$," ,"# (%,$+#%$&
/#,#'3$%(%, 8#4$,.4#9 $) #),(-<$)"#/5

9(%1+,-$ U$)#()#?&(2)$%+ .'+(%$)3

9#$+0&%+3#3 C'.&#)) -0 7"$&" 1<2$/) .' *#'0 )3(<< 4(',$&<#) ('# $%&.'4.'(,#/ $%,. ( &#<<5

9+G-K--5 '#%+,-$ L#&,$%) .1 !"#$%&'((' ')*+,('-'5 A% #K4#'$3#%,(< $332%.<.+0G ,"$)

!..-$5#2

69VS7 3$,.+#% $) 2)#/ 1.' ),$32<(,$.% .1 <034".&0,#) (%/ 3(&'.4"(+#)5

9*#'(*& *-3.+$3- A%$,$(< $332%# '#)4.%)# 8&#<<2<(' .' "23.'(<9 (1,#' ,"# 1$'), #K4.)2'# ,. (
)4#&$1$& (%,$+#%5

9*#'#$, !"# $%$,$(< )#%)$,$D(,$.% .1 ( &#<< ,. ( )4#&$1$& (%,$+#%5

" 93-)5+(//-/-3

93-)5+,-$-3
!(%/#3 *('$(%,) .1 ( +#%# ,"(, .&&240 %.%".3.<.+.2) 4.)$,$.%) .% ,"#
&"'.3.).3# 8#5+5G ;^95

R#%#) ,"(, "(*# ),'2&,2'#) ".3.<.+.2) ,. ,".)# .1 .,"#' +#%#) -2, ('#
%., #K4'#))#/5

H-0+$5(*& *-3.+$3- !"# $332%# '#)4.%)# ,. ,"# )#&.%/ #K4.)2'# (%/ #(&" )2-)#[2#%,
#K4.)2'# ,. ( )4#&$1$& (%,$+#%5

H-0*-%+*& 0+'.+$-$% ;.%),$,2#%, .1 )#&'#,.'0 A+=5 A, 1(&$<$,(,#) ,"# ,'(%)4.', .1 ,"# $332%.?
6H:7 +<.-2<$% ,"'.2+" ,"# $%,#),$%(< #4$,"#<$23 (%/ 4'.,#&,) $, 1'.3 4'.,#.?
<0,$& /#+'(/(,$.% -0 #%D03#)5

H+'(%#0 ')%(%#+$ W#(''(%+#3#%, .1 (%,$-./0 +#%#) .&&2') /2'$%+ P?&#<< 3(,2'(,$.%G

'#)2<,$%+ $% ,"# /#*#<.43#%, .1 ( 7$/# '(%+# .1 (%,$-./0 )4#&$1$&$,$#)5

H&$,-$-#0 =%$3(<) .1 $%-'#/ ),'($%) ('# )0%+#%#$& $1 (<< .1 ,"#$' (2,.).3(< 4($') ('#
$/#%,$&(<5

W81-/.-* 0-// :23(% !?"#<4#' 8!:9 <034".&0,#) -#(' (%,$+#% 3('M#') .1 ,"# ;U^
)2-&<())5 !"#0 4<(0 ( &#%,'(< '.<# $% ,"# $%$,$(,$.% (%/ 3($%,#%(%&# .1

!
$332%# '#)4.%)#)5 !"#0 '#&.+%$D# (% (%,$+#% .%<0 $1 $, .&&2') $% &.%?
_2%&,$.% 7$," ( &<()) AA 6:; 3.<#&2<#5

W+/-*($0- I,(,# .1 )4#&$1$& $332%.<.+$& 2%'#)4.%)$*#%#))5

<=X
E-,)/(%+*& W 0-// 6WE7
;/+33(*&

= '#+2<(,.'0 ! &#<< 8!W9 $) ( )244'#)).' ! &#<< ,"(, "() ( '#+2<(,.'0 #11#&, .%

!
,"# &.2')# .1 "23.'(< (%/ &#<<?3#/$(,#/ $332%# '#)4.%)#)5 :#%&#G !W
&#<<) 4<(0 (% $34.',(%, '.<# $% ,"# (*.$/(%&# .1 (<<#'+$& '#(&,$.%) (%/
(2,.$332%# /$)#()#)5

Y-$+,-$-#0 C#',($%$%+ ,. (%,$+#%$& /$11#'#%&#) -#,7##% /$11#'#%, )4#&$#)5

!..-$5#2
"

!
<=Z

"
 45+$6"+ +"210,7 2,1 0335($+2$0&, -+"10$(
!"#$%&# '&()*+,
!"#$%&&'(
!""#$ !%& '()*+,#- !./ !"#$%
&''()*+*,-. /()%0$*)# ")1
2$#*3143# *5 064 &''()4
7-#04'/ 0*(1#2314*(#5 6/7/
8#9-23:$ ;<& =>>?/
!""#$ !%& '()*+,#- !./ 84++(9
+"3 ")1 :*+4%(+"3 &''()*+9
*,-/ @+* 32/ 0*(1#2314*(#5
8#9-23:$& =>>A/
B3<:C3 !DE& F:)* ;G& 32$/ 2$",9
)*#0$% ")1 ;643"<4(0$% =)0$9
>*1$4#/ E<+<H#& ID5 .9,#-#
0:3$$& =>>>/
D#-3H#J ;!& E:#K3:$ 0& 6#14<:+
L& 8*1<,)*(M L/ &''()*9
>$*+*,-/ @+* 32/ G2(-"9:C*5
;*9:)*(11 '(K(-C$+<-3& =>>?/
%#9N,#-- 8.G& 8*3: !&
!*,32 O& 32$/ &''()*+*,-
*5 &)54%0$*(# 2$#4"#4#/ 6#P
$*(-C+<-& Q;5 !8L 0:3$$&
=>>=/
0#91 6G& 32/ /()1"'4)0"+ &'9
'()*+*,-/ R+* 32/ 0*(1#231P
4*(#5 '(44(-)<++PO#K3-&
?SSS/
O<(++ T& 7:<$+<NN D& L#13 Q& 32$/
&''()*+*,-/ U+* 32/ G2(-P
!
89:
"9:C*V I3H W<:M5 L<$"J& !:+*:(+($ #-2 O*39,#+($,/
=>>?/ L<-+*1J/ I3H W<:M5 D<*-
8311 8& L#X GG/ &''()*+*,-? 6(13J 8<-$/ T88I5 >>>RP
&''()*<"06*+*,-? ")1 &'9 A@S?/
'()$0-/ U+* 32/ 6#$*(-C+<-& ;9::3-+ ]4(-(<- (- T,,9-<1P
Q;5 !8L 0:3$$& =>>?/ <CJ/ 7(,<-+*1J/ '<-2<-5
;9::3-+ 7(<1<CJ/ T88I5
)"*"+",-" .&+'( >S@=PYS?@/
;9::3-+ ]4(-(<- (- O*39,#P
7#:)1#J !I& 7:<H- L.& '#H
+<1<CJ/ 7(,<-+*1J/ 0*(1#231P
8%!& 3+ #1/ ;64 @4(A*%-04
4*(#5 '(44(-)<++ 6(11(#,$
=)0$,4) /"%0#>**A/ =-2 32/
6(1M(-$/ T88I5 ?>R>PZY??/
8#- Q(3C<5 !)#23,() 0:3$$&
T,,9-(+J/ L<-+*1J/ ;#,P
?SSY/
":(2C3& L!5 ;311 0:3$$/
Q31K3$ 0D& O<(++ TL& 32$/ B)%-9
T88I5 ?>YRPYU?A/
%+*<41$" *5 &''()*+*,-/
D<9:-#1 <N T,,9-<1<CJ/ 83,(P
=-2 32/ 8#- Q(3C<5 !)#P
,<-+*1J/ 73+*3$2#& LQ5
23,() 0:3$$& ?SSZ/
!,3: !$$<) T,,9-<1<C($+$/
[(+\C3:#12 %!& ]^I3(11 '!D&
T88I5 >>==P?YUY/
B3#:(-C !D./ ;64 8-0*A$)4
E:3-2$ (- T,,9-<1<CJ/
/"%0#>**A/ =-2 32/ 8#- Q(3P
L<-+*1J/ ]XN<:25 G1$3K(3:
C<5 !)#23,() 0:3$$& =>>?/
8)(/ T88I5 ?RY?PRS>U/
/"+0&10-23(
!2K#-)3$ (- T,,9-<1<CJ/ !-P
-9#1/ 8#- Q(3C<5 !)#23,()
0:3$$/ T88I5 >>U@P=YYU/
!--9#1 O3K(3H <N T,,9-<1P
<CJ/ 0#1< !1+<& ;!5 !--9#1
O3K(3H$/ T88I5 >YA=P>@Z=/
 !"#$%&# #&'()*+ '*( ),,"-$#'$).* /#&()$-

!""#$%&'%()* +&,-(%$

!"# $%%&'()*($+, +, -*.# /01 B%%&'()*($+, =>I +, -*.# IMF

2*' *3*-(#3 4)+5 16+)75*, 2*' (*7#, 4)+5 O++%5*, 9:
89: ;*-#) <=: ;*5)*+&$ 1: #( P+Q"5 OR> '"()*&+"#,"( -&%
*%> !"# 4+)#$., *,($.#, ?$,3$,. ./0)*&1/&> ;(&((.*)(L !"$#5#:
'$(# *,3 ! @#%% )#@+.,$($+, )#A IFFJ>
.$+,' +4 @%*'' B "$'(+@+5-*(A
$?$%$(C *,($.#,'> !"#$%& DEF
GH@(+?#) IFJ0KL MIENIJ>

!
012

"
 !"#$%
!"#$%
!"#$% &'($ )*+,$-. /) !"#$!%& -$0$- #" /11*.#-'#/").
& '1T$"1/#/.
2 ')#/($) 3345 ''(
23 ')#/($) 3645 ')(
278 .9.#$+ 3345 ''(
: "-(') #9&/)( 3;65 '*+
: #-').&1')#
/++*)"($)/</#9 3;45 '*(
'<$#91<="1/)$ 6>?5 )+,
'<$#91<="1/)$ -$<$&#"- 6>?5
)+,
'<#/) 4@5 -'
'<#/)"+9<$#$.5 #=$-+"&=/1/<
63?5 )',
'<*#$ &".#.#-$&#"<"<<'1 (1"A
+$-*1")$&=-/#/. B2CDE!F
66;5 )).
'GG-$../). ;45 *(
'G=$./") +"1$<*1$ ,1"<H'G$
6;@5 )*'
'G-$)"<"-#/<'1 /).*00/</$)<9
6>@5 )+'
'G*1# IA<$11 19+&="+'J
1$*H$+/' 3>K5 3K65 '(+
'((1*#/)'#/")
: -$'<#/"). L;5 ..
: #$<=)/M*$. ?@5 /'
2NOD 3@?5 33@5 '''
: DP"Q(-$)R. .9)G-"+$ G/00$-A
$)#/'1 G/'()"./. 3S@
: T'<</)$ 6K6
: &00 #$&1 UNVJUNV /)0$<#/")
'/- <")G/#/")$- 1*)( 63?5 )',
'1G".#$-")$ 6665 ))+
'1H'1/)$ &=".&='#'.$ ?;5 /.
'11$-($). ;;5 *.
: <")P*)<#/T/#/. 6465 )-+
: <")#'<# 6@65 )2+
'11$-(/< '1T$"1/#/.5 $W#-/)./<
63?5 )',
!
&'(
'11$-(/< -=/)/#/. 6345 )'(
'11$-(9 >@@
: *-#/<'-/' 6@@
'11"/++*)/X'#/") 3645 ')(
'1&=' 0$#"&-"#$/) B2YCF 3K65
'(+
: <-9&#"($)/< 0/,-"./)( 63;5
)'.
: $W#-/)./< '11$-(/< 63?5 )',
: (-')*1"<9#/< 63;5 )'.3 63?5
)',
21X=$/+$-R. G/.$'.$ 34?
2Z[A3 ($)$ ?;5 /.
'+91"/G 25 .$-*+ 34?5 '-,
'+91"/G 2 '+91"/G"./. 34?5
'-,
'+91"/G"./. 34?5 '-,
: .$)/1$ 34?
: DP"Q(-$)R. .9)G-"+$ G/00$-A
$)#/'1 G/'()"./. 3S@
')'&=91'#"W/). ;@5 *'3 ;;
')'&=91'W/. >@@
: *-#/<'-/' 6@@
')'&1'.#/< 19+&="+' H/)'.$
B2[\F ($)$ 3>K
')$+/'
: '&1'.#/< 36;5 ').3 3;@5 '*'
: '*#"/++*)$ =$+"19#/<
36@5 ')'
: &$-)/</"*. 6@?5 )2,3 6>@5
)+'
')$-(9 3;45 '*(
')(/"$G$+' 3@;5 '2.
')(/"/++*)",1'.#/< 19+&='A
G$)"&'#=9 ]/#=
G9.&-"#$/)$+/' 3>K
')(/")$*-"#/< $G$+' ;@
')=9G-/G$. 63?
')/."<9#"./. 36@
')H91"./)( .&")G91/#/. 3L45
3L;5 '..
')#/A2 ')#/,"G/$. 334
')#/A7 ')#/,"G/$. 334
')#/A<'-G/"1/&/)
'*#"')#/,"G/$. 64?5 )-,
')#/A^O4 +")"<1")'1
')#/,"G9 6;@5 )*'
')#/A^O6@ +")"<1")'1
')#/,"G9 36@5 ')'3 3665
')+3 36;
: <')<$- #=$-'&9 3K;
')#/A^OSK +")"<1")'1
')#/,"G9 3K;
')#/A<$)#-"+$-$ ')#/,"G/$.
3??5 '/,
')#/AO!2 ')#/,"G/$. 3?;5 '/.
')#/AE7Z ')#/,"G/$. 66;
')#/AN^2ZA3 Z2, 6;@5 )*'
')#/A/G/"#9&/< )$#]"-H L65 .+
')#/A/)01'++'#"-9 G-*(.
6K45 )((
')#/A[' ')#/,"G/$. 3S@5 ','3
64?5 )-,3 6;>
')#/AZU^ ')#/,"G/$. 6;@
')#/A+/#"<=")G-/'1 ')#/,"G/$.
B2Z2F 6365 )'+
')#/A+9"<'-G/'1 ')#/,"G/$.
6>65 )++
')#/A)$*#-"&=/1 <9#"&1'.+/<
')#/,"G/$. B<A2!^2F 3S;5
',.3 63@5 66;
')#/A)*<1$'- ')#/,"G/$.
B2!2F 3;;5 3?45 3S@
: -=$*+'#/< G/.$'.$. 6;>
: .<1$-"G$-+' 3??5 '/,
')#/A-/,")*<1$'.$ C B_3A`!CF
')#/,"G/$. 3??5 '/,3 6;>
')#/A`" ')#/,"G/$. 3S@5 ','3
64?5 )-,3 6;>
')#/A.9)#=$#'.$ .9)G-"+$
3S65 ',+
')#/AI^` ')#/,"G/$. 6;@
')#/AI!Y ')#/,"G/$. 6;@5 )*'
')#/,/"#/<.
: '11$-(9 )2+
: +'<-"1/G$ 6K?5 )(,
')#/,"G/$.
: '00/)/#9 33?5 '',
: ,/.&$</0/< 3>65 '++3 3K;5 '(.
: <"1G 36@5 3665 ')+
: <"+&1$#$J/)<"+&1$#$ ?@5
33?5 '',
: G$#$<#/") ?@
: .$1$<#/T$ G$0/</$)</$. 3@@
: ]'-+ 36@5 ')'
: &00 #$&1 +")"<1")'1 ')#/,"A
G/$.

')#/,"G9AG$&$)G$)# <$11A
+$G/'#$G <9#"#"W/</#9
B2O^^F >?5 +,3 ;;5 *.33K;5
'(.
: +")"<1")'1 ')#/,"G/$.
6;@5 )*'
: #-').&1')# -$P$<#/") 3;45
'*(
')#/($) &-$.$)#/)( <$11.
B2C^.F 35 >@@
: '11$-(/< '.#=+' 6345 )'(
: '11"($)$/< #-').&1')#'#/")
3;@5 '*'
: <")#'<# G$-+'#/#/. 6@65
)2+
: &-"0$../")'1 6@5 L@5 3;45
'*(
: IA<$11 -$.&").$ /)G*<#/")
3K45 '((
: .'-<"/G"./. 63;
: I <$11 /)#$-'<#/"). >;5 +.
: #-').&1')# -$P$<#/") 3;45
'*(
')#/($). 3
: ,/)G/)( 4
: G$#$<#/") ?@
: U$/G$1,$-($- &-$</&/#'#/")
<*-T$ L;5 ..
: &='("<9#"./. 6;@5 )*'
: &-$.$)#'#/") K;5 (.
: '*#"')#/,"G9A+$G/'#$G
L@5 .'
: +")"<9#$. 465 -+
: &-"<$../)( 6@5 K;5 (.3 >@@
: .$M*$.#$-$G L65 .+3 3;6
: $9$ 64@5 )-'
')#/(1",*1/) #$.# 33?5 '',
')#/+$#',"1/#$ G-*(. 6K;5
)(.
')#/&=".&="1/&/G .9)G-"+$
3?45 6;4
')#/T/-'1 G-*(. 3365 ''+
2CA3 <"+&1$W 3?
2C22C /++*)"=/.#"<=$+/<'1
.#'/)/)( ?;5 /.
'&"&#"./. 365'+3 665 )+3 L45 .(
: <$)#-"<9#$. 645 )(
: <9#"#"W/</#9 #$.#. S65 ,+
: G$0/)/#/") >@@
: ($-+/)'1 <$)#$- -$'<#/")
645 )(
: +'#$-)'1 I 19+&="<9#$.
64?5 )-,
: !\ <$11 <9#"19#/<
+$<=')/.+. >?5 +,
: -$(*1'#/") L45 .(
'&"&#"./. -$<$&#"-. >?
'M*'&"-/). 4@
'-#=-/#/.
: P"/)#. 3;?5 '*,
: -$'<#/T$ 3L;5 '..
: &00 #$&1 "1/("'-#=-/#/.a &."-A
/'#/< '-#=-/#/.a -=$*+'#"/G
'-#=-/#/.a .&")G91'-#=-"A
&'#=9
2.<="00R. ,"G/$. 6>65 )++
'./'1"(19<"&-"#$/) -$<$&#"-
0'+/19 >45 +(
'.#=+'5 ,-")<=/'1 6345 )'(
'.#-"<9#$. 6>45 )+(
'#'W/' #$1')(/$<#'./' 3@65 '2+
'#"&9
: '.#=+' 6345 )'(
: G$-+'#/#/. 6@45 )2(
: H$-'#"<")P*)<#/T/#/. 646
'*#"')#/,"G/$. 3?65 '/+
: (1*#$)A.$)./#/T$
$)#$-"&'#=9 6@?5 )2,
: /)#$-<$&#/") "0 &'#="($)/<
6;@5 )*'
: .9.#$+/< 1*&*.
$-9#=$+'#".*. 3?;5 '/.
: .9.#$+/< T'.<*1/#/. 3S45 ',(
'*#"')#/($). L@5 .'
'*#"(-'0# &*-(/)( 3K?5 '(,
'*#"/++*)$ G/.$'.$ L65 .+
: '*#"')#/,"G/$. 3?65 '/+
: G/'()".#/< 6;4
: )$")'#'1 64?5 )-,
'*#"/++*)$ =$+"19./.
: <"1G ')#/,"G9 3665 ')+
: G-*(A/)G*<$G 3645 ')(
'*#"/++*)$ =$+"19#/<
')$+/' 36@5 ')'
'*#"/++*)$ &"19(1')G*1'-
.9)G-"+$ B2CDF 6>@5 )+'
'*#"/++*)$ -$.&").$ L@5 .'
: /)G*<#/") L65 .+
'T/G/) 3K?5 '(,
'W") G$+9$1/)'#/") 6>45 )+(
'X'#=/"&-/)$ 6K;5 )(.
'X/G"#=9+/G/)$ B2bIF 3365''+
' '-(3 34?
7 ')#/($) 3345 ''(
7A,1'.#. 645 )(
7A<$11 -$<$&#"- B7^`F
<"+&1$W >45 +(
!"#$%
7A<$11 #*+"-.5 &-$<*-."- 3>?5
'-2
7 <$11. B7 19+&="<9#$.F 35 6
: '<#/T'#/") 645 )(3 S;5 ,.
: G$T$1"&+$)# 45 665 )+
: G/00$-$)#/'#/")
: '..'9 S;5 ,.
: .<=$+$ >65 ++
: $W#-'0"11/<*1'- 66
: ($-+/)'1 <$)#$- -$'<#/")
645 )(
: /++*)"(1",*1/)
: $W&-$../") 6?5 ),
: +"G$1/)( G*-/)(
G/00$-$)#/'#/") >65 ++
: /)=/,/#/") ,9 1$01*)"+/G$
6K?
: 1/(=# <='/) -$.#-/<#/") >6
: 19+&= )"G$ ?
: Z2[I ?
: +'#*-'#/") 4
: +$+"-9 645 ;@5 *'
: +/(-'#/") ;45 *(
: &-"($)/#"- >65 ++
: &-"1/0$-'#/") S;5 ,.
: -$</-<*1'#/") ?
: -=$*+'#"/G '-#=-/#/. 3;?5
'*,3 3L@5 '.'
: /+&'/-$G -$(*1'#/") 3L65
'.+
: .$&'-'#/") ??5 /,
: .&1$$) ?
: I <$11 /)#$-'<#/"). ]/#=
2C^. >;5 +.
,'</11$ ^'1+$##$:E*c-/) B7^EF
: /++*)"#=$-'&9 3K4
: T'<</)$ 6K@5 )('
,'<#$-/'1 '((1*#/)'#/") ?@
,'."&=/1 G$(-')*1'#/") ;@5
*'
4#5 ($)$ L45 .(
4%$6) ($)$ L45 .(
789::7; #-').1"<'#/") 3K65
'(+
7$=<d$#R. .9)G-"+$ 3?@5 '/'
: "<*1'- +')/0$.#'#/"). 64;5
)-.
!
: *T$/#/. 64;5 )-.
7$)<$ e")$. &-"#$/) 3465 3445
,/1/'-9 </--="./.5 &-/+'-9 63@5
6365 )'+
7/-,$<H (-')*1$. 4@5 44
,/-G ,-$$G$-R. 1*)( 63?5 )', &')
"
 !"#$%
,/-G.="# <="-/"-$#/)"&'#=9
6445 )-(
,1""G
: <"-G 3;@
: ".+"#/< &-$..*-$ 6665 ))+
: -$0$-$)<$ T'1*$. 6;L
: #9&/)( 3345 ''(3 33;5 ''.
: &00 #$&1 278 .9.#$+a -=$.*.
B`=F .9.#$+
,1""G #-').0*./") 366
: -$'<#/"). 3645 ')(
,")$ +'--"] 65 4
: +*1#/&1$ +9$1"+' 344
,")$ +'--"] #-').&1')#'#/")
: '11"($)$/< 3;@5 '*'
: '*#"1"("*. 3K?5 '(,
7"]+')R. <'&.*1$ 6665 66;
,-'/) G$'#= 3;65 '*+
,-$'.# <')<$- #=$-'&9 3K;5
6;@
,-$'.# +/1H 6?5 ),
,-")<=/'1
=9&$--$.&")./T$)$..
6345 )'(
,-")<=*.A'.."</'#$G 19+A
&="/G #/..*$ B72[IF ,
7-*#")R.
'('++'(1",*1/)$+/'
3@@5 '2'
,*11"*. &$+&=/("/G 6@;5 )2.
7*-H/##R. 19+&="+' 3>S5 '-2
,9.#')G$- $00$<# 3K;
( : IA<$11 '<#/T'#/") 3;5 ',
^3 /)=/,/#"- ;@
: G$0/</$)<9 3@;5 '2.
^3M ."1/G &='.$ c[ND2 ?65 /+
^> <")T$-#'.$ 6645 ))(
^> )$&=-/#/< 0'<#"- 6645 ))(
^> &-"#$/) K?5 (,3 ;@5 *'
: -$(*1'#/") 3@;
^>' ;;5 *.
^K <")T$-#'.$ K?5 (,
^K &-"#$/) ;@5 *'
^K' ;;5 *.3 6665 ))+
<'1</)$*-/) 3?
!
<'1+"G*1/) 3?
<'1)$W/) K45 ((
8#<=>$14#%"0? @0@AB! 6>;5
)+.
<')<$-
&*' : ')#/,"G9 #=$-'&/$. 3K;5
'(.
: ,-$'.# <')<$- 3K;5 6;@
: <"1"-$<#'1 <'-</)"+' 63@
: /++*)".*-T$/11')<$ 6@
: 1*)( <')<$- 6>?5 )+,
: &'-')$"&1'.#/< )$*-"1"(/<'1
.9)G-"+$. 6>;5 )+.
: -$)'1 <$11 <'-</)"+' 3K45
'((
: .9.#$+/< T'.<*1/#/. 3S45 ',(
: &00 #$&1 <=$+"#=$-'&9a 1$*A
H$+/'a 19+&="+'a #*+"-
')#/($).a #*+"- <$11.a #*A
+"- /++*)"1"(9
8#BC!C# $."&='(/#/. 33@5 '''
<')G/G/'./. 6>@5 )+'
<'-</)"$+,-9")/< ')#/($)
B^c2F 3K65 '(+
<'-</)"+' <$11.5 ^O4@
$W&-$../") >45 +(
<'-#/1'($5 &"19<=")G-/#/. 3?@5
'/'
<'.&'.$ '<#/T'#/") ,9
+/#"<=")G-/' L45 .(
^O B<1*.#$- "0 G/00$-$)#/'#/")F
')#/($). 365 '+3 3;
: G$0/)/#/") >@3
: )"+$)<1'#*-$ 6L@:L
^O3 3@5 ''3 3;5 '.3 6L@
^O3' 465 6L@
^O6 3@5 ''3 3;5 '.3 6L@
^O> 3@5 ''3 3;5 '.3 6L@
: ,/.&$</0/< ')#/,"G/$. 3K;5
'(.
: 01"] <9#"+$#-9 ?45 /(
^O4 345 '(3 3;5 '.3 6;5 ).3 6L@
: 01"] <9#"+$#-9 ?45 /(
: .*-0'<$ .#'/)/)( S45 ,(
: IA<$11 '<#/T'#/") 3?5 ',
^O4f I <$11. 6@
: '<#/T'#/") K45 ((
: '11$-(/< '.#=+' 6345 )'(
: G$-+'#"+9"./#/. 3S65 ',+
: $W#-/)./< '11$-(/< '1T$"1/#/.
63?
: UNV /)0$<#/") 3@?5 '2,3 3365
''+
: /G$)#/0/<'#/") S45 ,(
: /)=/,/#/") 6;@5 )*'
: +9'.#=$)/' (-'T/. 6>?5 )+,
: -$(*1'#"-9 0*)<#/") L6
: .'-<"/G"./. 63;
: .<1$-"G$-+' 3??5 '/,
: .9)"T/'1 +$+,-')$ 3;?5
'*,
: #*,$-<*1"./. (-')*1"+'
66@5 ))'
: T$-)'1 <")P*)<#/T/#/. 646
^OK 3;5 '.3 6L@
^OKf 7 <$11. 665 )+
^OL 3@5 ''3 3;5 '.3 6L@
^O? 3@5 ''3 345 '(3 6;5 ).3 6L@
: 0*)<#/") 3;5 '.
: =$1&$- +"1$<*1$ K@5 ('
: .#-*<#*-$ 3;5 '.
: .*-0'<$ .#'/)/)( S45 ,(
: IA<$11 '<#/T'#/") 3?5 ',3 >;
^O?f I <$11.
: <"))$<#/T$ #/..*$ 3;?
: $W#-/)./< '11$-(/< '1T$"1/#/.
63?5 )',
: U'.=/+"#"R. #=9-"/G/#/.
66?5 )),
: UNV /)0$<#/") 3365 ''+
: /G$)#/0/<'#/") S45 ,(
: &"19+9"./#/. 3S65 ',+
: -$(*1'#"-9 0*)<#/") L6
: .9+&'#=$#/< "&=#='1+/'
64;5 )-.
: #*,$-<*1"./. 66@5 ))'
: #*+"- ')#/($)
&-$.$)#'#/") 3K@5 '('
^O3@ >65 ++3 >45 +(3 6L@
^O33 465 -+3 6L@
^O34 465 -+3 6L@
: +9<",'<#$-/'1 ')#/($).
66@5 ))'
^O3; 465 -+3 6L@
^O3? 465 -+3 6L@
^O3S 665 )+3 6;5 ).3 >65 ++3
6L@
: $W&-$../") >45 +(
^O6@ 6L@
: &00 #$&1 ')#/A^O6@ +")"A
<1")'1 ')#/,"G9
^O63 665 )+3 >65 ++3 6L@
: $W&-$../") >45 +(
^O66 665 )+3 6;5 ).3 >65 ++3
6L@
: ')#/,"G/$. ?;5 /.
: $W&-$../") >45 +(
^O6> 665 )+3 645 )(3 >65 ++3
6L@
: $W&-$../") >45 +(3 S;5 ,.
^O6K 6@5 S;5 ,.3 6L3
^O6? 3;5 '.3 6@5 )'3 6L3
: ^O?@J^O?; /)#$-'<#/") >45
+(3 >;5 +.
^O6S 3@5 ''3 6L3
^O>6 465 -+3 6L3

^O>4 665 )+3 >65 ++3 6L3
^O>4f .#$+ <$11. 3K?5 '(,3
3;@
^O>; L45 .(3 6L3
^O>L 665 )+3 6L3
^O>? 645 )(3 6L3
^O>S 665 )+3 645 )(3 6L3
^O4@ >45 +(3 465 -+3 6L3
^O4@J^O4@ 1/(')G .9.#$+
6@5 )'3 645 )(3 >45 +(3 6L3
: 7 <$11 &-"1/0$-'#/") S;5 ,.
: I <$11 /)#$-'<#/"). ]/#=
2C^. >;5 +.
^O4K`2 3@5 ''3 6L3
: IA<$11 '<#/T'#/") 3?5 ',
^O4K`8 3@5 ''3 3;?5 6L3
^O4; 3;65 '*+3 6L3
^O4SG >;5 +.3 6L3
^OK4 6;@5 6L6
^OKK 3;65 '*+3 6L6
^OK; 6;5 ).3 6L6
^OK? 3;5 '.3 6L6
^OKS 3;65 '*+3 6L6
^O;4 465 -+3 6L6
^O;? 465 -+3 6L6
^O;S S;5 ,.3 6L6
^OL3 S;5 ,.3 6L6
^OL6 >45 +(3 6L6
^OLL 645 )(3 6L>
^O?@ 6@5 )'3 6L>
: ')#/($) &-$.$)#'#/") 465
-+
: $W&-$../") >45 +(
: I <$11 '<#/T'#/") >;5 +.3 3K45
'((
^O?> 465 -+3 6L>
^O?; >45 +(3 6L>
: ')#/($) &-$.$)#'#/") 465
-+
: I <$11 '<#/T'#/") 3K4
^OSK L45 .(3 3K;5 6L>
^O3@; >;5 +.3 6L>
^O33L 665 )+3 >65 ++3 6L4
^O3K6 3;5 '.3 >;5 +.3 6LK
^O6@K 465 6L;
^O6@; 6L;
: &00 #$&1 +'))".$ -$<$&#"-
<$11 <"*)#5 G/00$-$)#/'1 6;L
<$11 <9<1$ ')'19./. S@
<$11 0-'<#/").5 ')#/,"G9A
+$G/'#$G .$&'-'#/") ??5
/,
<$11 ="+$".#'./. L4
<$11 .$&'-'#/")5 01"]
<9#"+$#-9 ??5 /,
<$)#-",1'.#. ?5 645 )(
<$)#-"<9#$. ?5 645 )(
<$-$,-".&/)'1 01*/G B^DYF -$A
0$-$)<$ T'1*$. 6;S
^='('.R G/.$'.$ 6>65 )++
<='&$-")$ &-"#$/). K;
^=$G/'H:U/('.=/ .9)G-"+$
3@45 '2(
<=$+/<'1 ]"-H$-R. 1*)( 63?5
)',
<=$+"H/)$B.F 65 ;45 *(3
6??:SS
: <")#'<# G$-+'#/#/. 6@6
: UNV /)0$<#/") #-$'#+$)#
336
<=$+"H/)$ -$<$&#"-. ;45 *(3
3365 ''+
: O*009 ')#/($) 33;5 ''.
<=$+"#'<#/< 0'<#"-. 4
<=$+"#'W/. 465 -+3 ;@5 *'3
>@3
<=$+"#=$-'&9
: U"G(H/)R. G/.$'.$ 3>65 '++
: "-(') G'+'($ 3;@5 '*'
: .#$+ <$11 -$/)0*./") 3K?5
'(,
<="1$-' T'<</)$ 6K@5 )('
<="1$.#$-"1 636
<="-/"-$#/)/#/. 6445 )-(3 64;5
)-.
<="-/"-$#/)"&'#=95 ,/-G.="#
6445 )-(
<="-"/G/#/.5 +*1#/0"<'1 64;5
)-.
<=-"+$ '11$-(9 ;;5 )2+
<=-"+/*+ -$1$'.$ '..'9 S6
<=-"+"."+$ L 345 '(
<=-"+"."+$ ?%63 #-').1"<'A
#/") ?;5 /.
<=-"+"."+$ 34 345 '(
^=*-(:D#-'*.. .9)G-"+$
3S;5 ',.3 6;;
</1/'-9 ,"G9 6445 )-(
: $G$+' 64;
<1'.. NN '.."</'#$G /)T'-/')#
<='/) &$&#/G$ B^[NCF K4
<1'#=-/) 4@5 -'
<1")'1 $W&')./") 3
8$1&"?!C!A< "0"#B! 6K@
<"'(*1'#/") -$0$-$)<$ T'1*$.
6;?
<"1G =$+'((1*#/)/) G/.$'.$5
<=-")/< /G/"&'#=/< 3665
')+
<"11'($) #9&$ VNN 6@;
!"#$%
<"1"-$<#'1 <'-</)"+' 63@
<"++") '<*#$ 19+&=",1'.#/<
1$*H$+/'A'.."</'#$G
B^2[[2F ')#/($) &00 ^O3@
<"++") 1$*H"<9#$ ')#/($)
3@
<"++") T'-/',1$
/++*)"G$0/</$)<9 3@@5
'2'
<"+&1$+$)#
: '<#/T'#/") K?5 (,3 6465 )-+
: '<#/T/#9 -$(*1'#/") ;@5 *'
: '1#$-)'#/T$ &'#=]'9 K?5 (,
: ^>G 0-'(+$)# -$<$&#"- >6
: <'.<'G$ '<#/T'#/") 3K;5 '(.
: <1'../<'1 &'#=]'9 K?5 (,
: <1$'T'($ G$&"./#. 6665 ))+
: <"+&")$)#. >@3
: /++*)"1"(/<'1 $00$<#. ;@5
*'
: /)01'++'#"-9 $00$<#. ;@5 *'
: 19#/< #$-+/)'1 .$M*$)<$ K?5
(,
: #$'- 01*/G 6465 )-+
<"+&1$+$)#A,/)G/)(
-$'<#/") ?@5 /'
<"+&1$+$)# -$<$&#"-. B^`F
4@5 -'3 465 -+
: G$0/</$)<9 3@;
: #9&$. 3:> B^`3:^`>F ;@5 *'
<"+&1$+$)#'-/#9AG$#$-+/)A
/)( -$(/"). B^O`F 6;5 ).3
>@6
: (-'0#/)( 6;@
<"+&".# 1*)( 63?5 )',
<")P*)<#/T'5 (/')# &'&/11'$
6465 )-+
<")P*)<#/T/#/. 6465 )-+
<"))$<#/T$ #/..*$5 ^O?f I <$11.
3;?
<"))$<#/T$ #/..*$ G/.$'.$
3?4:SS
: .<1$-/#/. 6465 )-+
^""+,. #$.# 33?5 '',
<"-)$'5 &'#="1"(9 6465 )-+
<"-)$'1 (-'0#/)( 3;65 '*+
<"-)$'1 *1<$-. 6465 )-+
!
<"-#/."1 -$0$-$)<$ T'1*$. 6;S
81?>B04#%"0?!A< C!=D"D0?!#0
6K@
<"*)#$-<*--$)#
$1$<#-"&="-$./. L?5 .,
^8g3 ')G ^8g6 6K45 )((
^"W.'<H/$T/-*. 6>@5 )+'3 6>65 &**
"
)++
 !"#$%
<-')/'1 '-#$-/#/. 3S?
^`cDI .9)G-"+$ 3??5 '/,
^-"=)R. G/.$'.$ 63@5 )''
: '*#"/++*)$ =$&'#/#/. 6365
)'+
<-9"(1",*1/)$+/' 34;5 '-.
: '*#"/++*)$ =$&'#/#/. 636
: $..$)#/'1 T'.<*1/#/. 6;;
<-9"(1",*1/). 34;5 '-.
<-9&#"($)/< 0/,-"./)(
'1T$"1/#/. 63;5 )'.
^I[2A4 &00 ^O3K6
<9<1/#/. 6445 )-(
<9<1""W9($)'.$ /)=/,/#"-.
6K45 )((
<9<1"&=".&='+/G$ 6K;5 )(.
<9<1".&"-/) 2 6K?5 )(,
<9#"<=-"+$ 4KK? G$0/</$)<9
3@45 '2(
<9#"H/)$ +/1/$* 6@5 )'
<9#"H/)$ .$<-$#/") '..'9 S45
,(
<9#"H/)$. 35 65 6L?:?L5 >@6
: <")#'<# G$-+'#/#/. 6@65
)2+
: ($)$. 3?5 ',
: /)01'++'#"-9 ;45 6>;5 )+.
: /)#-'<$11*1'- .#'/)/)( S45 ,(
: H$-'#/#/. 646
<9#"+$('1"T/-*. B^ZVF 33@5
'''3 3665 ')+
: '11"($)$/< "-(')
#-').&1')#'#/"). 3;65 '*+
: <=$+"#=$-'&9
<"+&1/<'#/"). 3;@5 '*'
: E*/11'/):7'--c .9)G-"+$
6>;5 )+.
: &')*T$/#/. 64;5 )-.
<9#"&$)/'. 334:6L
<9#"#"W/< -$'<#/").5 ')#/,"G9A
+$G/'#$G ;;5 *.
<9#"#"W/< I 19+&="<9#$.
B^I[.F
: ')#/($)A.&$</0/< S6
: &00 #$&1 ^O?
<9#"#"W/</#9 #$.# S65 ,+
)
!
O'1$):Y*<=. )"G*1$. 64;5
)-.
O^A3 ')G O^A6 <$11. 4;5 -.
&*+ G$<'9A'<<$1$-'#/)( 0'<#"-
BO2YF ;@5 3;65 '*+
G$0$).$ +$<=')/.+.5
)")<1")'1 3
G$)G-/#/< <$11. 65 365 '+3 4@5 -'3
445 -(
: ')#/($) $W&-$../") 465 -+
: ')#/($)A&-$.$)#/)( ;?5 *,
: ^O4@ $W&-$../") >45 +(
: G$0/)/#/") >@6
: ($-+/)'1 <$)#$- 4@5 -'
: /))'#$J'G'&#/T$ /++*)/#9
1/)H ;65 *+
: /)#$-G/(/#'#/)( 4@5 -'
: /)#$-.#/#/'1 445 -(
: 1/0$ <9<1$ 445 -(
: 19+&="/G 4@5 -'
: +'#*-'#/") 4;5 -.
: +/(-'#/") 445 -(3 ;45 *(
: +")"<9#$AG$-/T$G 445 -(
: I <$11 /)#$-'<#/"). ]/#=
2C^. >;5 +.
: #$1"($)/< &"#$)#/'1 4;5 -.
: IU -$.&").$ &"1'-/X'#/")
4;5 -.
G$-+'#/#/.
: '#"&/< 6@45 )2(
: <")#'<# 6@65 )2+
: =$-&$#/0"-+/. 6@;5 )2.3
6@?
: #"W/< 6@65 )2+
G$-+'#"+9"./#/. 3?65 3S65
',+
G$.+"(1$/). 6@;
O/ E$"-($ .9)G-"+$ 3@65 '2+
G/',$#$. +$11/#*. L65 .+3 6>@5
)+'
G/'<91(19<$-"1 BO2EF 3?5 ',
G/=9G-""-"#'#$ G$=9G-"($)A
'.$ BOU8AOUF 6K?5 )(,
G/&=#=$-/' T'<</)$ 6K@5 )('
G/..$+/)'#$G /)#-'T'.<*1'-
<"'(*1'#/") BON^F 33?
O!2
: G"*,1$A.#-')G$G 3?;5 '/.3
6;>
: &*-/0/$G 0"- T'<</)$. 6K6
: .$M*$)</)( S?5 ,,
: ./)(1$A.#-')G$G 6;>
: .9)#=$./. 6K?5 )(,
O!2 &-",$. ?;5 /.
O` ')#/($). 4?5 -,3 K@5 ()3 L65
.+
: &00 #$&1 !BC!E!CA#$ U[2AO`&
O-$..1$-R. .9)G-"+$ 6>65
)++
G-*( ',*.$ 6645 ))(
O*009 ')#/($). 3645 ')(
O*009 ,1""G (-"*& .9.#$+
33;5 ''.
O*=-/)(R. G/.$'.$ 6@;5 )2.
G9.('++'(1",*1/)$+/' 3@@5
'2'
*
$<X$+' 6@65 )2+
$1$<#-"/++*)"G/00*./") L?5
.,
$1$<#-"&="-$./.
: +$#="G. L?5 .,
: -$0$-$)<$ T'1*$. 6;L
$)G"<9#"./. +$<=')/.+. 4@5
-'
$)G"+9./*+ 6@;5 6@?
$)X9+$A1/)H$G /++*)"."-A
,$)# '..'9 Bc[ND2F ?65 /+
: UNV /)0$<#/") G/'()"./.
3365 ''+
$)X9+$A1/)H$G /++*)"."-A
,$)# .&"# '..'9 Bc[NDC8IF
S45 ,(3 S;5 ,.
$)X9+$ -$0$-$)<$ T'1*$. 6;?
$"./)"&=/1.
: #*,*1"/)#$-.#/#/'1 )$&=-/#/.
66;
: T$-)'1 <")P*)<#/T/#/. 646
$&/G$-+"19./. ,*11".'
'<M*/./#' 6@;5 )2.
$&/.<1$-/#/. 6465 )-+
$&/#=$1/'1 <$11.5 ^O4@
$W&-$../") >45 +(
$&/#"&$ >@6
: .&-$'G/)( 3?;5 '/.
c&.#$/):7'-- T/-*. Bc7VF 33@5
'''3 3665 ')+
: E*/11'/):7'--c .9)G-"+$
6>;5 )+.
: -$<$&#"- >6
: T/-'1 &-"#$/). 3K6
$-9#=$+' +'-(/)'#*+ 6>65
)++
$-9#=$+' )"G".*+ 63;5 )'.
$-9#=-",1'.#. 6
$-9#=-"<9#$ .$G/+$)#'#/")
-'#$ 6;L
$-9#=-"<9#$. 6
: &='("<9#"./. 33?
cI8 ($)$ ?;5 /.
$W"&=#='1+". 66?5 )),

$W&$-/+$)#'1 '*#"/++*)$
$)<$&='1"+9$1/#/. Bc2cF
6>45 )+(
$W&$-/+$)#'1 '*#"/++*)$
*T$"-$#/)/#/. Bc2_F 64@5
)-'
$9$ 64@5 )-'
: <"-)$'1 (-'0#/)( 3;65 '*+
: H$-'#"&1'.#9 3;65 '*+
: &-"#$<#/T$ +$<=')/.+.
64@5 )-'3 6465 )-+
: .9+&'#=$#/< "&=#='1+/'
L65 64;5 )-.
: .9.#$+/< G/.$'.$
+')/0$.#'#/"). 64;5 )-.
: &00 #$&1 "&=#='1+/< G/.A
$'.$.a *T$/#/.
$9$,'11 &$-0"-'#/") 6465 )-+
+ : ')#/,"G/$. 66;
0'-+$-R. 1*)( 63?5 )',
Y'. 1/(')G. 64?5 )-,
Y< -$<$&#"-. 6?5 ),3 4@5 -'
Y$1#9R. .9)G-"+$ 36;5 ').
0/,-",1'.# (-"]#= 0'<#"- 3L@5
'.'
0/,-")$<#/) -$<$&#"- 3@
01"] <9#"+$#-9 ?45 /(
: <$11 .$&'-'#/") ??5 /,
01*"-$.<$/) /."#=/"<9')'#$
BYNI^F ?45 /(
01*"-$.<$)<$A'<#/T'#$G <$11
."-#$- BY2^DF ??5 /,
01*"-$.<$)<$ $+/../") ?45 /(
01*"-$.<$)# !B &!"A =9,-/G/X'A
#/") BYNDUF ?;5 /.
0"<'1 .$(+$)#'1
(1"+$-*1".<1$-"./. 6645
))(
0"11/<*1'- G$)G-/#/< <$11.
BYO^.F 645 )(
: 7A<$11 +/(-'#/") ;45 *(
: ^O4@ $W&-$../") >45 +(
<AF1& 3?5 ',
Y*<=R. G/.$'.$ 6445 )-(
0*)('1 ')#/($). 63?5 )',
, 3645 ')(
('++'A(1",*1/) &-"1/0$-'#/")5
&"19<1")'1 E& +")"<1")'1
3465 '-+
('.#-/#/.5 <=-")/< '#-"&=/<
6@?5 )2,
('.#-"/)#$.#/)'1 G/.$'.$.
6@?:3>
($)$.5 /)T$-./")J
-$'--')($+$)# 345 '(
($)$#/< <"))$<#/T$ #/..*$
G/.$'.$ 3?6
($-+/)'1 <$)#$- G$)G-/#/< <$11.
BE^O^F 4@5 -'
($-+/)'1 <$)#$- -$'<#/") 665
645 )(
(/')# <$11 '-#$-/#/. 3S?5 ',,3
6;;
(/')# <$11. 3L65 '.+
(/')# &'&/11'-9 <")P*)<#/T/#/.
646
(1/'G/) 6@?5 )2,
(1"+$-*1'- ,'.$+$)#
+$+,-')$ ;;5 6665 ))+
(1"+$-*1")$&=-/#/.
: '*#"/++*)$ =$&'#/#/. 6365
)'+
: +$+,-')"&-"1/0$-'#/T$
6645 ))(
: +$+,-')"*. 6645 ))(
: +/)/+'1 <=')($ 666
: &'*</A/++*)$ 66;5 )).
: &".#/)0$<#/"*. 66;5 )).
: -'&/G19 &-"(-$../T$ 6665
))+3 66;5 )).
(1"+$-*1".<1$-"./.5 0"<'1
.$(+$)#'1 6645 ))(
(1*<"<"-#/<"/G. 6K45 )((
(1*#'+'#$ G$<'-,"W91'.$ ;K
BE2O;KF 6>@5 )+'
(1*#'+'#$ -$<$&#"- BE1*`>F
6>;5 )+.
(1*#$)A.$)./#/T$ $)#$-"&'#=9
6@?5 )2,
(19<".91&=".&='#/G91/)"./#"1
BECNF K?5 3@;5 '2.
(",1$# <$11. 634
("1G #=$-'&9 6K;5 )(.
E""G&'.#*-$R. .9)G-"+$ ;;5
66;
E"##-")R. ./() 3S65 ',+
("*# 3?@5 '/'
(-'0#AE0?&A&A=".# -$'<#/")
: '11"($)$/< #-').&1')#'#/")
3;@5 '*'
(-'0#AE0?&A&A1$*H$+/' $00$<#
3;@5 '*'
!"#$%
(-')*1"<9#$ <"1")9 .#/+*1'#A
/)( 0'<#"- BEA^DYF 4@5 -'3
6?4:K
: -$<"+,/)')#
=$+'#"&"/$#/< 3K?5 '(,
(-')*1"<9#$:+'<-"&='($ <"1A
")9 .#/+*1'#/)( 0'<#"-
BEZA^DYF 6@5 )'3 4@5 -'3
6?4:K
: -$<"+,/)')#
=$+'#"&"/$#/< 3K?5 '(,
: -=$*+'#"/G '-#=-/#/. 3L@5
'.'
(-')*1"<9#$. 35 4@5 -'
: '<#/T'#/") ;@
: #$'- 01*/G 6465 )-+
: #*,*1"/)#$-.#/#/'1 )$&=-/#/.
66;
(-')*1"+'#"*. G/.$'.$5
<=-")/< 64;
(-')X9+$. S65 3K;5 '(.
E-'T$.R G/.$'.$ 66?5 )),
E-*,$- +$#="G ?@
E*/11'/):7'--c .9)G-"+$
6>;5 )+.
(*#A'.."</'#$G 19+&="/G #/.A
.*$ BE2[IF ,
-
U ')#/($) 334
G#0<1=D!$A& !BF$A0BH#0
T'<</)$ 6K@5 )('
='/- G9$. )2+
='&#$). ;;5 *.3 3645 6@6
: G$0/)/#/") >@6
='&#"(1",/) 33?5 36@5 ')'
U'.=/+"#"R. #=9-"/G/#/. 6@?5
66?5 )),
: '*#"/++*)$ =$&'#/#/. 6365
)'+
U'..'11R. ,"G/$. ;5 .
=$'-# G/.$'.$ 6>65 )++
=$'-# .*-($-9 6>65 )++
=$'T9 <='/) G/.$'.$ 3465 '-+
U$/G$1,$-($- &-$</&/#'#/")
!
<*-T$ L;5 ..
=$+'((1*#/)'#/") ?@5 /'
=$+'#"1"(/<'1 G/.$'.$
36?:4S
=$+"G/'19./.A'.."</'#$G
'+91"/G"./. 34?5 '-,
=$+"(1",/)A,/)G/)( &-"#$/) &*&
"
33?5 36@5 ')'
 !"#$%
=$+"19./.
: '*#"/++*)$ 3665 ')+3 3645
')(
: <1/)/<'1 ./(). 36@5 ')'
: /))"<$)# ,9.#')G$-
+$<=')/.+ 3645 ')(
: +$<=')/.+. 33?5 '',
=$+"19#/< ')$+/'5
'*#"/++*)$ 36@5 ')'
=$+"19#/< G/.$'.$ 334:6L
: "0 #=$ )$],"-) 33;5 ''.
=$&'#/#/.
: '*#"/++*)$ 63@5 )''3 6365
)'+
: &"19(1')G*1'- .9)G-"+$
6>@5 )+'
: *-#/<'-/' 6@@
=$&'#/#/. 7
: +$+,-')"&-"1/0$-'#/T$
(1"+$-*1")$&=-/#/. 6645
))(
: T'<</)$ 6K@5 )('
=$&'#/#/. ^ /)0$<#/") 34;5 '-.
: +$+,-')"&-"1/0$-'#/T$
(1"+$-*1")$&=-/#/. 6645
))(
=$-&$. ./+&1$W T/-*. BUDVF5
H$-'#/#/. 6465 )-+
=$#$-"<=-"+/< *T$/#/. 6445
)-(
U$9+'))R. )$&=-/#/. 666
=/(= $)G"#=$1/'1 T$)*1$.
BUcVF 45 ;45 6445 )-(
=/.#")$. 6;>
=/.#"&1'.+"./. 6445 )-(
UNVJUNV /)0$<#/") 3@?5 '2,
: '11"($)$/< "-(')
#-').&1')#'#/"). 3;65 '*+
: <"*-.$ 33@5 '''
: G/'()"./. 3365 ''+
: 0"<'1 .$(+$)#'1
(1"+$-*1".<1$-"./. 6645
))(
: ($)"+$ .#-*<#*-$ 3@?5 '2,
: =".# <$11 ,/)G/)( 3@?5 '2,
: /++*)$ .9.#$+ -$.&").$
33@5 '''
: &')*T$/#/. 64;5 )-.
!
: -$&1/<'#/") <9<1$ 3@?5 '2,
: .*.<$&#/,1$ <$11. 3@?5 '2,
: #-$'#+$)# .#-'#$(/$. 3365
''+
: T'<</)$. 3365 ''+
&*, : T/-/") .#-*<#*-$ 3@?5 '2,
: &00 #$&1 2NOD
U[2 <"+&'#/,/1/#9 3;@5 '*'3
3L@5 '.'
U[2 <"+&1$W
: <1'.. N +"1$<*1$ K@5 ('
: <1'.. NN
: ',$--')# ')#/($). L@5 .'
: '11$1$. K@5 ('
: -=$*+'#"/G '-#=-/#/. 3L@5
'.'
: G/.$'.$ -$1'#/").=/& L65 .+
: OC '11$1$. K@5 (+
: Oh '11$1$. K@5 (+
: O` '11$1$. 4?5 -,3 K@5 ()
: G/.$'.$ '.."</'#/"). L65
.+
: ($)"+/< "-(')/X'#/") 4?5 -,
U[2A2> 6@?
U[2A26S 6445 )-(
U[2A7K 64;
U[2A7L 6@?
U[2A7? 6@;5 6@?5 6365 )'+
: E-'T$.R G/.$'.$ 66?5 )),
: +9'.#=$)/' (-'T/. 6>?5 )+,
U[2A73> 6@;5 )2.
U[2A76L L65 3L45 '.(
: &-$T'1$)<$ 3L;5 '..
: .&")G91'-#=-"&'#=9 3L;5
'..3 3L?5 '.,
: *T$/#/. 6445 )-(
U[2A7K6 3?@5 '/'
U[2A^]; 6@;5 )2.
U[2AO> 6>?5 )+,
U[2AO;h 6>45 )+(
U[2AOh3 3S@5 ','
U[2AOh6 3S@5 ','
U[2AOh]K 63@5 )''
U[2AO`3 63@5 )''
U[2AO`6 6@?
U[2AO`> 3S@5 ','3 6@;5 6@?5
6365 )'+
: E-'T$.R G/.$'.$ 66?5 )),
: U'.=/+"#"R. #=9-"/G/#/.
66?5 )),
U[2AO`4 3S?5 6@?5 64;
U[2AO`K 66?5 )),
U[2AO`L 6@;5 )2.
U[2AO`3K 6>45 )+(
U[2AE 64?5 )-,
U[2 #9&/)( 3;65 '*+
U[2]K>f 64;
U"G(H/)R. G/.$'.$ 36@5 ')'3
3>@5 '+'3 3>65 '++
: -/#*W/+', 6;@
="-+")$ -$.&").$ $1$+$)#.
6K4
U"-#")R. '-#$-/#/. 3S?
UI[VA3 3>K5 3K65 '(+
U* ')#/($) 6>;5 )+.
=*+') ')#/A+*-/)$ ')#/,"A
G/$. BU2Z2F 3K;5 '(.
=*+') =$-&$. T/-*. ? BUUVA
?F 33@5 344
=*+') 1$*H"<9#$ ')#/($) &00
U[2 <"+&1$W
=9,-/G"+' <$11. 3K@5 '('3 >@6
=9&$-AN(Z .9)G-"+$ 3@@5'2'
=9&$-('++'(1",*1/)$+/'
63;
=9&$-1/&/G$+/' 6665 ))+
=9&$-.$)./#/T/#9 -$'<#/").
;;5 *.
: $W#-/)./< '11$-(/< '1T$"1/#/.
63?
: #*,*1"/)#$-.#/#/'1 )$&=-/#/.
66;
: #9&$. ;;5 *.
: T$-)'1 <")P*)<#/T/#/. 646
=9&$-#=9-"/G/.+ 6@?5 66?5
)),
: )$")'#'1 64?5 )-,
=9&"'1,*+/)$+/' 6665 ))+
=9&"<'1<$+/< #$#')9 3@65 '2+
=9&"&'-'#=9-"/G/.+ 6>@5
)+'
=9&"&9") 64;5 )-.
=9&"#=9-"/G/.+ 66?5 )),
!
/G/"&'#=/< #=-"+,"<9#"&$)/<
&*-&*-' 36;5 ').
N(2 )$&=-"&'#=9 6@45 63@5
)''3 66;5 )).
: 0"<'1 .$(+$)#'1
(1"+$-*1".<1$-"./. 6645
))(
/++*)$ <"+&1$W -$'<#/")
;;5 *.
/++*)$ <"+&1$W$. >@>
: 1$*H"<9#"<1'.#/< T'.<*1/#/.
6@45 )2(
: .9.#$+/< 1*&*.
$-9#=$+'#".*. 3?;5 '/.
/++*)$ $.<'&$ +$<=')/.+.
K;5 (.
/++*)$ -$.&").$
: IA<$11A+$G/'#$G 3K45 '((
: #*,$-<*1"./. 66@5 ))'
/++*)$ .9.#$+ 3

: <$11 "-/(/). 65 +
: )").&$</0/< 3
: -$.&").$ #" UNV /)0$<#/")
33@5 '''
: .&$</0/< 3
/++*)$ #=-"+,"<9#"&$)/<
&*-&*-' BNICF 64?5 )-,
/++*)/#95 'G'&#/T$J/))'#$ 6
/++*)",1"##/)( ?65 /+
/++*)"<")P*('#$.5 -'G/"A
1',$1$G 3K;5 '(.
/++*)"G$0/</$)</$. 3@@:3>
/++*)"G/00*./") +$#="G.
L;5 ..3 L?5 .,
/++*)"$1$<#-"&="-$./. L?5
.,
/++*)"01*"-$.<$)<$ ?45 /(
/++*)"(1",*1/)B.F
: '11"#9&/< G$#$-+/)')#. 6;
: ')#/($) .&$</0/</#9 G$#$-+/A
)'#/") ,9 =9&$-T'-/',1$
-$(/"). 6;5 ).
: ^O` -$(/"). 6;5 ).
: <1'.. .]/#<=/)( >@5 +'
: G/00$-$)# #9&$. 6?5 ),
: 0$'#*-$. 6?5 ),
: U ($)$ "-(')/X'#/")J
-$'--')($+$)# >@5 +'
: =$'T9 <='/). >@5 +'
: /G/"#9&/< G$#$-+/)')#. 6;
: /)#-'T$)"*. 6>;5 )+.
: /."#9&/< 6;
: ! 1/(=# <='/) ($)$. >@5 +'
: " 1/(=# <='/) ($)$. >@5 +'
: +")"<1")'1 34;5 '-.
: &"19<1")'1 34;5 '-.
: -$0$-$)<$ T'1*$. 6;?
: .#-*<#*-$ 6;5 ).3 6?5 ),
: .*&$-0'+/19 6;5 ).
: .]/#<=/)( .$M*$)<$ >@5 +'
: .9)#=$./. 665 )+
: VOe .$M*$)<$. >@5 +'
: &00 #$&1 -=$*+'#"/G 0'<#"-.
/++*)"(1",*1/) 2 BN(2F )2(
: G$0/</$)<9 364
: .$<-$#/") 6?5 ),
: .$1$<#/T$ G$0/</$)</$. 3@@
: .#-*<#*-$ 6?5 ),
: #$'- 01*/G 6465 )-+
: &00 #$&1 N(2 )$&=-"&'#=9
/++*)"(1",*1/) O BN(OF 665
)+
: .#-*<#*-$ 6?5 ),
/++*)"(1",*1/) c BN(cF
: '11$-(/< '.#=+' 6345 )'(
: '11$-(/< <")P*)<#/T/#/. 6465
)-+
: '11$-(/< -=/)/#/. 6345 )'(
: /++$G/'#$
=9&$-.$)./#/T/#9 ;;5 *.
: &-"G*<#/") -$(*1'#/") 6@5
)'
: .#-*<#*-$ 6?5 ),
: #*,*1"/)#$-.#/#/'1 )$&=-/#/.
66;
/++*)"(1",*1/) E BN(EF
: -'&/G19 &-"(-$../T$
(1"+$-*1")$&=-/#/. 66;5
)).
: .$1$<#/T$ G$0/</$)</$. 3@@5
'2'
: .#-*<#*-$ 6?5 ),
: #-').&"-# #=-"*(= /)#$.#/)'1
$&/#=$1/*+ 6?5 ),
/++*)"(1",*1/) Z BN(ZF 665
)+
: -$G <$11 '((1*#/)'#/") 33?5
'',
: .#-*<#*-$ 6?5 ),
: &00 #$&1 =9&$-AN(Z .9)A
G-"+$
/++*)"("1",*1/)A1/H$ #-')A
.<-/&#. BN[I.F >?
/++*)"=/.#"1"(/<'1 .#'/)/)(
?;5 /.
/++*)"+'()$#/< .$&'-'#/")
??5 /,
/++*)"&-"#$'."+$ K;5 (.
/++*)"-$<$&#"- #9-"./)$A
,'.$G '<#/T'#/)( +"#/0
BNI2ZF >?5 4@5 -'
/++*)"-$<$&#"- #9-"./)$A-/<=
/)=/,/#"-9 +"#/0 BNINZF >?
/++*)".*&&-$../") 36@5
')'
: '11"($)$/< "-(')
#-').&1')#'#/"). 3;65 '*+
: G-*(. 6K?5 )(,
: (-'0#AE0?&A&A=".# G/.$'.$
3;@5 '*'
: /)0$-#/1/#9 64?5 )-,
/++*)"#"W/). 3K;5 '(.
/)<1*./") ,"G9 +9"./#/. 3S65
',+
/)G*</,1$ IA<$11 <"A.#/+*1'#"-
BN^8DF >;5 +.
/)0')#/1$ .$&#/<
(-')*1"<9#"./. 3@45 '2(
/)0$<#/")
!"#$%
: '<*#$ &".#.#-$&#"<"<<'1
(1"+$-*1")$&=-/#/. 66;5
)).
: ,'<#$-/'1 3@;
: ,1""G #-').0*./") 3645 ')(
: <=$+"#=$-'&9
<"+&1/<'#/"). 3;@5 '*'
: G$0$).$ +$<=')/.+. 65 +
: .9.#$+/< T'.<*1/#/. 3S45 ',(
: *-#/<'-/' 6@@
: i=/&&1$R. G/.$'.$ 6@?5 )2,
/)0$-#/1/#95 /++*)$A+$G/'#$G
64?5 )-,
/)01'++'#"-9 ,"]$1 G/.$'.$
3L;5 '..
/)01'++'#"-9 -$.&").$ 35
6K45 )((
/)"./#"1 #-/&=".&='#$ BNC>F 3?5
',
/).*1/) 6>@5 )+'
/)#$-G/(/#'#/)( G$)G-/#/< <$11.
BNO^F 4@5 -'
/)#$-0$-")B.F >@>
/)#$-0$-") # BNY!#F 3365
6?4:K
: .9.#$+/< 'G+/)/.#-'#/")
3K45 '((
/)#$-0$-") $ BNY!$F 6@5 )'3
6?4:K
/)#$-0$-") $ BNY!$F c[NDC8I
S45 ,(
/)#$-1$*H/)B.F 6L?:?>5 >@>
: UNV /)0$<#/") #-$'#+$)#
3365 ''+
/)#$-1$*H/) 3% <")T$-#/)(
$)X9+$ BN^cF L45 .(
/)#$-1$*H/) 6 BN[A6F 3?5 6@5 )'3
6L?:S
: !\ <$11 +'#*-'#/") >?
: .9.#$+/< 'G+/)/.#-'#/")
3K45 '((
/)#$-1$*H/) 4 BN[A4F 6@5 )'3 4@5
-'3 6L?:S
: '11$-(/< '.#=+' 6345 )'(
/)#$-1$*H/) K BN[AKF 6@5 )'3
6L?:S
/)#$-1$*H/) ? BN[A?F 63;5 )'.
!
: 7$=<d$#R. .9)G-"+$ 64;5
)-.
/)#$-1$*H/) 3@ BN[A3@F 64?5
)-,3 6?@:3
/)#$-1$*H/) 36 BN[A36F 6@5 )'3
6?@:3
: ^-"=)R. G/.$'.$ 63@ &*-
"
: G$)G-/#/< <$11 &-"G*<#/") >;
 !"#$%
: $W&$-/+$)#'1 '*#"/++*)$
*T$"-$#/)/#/. 64@5 )-'
: UNV /)0$<#/") #-$'#+$)#
336
/)#$-1$*H/) 3> BN[A3>F 6@5 )'3
6?@:3
: '.#=+' 6345 )'(
/)#$-1$*H/) 3K BN[A3KF >?5
6?@:3
/)#$-1$*H/) 3? BN[A3?F >?5
6?6:>
/)#$.#/)'1 $&/#=$1/*+
: G"+$ ?5 ,
: N(E #-').&"-# 6?5 ),
/)#$.#/)'1 ]'115 /)01'++'#"-9
-$'<#/"). )''
/)#-'<$11*1'- 'G=$./") +"1$A
<*1$. BN^2Z.F5 ,1"<H'G$
6;@5 )*'
/)#-'<9#"&1'.+/< .&$-+
/)P$<#/") 64?5 )-,
/)#-'#=9+/< ,'--/$- ;
/-/G"<9<1/#/. 6445 )-(
/-/#/. 6445 )-(
: V"(#:\"9')'(/:U'-'G'
.9)G-"+$ 64;
/.1$# <$11 '*#"')#/($). 6>@5
)+'
/."<9')'#$. 63?5 )',
.
P'+ #$.# S65 ,+
e"A3 ')#/,"G/$. 3S65 ',+
P*T$)/1$ <=-")/< '-#=-/#/. 3L45
'.(
: "<*1'- +')/0$.#'#/"). 64;5
)-.
: &"19'-#/<*1'- 3L45 '.(
: .9.#$+/< 3L45 '.(
: '*'
/ 36;5 ').3 3>4
\'&"./R. .'-<"+' 3@?5 33@5
!
'''
\'&"./R. .'-<"+'A'.."</'#$G
UUVA? 344
\']'.'H/R. G/.$'.$ 6;;
\$11 ')#/($). 3645 ')(
&*. \$11 ,1""G (-"*& .9.#$+ 33;5
''.
H$-'#/#/. 6465 )-+
H$-'#"<")P*)<#/T/#/.5 '#"&/<
646
H$-'#"&1'.#9 3;65 '*+
H/G)$9
: 1*&*. )$&=-/#/. 3?45 '/(3
3?;5 '/.
: &"19'-#$-/#/. )"G".' 3S;
: #-').&1')#'#/") 3;65 '*+
: &00 #$&1 -$)'1 G/.$'.$
H/11$- <$11 /++*)"(1",*1/)A
1/H$ -$<$&#"-. B\N`.F >?5
+,
0 : /)01'++'#"-9 <9#"H/)$. ;4
1',/'1 ,/"&.9 3S@5 ','
1'<#"0$--/) 6465 )-+
['+,$-#:c'#") .9)G-"+$
6>?5 )+,
[')G"*X9R. .$&./. 66@5 ))'
[')($-='). <$11. ;;5 *.3 6@65
)2+
: &='("<9#"./. 4@5 -'
1'-($ (-')*1'- 19+&="<9#$.
B[E[.F >?
1'#$W '((1*#/)'#/") ?@5 /'
1$01*)"+/G$ 6K?5 )(,
;0!&D<#B!# /)0$<#/") 6@
1$*H$+/' 36?5 '),
: '<*#$ 19+&="/G 36?5 '),3
3;@5 '*'
: '<*#$ +9$1"/G 36?5 '),3
3;@5 '*'
: <=-")/< 19+&="<9#/< 36@5
')'3 3>?5 '-2
: <-9"(1",*1/). 34;5 '-.
: <=-")/< +9$1"/G 3K65 3;@5
: ='/-9 <$11 3>S5 '-2
: 1'-($ (-')*1'- 19+&="<9#$
: &-$<*-."- IA19+&=",1'.#/<
3>45 '+*
: &-"19+&="<9#/< 3>?5 '-2
: IA<$11 <=-")/< 19+&="<9#/<
3>45 '+*
: &00 #$&1 19+&="+'J1$*H$A
+/'
1$*H"<9#$ 'G=$./") &-"#$/)
G$0$<#. 3@45 '2(
1$*H"<9#$ 0*)<#/")A'.."</'#$G
')#/($) 3 B[Y2A3F >;5 +.3
465 -+
1$*H"<9#$ /++*)"(1",*1/)A
1/H$ -$<$&#"-. &00 /++*A
)"("1",*1/)A1/H$ #-')A
.<-/&#. BN[I.F
1$*H"<9#$. 65 ;45 *(
1$*H"<9#"<1'.#/< T'.<*1/#/.
6@45 )2(3 6;;
1$*H"#-/$)$. 63;5 )'.
[=$-+/##$R. ./() 6>45 )+(
1/(=# <='/) '+91"/G"./. 34?5
'-,
1/(=# <='/) -$.#-/<#/") >6
1/&"'-',/)"+'))') 66@
1/&"&"19.'<<='-/G$ B[CDF 465
-+3 ;6
1/T$-:H/G)$9 +/<-"."+'1
')#/,"G/$. B[\ZF 636
["$0(-$)R. .9)G-"+$ 63;5 )'.
["*/.:7'- .9)G-"+$ 3@65 '2+
1*)(
: '11$-(/< G/.$'.$ 63?5 )',
: &00 #$&1 -$.&/-'#"-9 G/.$'.$.
1*)( <')<$- 6>?5 )+,
1*&*.5 )$")'#'1 64?5 )-,
1*&*. )$&=-/#/. 3?45 '/(3 3?;5
'/.
[9+$ G/.$'.$
: &')*T$/#/. 64;5 )-.
: *T$/#/. 6445 )-(
19+&= )"G$. 45 (3 ;
: =/(= $)G"#=$1/'1 T$)*1$.
;4
: ./)*.$. ?5 ,
: .#-*<#*-$ ?5 ,
19+&='G$)"&'#=9 3S@
: ')(/"/++*)",1'.#/< ]/#=
G9.&-"#$/)$+/' 3>K
: =/1'- 63;5 )'.
19+&='G$)"&'#=9 .9)G-"+$
B[2DF 33@
19+&='#/< 0"11/<1$. ?5 66
19+&='#/< -$</-<*1'#/") 45 (
19+&='#/< .9.#$+ .#-*<#*-$
45 (
19+&="<9#$ 0*)<#/") ')#/($)
3 B[Y2A3F 3;
19+&="<9#$ .#/+*1'#/")
'..'9 S@
19+&="<9#$. 35 6
: +9<"&=$)"1'#$ G'+'($
6K?
 !"#$%

: .*,&"&*1'#/") G/.#-/,*#/") : 0*)<#/") 465 -+ +$+,-')$ <"0'<#"- 3;65 '*+

6;L
: #=9+*. ;
: &00 #$&1 7 <$11.
B7 19+&="<9#$.Fa I <$11.
BI 19+&="<9#$.F
19+&="/G "-('). 45 (3 ;
19+&="+'
: ')'&1'.#/< 1'-($ <$11 3>45
3>K5 '+*
: ')(/"<$)#-/< 3>K5 '+.
: ')(/"/++*)",1'.#/< IA<$11
3>4:K5 '+.
: 7A<$11 '+'3 3K;
: 7*-H/##R. 3>S5 '-2
: G/00*.$ 1'-($A<$11 3>S
: ($-+/)'1 <$)#$- 3>?5 '-'
: (1*#$)A.$)./#/T$
$)#$-"&'#=9 6@?
: /)#$.#/)'1 IA<$11 3>K
: \/$1 <1'../0/<'#/") 3>@5 '+'
: 19+&="<9#/< &1'.+'<9#"/G
3>?5 '-'
: +')#1$ <$11 3>?5 '-'
: +'-(/)'1 X")$ 3>?:S5 '-2
: Z$G/#$--')$') 346
: !\ <$11 '+'
: )")AU"G(H/)R. 36@5 ')'3
3>45 3>?:S5 '-2I'
: <-9"(1",*1/). 34;5 '-.
: DP"Q(-$)R. .9)G-"+$
&-"(-$../") 3S@5 ','
: &$-/&=$-'1 IA<$11 3>4
: `$T/.$G c*-"&$'):2+$-/A
<') [9+&="+' ^1'../0/<'A
#/") B`c2[F 3>@5 '+'3 3>S
: .&1$)/< +'-(/)'1 X")$ 3>S
: I <$11 '+'
: &00 #$&1 U"G(H/)R. G/.$'.$
19+&="+'J1$*H$+/'
: &-$<*-."- 7A19+&=",1'.#/<
3>?5 '-2
: &-$<*-."- IA19+&=",1'.#/<
3>45 '+*
19."X9+$ 6465 )-+
: E*/11'/):7'--c .9)G-"+$
6>;5 )+.
: -'&/G19 &-"(-$../T$
(1"+$-*1")$&=-/#/. 66;
: -=$*+'#"/G '-#=-/#/. 3L@5
'.'3 3L65 '.+
: .<'T$)($- 0*)<#/") 465 -+
: .9)"T/'1 3L@5 3L65 '.+
: #*,$-<*1"./. 66@5 ))'
+'<-"&='($ /)01'++'#"-9
&-"#$/) 3 BZNCA3F 336
+'<-"&='($ /)01'++'#"-9
&-"#$/) ># BZNCA>#F 445
-(
+'<-"&='($ /)01'++'#"-9
&-"#$/) >% BZNCA>%F ;4
+'P"- =/.#"<"+&'#/,/1/#9
<"+&1$W BZU^F 365 3;5 '.3
6@5 )'
: <1'.. N 6;5 ).
: UNV /)0$<#/") 33@
: <1'.. NN 6;5 ).
: ',$--')# ')#/($). L@5 .'
: ')<="- '+/)" '</G. K45
((
: ')#/($) &-"<$../)( K45 ((
: UNV /)0$<#/") 33@
: IA<$11 '<#/T'#/") K45 ((
: V"(#:\"9')'(/:U'-'G'
.9)G-"+$ 64;
: &'#="($)/< &$&#/G$
G/.&1'<$+$)# 6;@
: -$<$&#"-. >?
: #-').&1')#
/++*)"($)/</#9 3;45 '*(
: &00 #$&1 U[2 <"+&1$W
+'1/()')# +$1')"+' 3K45'((
Z')</)/ +$#="G L;5 ..
+'))".$A,/)G/)( 1$<#/) ;65
*+
+'))".$ -$<$&#"- 4@5 -'3 46
: ,/)G/)( ;65 *+
+'.# <$11.
: '11$-(/< -=/)/#/. 6345 )'(
: G$(-')*1'#/") ;@5 *'
: *-#/<'-/' 6@@5 )2'
+$+,-')$ /)=/,/#"- "0 -$'<A
#/T$ 19./. BZN`[F 3;65 '*+
+$+,-')"&-"1/0$-'#/T$
(1"+$-*1")$&=-/#/. 6645
))(
+$+,-')"*.
(1"+$-*1")$&=-/#/. 6645
))(
+$+"-9 -$.&").$ 3
6A+$-<'&#"$#=')$.*10")/<
'</G BZcD!2F 6K;
Zc-/$*W +*1#/#$.# S@5 ,'
+$#',"1/< G/.$'.$. 66?:>3
+$#'11"&-"#$'.$. 3;?
+$#="#-$W'#$ 6K;5 )(.
#A+$#=91G"&' 3645 ')(
+/<-"0"1G. &00 Z <$11.
+/<-"(1/' 6>45 )+(
%6A+/<-"(1",*1/) 4?5 34?5
'-,3 >@>
+/<-".<"&/< &"19')(//#/. 6;;
+/<-"T/11/ 6645 ))(
+/1/'-9 #*,$-<*1"./. 66@5 ))'
+/#"<=")G-/'5 <'.&'.$
'<#/T'#/") L45 .(
+/W$G <"))$<#/T$ #/..*$
G/.$'.$ 3??5 '/,
: G/'()".#/< '*#"')#/,"G/$.
6;4
+"1$<*1'- +/+/<-9 L@5 .'3
3L?5 '.,
: E*/11'/):7'--c .9)G-"+$
6>;5 )+.
: *T$/#/. 6445 )-(
+")",1'.#. 6
+")"<1")'1 ')#/,"G/$. 3;5
6;@5 )*'
: <')<$- #=$-'&9 3K;5 '(.
: -=$*+'#"/G '-#=-/#/. 3L@
: '('/).# #*+"- ')#/($).
3K@5 '('
+")"<9#$:+'<-"&='($
.9.#$+ 3
+")"<9#$. 4@5 -'
: '<#/T'#/") 465 -+
: G$)G-/#/< <$11. 445 -(

!
1 : T$-)'1 <")P*)<#/T/#/. 646 : $00$<#"- 0*)<#/") 465 -+
+'#$-)"0$#'1 #"1$-')<$ 64?5 : 0*)<#/") 465 -+
Z <$11. ?5 , )-, : -'&/G19 &-"(-$../T$
+'<-"&='($B.F 6@5 )' +$'.1$. T'<</)$ 6K@5 )(' (1"+$-*1")$&=-/#/. 66;
: '<#/T'#/") 465 -+ +$('H'-9"<9#$. 6 : .'-<"/G"./. 63;
: '1T$"1'- 63;5 )'.3 66@5 ))' +$1&='1') 344 : .<'T$)($- 0*)<#/") 465 -+
: $00$<#"- 0*)<#/") 465 -+ +$+,-')$ '##'<H <"+&1$W : I <$11 /)#$-'<#/"). ]/#= &*/

"
: Y< -$<$&#"-. 6>;5 )+. BZ2^F K?5 (,3 3@; 2C^. >;5 +.
 !"#$%
: #$'- 01*/G 6465 )-+
+")")*<1$'- <$11.
: /."1'#/") ??5 /,
: -=$*+'#"/G '-#=-/#/. 3;?5
'*,
: #*,*1"/)#$-.#/#/'1 )$&=-/#/.
66;
+")")*<1$'- &='("<9#/<
.9.#$+ 3?;5 >@4
+*<".'A'.."</'#$G 19+&="/G
#/..*$ BZ2[IF 45 (3 ;5 ?5 ,
+*<".'1 'GG-$../) <$11 'G=$A
./") +"1$<*1$ 3 BZ2GA
^2ZA3F ;45 *(
+*1#/&1$ +9$1"+' 3445 '-(
: <-9"(1",*1/). 34;
: 1/(=# <='/) '+91"/G"./. 34?
+*1#/&1$ .<1$-"./. 6>45 )+(
: *T$/#/. 6445 )-(
+*+&. T'<</)$ 6K@5 )('
+*.<1$ <$11 G$&"1'-/X'#/")
6>?5 )+,
+*.<*1".H$1$#'1 G/.$'.$.
3;;:?3
+*#')#.5 G$1$#/") 0"-
T'<</)$. 6K65 )(+
+9'.#=$)/'5 )$")'#'1
#-')./#"-9 64?5 )-,
+9'.#=$)/' (-'T/. 6>?5 )+,
<A<>% 3?5 ',
+9<",'<#$-/'
: G$0$).$ 34
: &00 #$&1 #*,$-<*1"./.
J>%14#%"0?!A< "A40?%A$1&!&
66@
+9<"&=$)"1'#$ 6K?5 )(,
J>%1=$#&<# /)0$<#/") 3665
')+
+9<"./. 0*)("/G$. 3>45 '+.
+9$1/) 6>45 )+(3 6>;5 )+.
+9$1",1'.#. 6
+9$1"&$-"W/G'.$ G$0/</$)<9
3@45 '2(
+9"<'-G/#/. 6>65 )++
+9"./) 6>6
+9"./#/. 6;4
2
!
!2OCU 3@45 '2(
)'-<"1$&.9 L6
)'#*-'1 H/11$- B!\F <$11. 35 65
&*( 3;5 >?5 +,
: &1'<$)#' 64?5 )-,
)$<-"./. L45 .(
)$"')#/($). 3K65 '(+
)$")'#'1 '*#"/++*)$
.9)G-"+$. 64?5 )-,
)$&=$1"+$#-9 L;5 ..
)$&=-/#/< .9)G-"+$ 6665
))+3 66;
)$&=-/#/.5 #*,*1"/)#$-.#/#/'1
66;5 )).
)$&=-"&'#=95 +/)/+'1
<=')($ 6645 ))(
)$&=-"#/< .9)G-"+$ 6665
))+
)$*-"G$-+'#/#/. 6@45 )2(
)$*-"1"(/<'1 G/.$'.$ 6>4:S
)$*-".'-<"/G"./. 63;5 )'.
)$*#-"&$)/'5 '*#"/++*)$
36;5 ').
)$T/-'&/) ''+
)/<H$1 '11$-(9 ;;5 )2+
)/#-/< "W/G$ 6>;5 )+.
!\E6O -$<$&#"- >?5 +,
)")A.#$-"/G'1 ')#/A/)01'++'A
#"-9 G-*(. B!D2NO.F 6K45
)((
!"-#=$-) ,1"##/)( S?5 ,,
)*<1$'- ,/)G/)( &-"#$/). 3?5
',
)*<1$'- 0'<#"- "0 '<#/T'#$G I
<$11. B!Y2IF 3?5 ',3 6K?5
)(,
)*<1$"&=".+/) ($)$ 3>K
)*<1$"./G$ ')'1"(*$. 336
3 &$-/&=$-'1 IA<$11 )$"&1'.+.
8 ($)$ 334
"1/("'-#=-/#/.
: 7$=<d$#R. .9)G-"+$ 3?@5
'/'
: $'-19A").$# 3L45 '.(
")<"0$#'1 ')#/($). 3K65 '(+
"&=#='1+/< G/.$'.$. L65 63;5
)'.3 64@:L
"&.")/X'#/") ;@5 ;65 >@4
"-'1 ='/-9 1$*H"&1'H/' 33@
"-,/#"&'#=95 $)G"<-/)$ 66?5
)),
".#$"19./.
: +*1#/&1$ +9$1"+' 3445'-(
: .'-<"/G"./. 63;5 )'.
8*<=#$-1")9 +$#="G L?5 .,
4
CA.$1$<#/) (19<"&-"#$/)
1/(')GA3 BCDE[A3F ;45 *(
&K;1<H 3?5 ',
&KS09) 3?5 ',
&')'-#$-/#/. )"G".' 64;5 )-.
&')<-$'. 6>@5 )+'
&'))/)( +$#="G ??5 /,
&')*T$/#/. 64;5 )-.
&'-')$"&1'.#/< )$*-"1"(/<'1
.9)G-"+$. 6>;5 )+.
&'-"W9.+'1 )"<#*-)'1 =$+"A
(1",/)*-/' BC!UF K?5 3@;5
'2.3 3;@5 '*'
&'#="($)A'.."</'#$G +"1$<*A
1'- &'##$-). BC2ZC.F ;65
*+
&'##$-) -$<"()/#/") -$<$&#"-.
BCC`.F ;65 *+
&'W/11/) 4@5 -'
&$+&=/(*. T*1('-/. 6@;5 )2.
&$)/</11/)
: <9#"#"W/< -$'<#/") ;;
: =$+"19./. 3645 ')(
&$&#/G$.
: .9)#=$#/< 0"- T'<</)$. 6K65
)(+
: T'<</)'#/"). 6;@
&$-0"-/) >?5 +,3 S6
: <9#"#"W/< 3K;5 '(.
&$-/'-#$-/"1'- 19+&="<9#$
.=$'#= BC2[DF ?
&$-/&=$-'1 )"G$ 'GG-$../)
BC!2GF ;45 *(
3>4:K5 '+*I.
&$-#*../. T'<</)$ 6K@5 )('
C$9$-R. &'#<=$. ?5 ;4
&='("<9#$. 65 4@5 -'
&='("<9#"./. 65 465 -+
: '1T$"1'- +'<-"&='($. 66@5
))'
: ')#/($). 6;@5 )*'
: '&"&#"#/< <$11. L45 .(
: <"/1/)( 4@5 -'
: <"+&1$+$)# -$<$&#"-A
+$G/'#$G 4@5 -'
: $-9#=-"<9#$. 33?
: Y<A+$G/'#$G 4@5 -'
: [')($-='). <$11. 4@5 -'
: +9$1/) 6>45 )+(3 6>;5 )+.
: .9.#$+/< 1*&*.
$-9#=$+'#".*. 3?;5 '/.

&='("."+$5 <"/1/)( 4@
&='-+'<"1"(95 /++*)$
6K4:;3
&='-9)("#")./11/#/. 6>6
=A&=$)91$)$ G/'+/)$ )2+
&=".&='#/G91/)"./#"1 &=".A
&="1/&'.$ BCNCF 3?5 ',
&=".&='#/G91.$-/)$ L45 .(
&/)"<9#"./. 4@5 -'3 >@4
&1'<$)#'5 =*+') 64?5 )-,
&1'M*$A0"-+/)( <$11 BCY^F
#$.#. S;5 ,.
&1'.+'<9#"+' 344
&1'.+'&=$-$./. 6>;5 )+.
&1$*-"&$-/<'-G/#/. 3?45 '/(
KB0A<1%>&"!& %#?!B!! &)$*+"A
)/' BC^CF 3@?5 33@5 '''
&)$*+"<9#$.5 #9&$ NN 63;5
)'.
&)$*+")/'5 <'.$'#/)( 66@5
))'
&)$*+")/#/.5
=9&$-.$)./#/T/#9 63?
&"G"<9#$. 6665 ))+3 6645 ))(
&"1/"+9$1/#/. T'<</)$ 6K@5
)('
&"19')(//#/.5 +/<-".<"&/< 6;;
&"19'-#$-/#/. )"G".' 3S;5 ',.3
6;;
&"19'-#=-'1(/' 3S@
&"19<=")G-/#/. 3?@5 '/'
&"19<1")'1 '<#/T'#"-. S@
&"19<1")'1 ')#/,"G/$. 6;@5
)*'
&"19+$-'.$ <='/) -$'<#/")
BC^`F S?5 ,,
: UNV /)0$<#/") G/'()"./. 336
&"19+$-/< /++*)"(1",*1/)
-$<$&#"-. B&"19AN(`F 6;5
).
&"19+"-&=")*<1$'- )$*#-"A
&=/1 (-')*1"<9#$. BCZ!F
3S;5 ',.
&"19+9'1(/' -=$*+'#/<' 3S?
&"19+9"./#/.JG$-+'#"+9"./#/A
. 3?65 3S65 ',+
&"./#/T$ 0$$G,'<H 1""&
G9.0*)<#/") 3@;5 '2.
&".#A&$-/<'-G/"#"+9
.9)G-"+$ 6>65 )++
&-$A7AN ')G ANN <$11. >65 ++
&-$AO^A3 ')G A6 <$11. 445 -(
&-$A#=9+"<9#$. 3@5 ''3 365 '+
: +/(-'#/") 365 '+
&-$</&/#'#/") -$'<#/"). L;5 ..
&-$<*-."- 7A19+&=",1'.#/<
19+&="+'J1$*H$+/'
3>?5 '-2
&-$<*-."- IA19+&=",1'.#/<
19+&="+'J1$*H$+/'
3>45 '+*
&-$#/,/'1 +9W$G$+' 66?5 )),
&-"($.#$-")$A/)G*<$G ,1"<HA
/)( 0'<#"- BCN7YF 64?5 )-,
&-"(-'++$G <$11 G$'#= 36
: &00 #$&1 '&"&#"./.
&-"(-'++$G G$'#= ($)$ 3
BCOA3F >;5 +.
&-"1/0$-'#/") '..'9 S@5 ,'
&-"+/.<*"*. 76L =9&"#=$./.
3L?5 '.,
&-"#$'.$ /)=/,/#"-. 336
&-"#$'.$. 6>;5 )+.
&-"#$/) $1$<#-"&="-$./. 6?5
),
&-"#$/) H/)'.$ ^ BC\^F 3?5 ',
&-"#$/)'.$ > 3S;5 ',.
&-"#$/).
: &1'.+' 6;L
: -$<"+,/)')# 0"- T'<</)$.
6K65 )(+
&."-/'./. 6@;5 )2.
&."-/'#/< '-#=-/#/. 3L;5 '..3
6@;5 )2.
&*1+")'-9 0/,-"./.5
/G/"&'#=/< 63;5 )'.
&*-$ -$G <$11 '&1'./' 36;5 ').
&*-/)$ ,/".9)#=$./. 6K?
C*-H/)P$ <$11. 6>;5 )+.
5 1$'- ')#/,"G/$. 6;>
M*/)/G/)$ 3645 ')(
6 <1'../0/<'#/") 6;6
-'G/'1 G"*,1$
/++*)"G/00*./") L?5 .,
-'G/"/++*)"'..'9 ?65 /+
-'G/"#=$-'&95 "-(') G'+'($
3;@5 '*'
-'&'+9</) 6K?5 )(,
-'&/G19 &-"(-$../T$ (1"+$-*A
1")$&=-/#/. B`CE!F 66;5
)).
`'.+*..$)R. $)<$&='1/#/.
6>;5 )+.
!"#$%
`'9)'*GR. &=$)"+$)") 3??5
'/,3 3S@5 ','
`'9)'*GR. .9)G-"+$ 3??
-$'<#/T$ '-#=-/#/G$. 3L;5 '..
-$'<#/T$ "W9($) -'G/<'1. 6>;5
)+.
-$<"+,/)')# T'<</)$ .#-'/).
6K65 )(+
-$G ,1""G <$11. 36@
: '((1*#/)'#/") 33?5 '',
: ,1""G (-"*& ')#/($). 334
: 19./. 33?
-$G <$11 '&1'./'5 &*-$ 36;5 ').
-$)'1 <$11 <'-</)"+' 3K45 '((
-$)'1 G/.$'.$ 666:L
: ')#/,"G9 G$&"./#. 6665 ))+
: &00 #$&1 H/G)$9
-$&-"G*<#/T$ /++*)"1"(9
64?5 )-,
-$.&/-'#"-9 G/.$'.$. 634:63
-$#/<*1/) 6@;5 )2.3 6@?
-$#/<*1"$)G"#=$1/'1 .9.#$+
33?5 '',
-$#/)/#/. 6445 )-(
-$T$-.$ =$+"19#/< CY^ '..'9
S;5 ,.
-$T$-.$ #-').<-/&#'.$
/)=/,/#"-. 3365 ''+
-$T$-.$ #-').<-/&#'.$ &"19A
+$-'.$ <='/) -$'<#/")
B`I:C^`F 336
-=$.*. B`=F .9.#$+ ;;5 *.3
33;5 ''.
: '11"/++*)/X'#/") '('/).#
`= ')#/($). 33;5 ''.
: ')#/,"G9 0"-+'#/") ?@
-=$*+'#/< G/.$'.$.5 ')#/)*<A
-=$*+'#/< 0$T$- 6>65 )++
-=$*+'#"/G '-#=-/#/. L65 .+3
3;;5 '*.
: 2^` <-/#$-/' 0"-
: '-#=-/#/< P"/)# <$11. 3;?5 '*,
: '*#"/++*)$ =$&'#/#/. 6365
)'+
: G/'()".#/< ')#/,"G/$. 6;4
!
: /+&'/-$G 7 <$11 -$(*1'#/")
3L65 '.+
: /)G*<#/") 3L@5 '.'
: +'<-"&='($. 3L@5 '.'3 3L65
'.+
: "<*1'- +')/0$.#'#/"). 64;5
)-. &*)
"
: &'#="($)$./. 3L@5 '.'
 !"#$%
: .<1$-/#/. 6465 )-+
: .*.<$&#/,/1/#9 3L@5 '.'
: .9)"T/'1 +$+,-')$ 3L65
'.+
-=$*+'#"/G 0'<#"-. 3;;5 3L65
'.+
: .<-$$)/)( ?@5 /'
: DP"Q(-$)R. .9)G-"+$ 3S@
`/ ')#/($) 6>;5 )+.
-/#*W/+', 6;@
`!2 &-",$. ?;5 /.
`!2 .9)#=$./. 6K?5 )(,
-"<H$# $1$<#-"&="-$./. L?5 .,
-".$##$ 0"-+'#/") ??5 /,
-*,,$- '11$-(9 ;;5 )2+
-*,$11' T'<</)$ 6K@5 )('
7 ."+'#/< =9&$-+*#'#/") 645
.'1/T'-9 (1')G .</)#/(-'&=9
3S@
.'M*/)'T/- ''+
.'-<"/G"./. 63;5 )'.
: "<*1'- +')/0$.#'#/"). 64;5
)-.
: *T$/#/. 6445 )-(
D<=/-+$-R. #$.# 3S@
D<="Q)1$/):U$)"<= &*-&*-'
6@45 )2(3 6;;
: N(2 G$&"./#/") 66;
: -'&/G19 &-"(-$../T$
(1"+$-*1")$&=-/#/. 66;5
)).
.<1$-' &'#="1"(9 6465 )-+
.<1$-/#/. 6465 )-+
.<1$-"G$-+' 3?65 3??5 '/,
: G/'()".#/< '*#"')#/,"G/$.
6;4
.<1$-"./)( <="1')(/#/.5 &-/+'-9
)''3 6365 )'+
.$1$<#/). 3@4
.$10A')#/($).5 #"1$-')<$ K;5
(.
.$&./.5 #*,$-<*1"*. 66@5 ))'
.$T$-$ <"+,/)$G /++*)"G$A
0/</$)<9 BD^NOF 3@65 '2+3
!
3;@5 '*'
DcX'-9 .9)G-"+$ 3>45 '+.
./'1"(-'&=9 3S@5 ','
./'191(19<"<")P*('#$. >4
./<<' .9+&#"+. 3S@5 ','
&+' ./+&1$ -'G/'1
/++*)"G/00*./") L;5 ..
./)"&*1+")'-9 .9)G-"+$ 3@6
DP"Q(-$)R. .9)G-"+$ 3?6
: '*#"/++*)$ =$&'#/#/. 636
: <1/)/<'1 0$'#*-$. 3S@5 ','
: G/'()"./. 3S@5 ','
: G/'()".#/< ')#/,"G/$. 6;4
: )$")'#'1 1*&*. 64?5 )-,
: "<*1'- +')/0$.#'#/"). 64;5
)-.
: &-/+'-9 ,/1/'-9 </--="./.
6365 )'+
: .<1$-/#/. )-+
: .$<")G'-9 3;;
: #$'- 01*/G 6465 )-+
.H/) G/.$'.$. 6@@:L
: ,*11"*. 6@;5 )2.
DZ ')#/($) 6;>
.)"],'11.J.)"]G-/0#. 6445
)-(
)(3 >@4
D"*#=$-) ,1"##/)( S?5 ,,
.&1$$) 45 (3 ;
: .#-*<#*-$ ?
.&1$)$<#"+9J.&1$)/<
-'G/"#=$-'&9 36@5 ')'
.&")G91'-#=-/#/. L6
.&")G91'-#=-"&'#=9 3L;5 '..
: cDDE <1'../0/<'#/") 6;6
: U[2A76L 3L;5 '..3 3L?5 '.,
: /)G*<#/") /) #-').($)/< -'#.
3L?5 '.,
: P*T$)/1$ 3L45 '.(
: "<*1'- +')/0$.#'#/"). 64;5
)-.
.&-*$ 6@?5 )2,
D-<A="+"1"(9A6 G"+'/). 3?
DDA2 ')G A7 '*#"')#/,"G/$.
3S@5 ','3 64?5 )-,3 6;>
.#'&=91"<"<<'1 $)#$-"#"W/).
>;
DI2I; 634
.#$+ <$11.5 =$+'#"&"/$#/< 6
: '11"($)$/< #-').&1')#'#/")
3;@5 '*'
: '*#"1"("*.#-').&1')#'#/")
3>65 '++
: ^O4@ $W&-$../") >45 +(
: <1")$. 3@;
: ='-T$.#/)( 3K?5 '(,
: +",/1/X'#/") 3K?5 '(,
: &1'.#/</#9 65 +
: #-').&1')#'#/") 3K?5 '(,
.#/,"&=$) 3645 ')(
D#/11R. G/.$'.$ 3L45 '.(
L"?0="1%1%%A& 66;5 6>6
.*,+*<".'1 +*<"*. (1')G
=9&$-#-"&=9 634
.*10'.'1'X/)$ 6K;5 )(.
.*&$-')#/($) .#/+*1'#/") >;5
+.
D9G$)='+R. <="-$' 6>65 )++
.9+&'#=$#/< "&=#='1+/' L65
64;5 )-.
.9)"T/'1 <$11.5 .#$11'#$ 3L65
'.+
.9)"T/'1 +$+,-')$ 3;?5 '*,
: -=$*+'#"/G 3L65 '.+
.9&=/1/. 64;5 )-.
.9.#$+/< G/.$'.$5 "<*1'-
+')/0$.#'#/"). 64;5 )-.
.9.#$+/< 1*&*. $-9#=$+'#".*.
BD[cF 36;5 ').3 3?6
: 2^` <-/#$-/' 0"-
<1'../0/<'#/") 6;K
: <1/)/<'1 0$'#*-$. 3?45 '/(
: G/'()".#/< '*#"')#/,"G/$.
6;4
: +$+,-')"&-"1/0$-'#/T$
(1"+$-*1")$&=-/#/. 6645
))(
: +/.<'--/'($ 64?5 )-,
: )$")'#'1 1*&*. 64?5 )-,
: "<*1'- +')/0$.#'#/"). 64;5
)-.
: &'#="($)$./. 3?;5 '/.
: -'&/G19 &-"(-$../T$
(1"+$-*1")$&=-/#/. 66;5
)).
: #-$'#+$)# 3?4
.9.#$+/< T'.<*1/#/. 3S45 ',(
: 2c^2A'.."</'#$G 3S45 ',(
: 2!^2A'.."</'#$G 3S45 ',(
: ^='&$1 U/11 G$0/)/#/") 3S45
',(3 6;;
: #=$"-9 "0 G$T$1"&+$)#
3S;5 ',.
8
IA<$11A/)G$&$)G$)# -$.&").$
665 )+
IA<$11 -$<$&#"-. 3@5 ''3 365 '+
: ')#/($) -$<"()/#/") >;5 +.
: <"+,/)'#/") &"#$)#/'1 345
'(
: <")0/(*-'#/") 345 '(
: G/.#-/,*#/") "0 #J% ')G $J&
3@5 ''3 345 '(

: ($)$ 0'+/1/$. 345 '(
: ($)$#/<'119 $)(/)$$-$G
3K;5 '(.
: /++*)"(1",*1/)
.*&$-0'+/19 6;5 ).
: +"G*1'#/") ;?5 *,
: -$'--')($+$)# 345 '(
: IA<$11 '<#/T'#/") 3L5 ',
: ' <='/) 3K;5 '(.
I <$11. BI 19+&="<9#$.F 35 6
: '<#/T'#/") 3;5 '.3 3?5 ',3 L@5
.'
: '..'9. S@5 ,'
: ZU^ <1'.. NN K45 ((
: +"1$<*1$. /)T"1T$G >;5
+.
: ./()'1. >;5 +.
: #-').&1')# -$P$<#/") 3;45
'*(
: ')#/,"G9 0"-+'#/") L@5 .'
: ')#/($) &-$.$)#/)( <$11
/)#$-'<#/"). >;5 +.
: ')#/($)A.&$</0/< <1")$
($)$-'#/") S65 ,+
: G$&1$#/") 3;@5 '*'
: G$T$1"&+$)# "0 +'#*-$ 3@5
''
: G/00$-$)#/'#/") ;
: G/00$-$)#/'#/") +"1$<*1$.
3;5 '.
: /)=/,/#/") ,9 1$01*)"+/G$
6K?
: 19+&= )"G$ ?
: Z2[I ?
: +'#*-'#/") 45 ;5 3@5 ''
: +$+"-9 6@5 3;?
: +/(-'#/") ;45 *(
: +/.&-"(-'++$G 36
: )'/T$ 6@
: &-"1/0$-'#/") 3;
: -$(*1'#"-9 6@5 >@K
: -$.&").$ /)G*<#/") 3K45
'((
: -=$*+'#"/G '-#=-/#/. 3;?5
'*,3 3L@5 '.'
: .'-<"/G"./. 63;
: .$1$<#/") 365 '+
: .$&'-'#/") ??5 /,
: .&1$$) ?
: #=9+/< ;5 3@5 ''
: #"1$-')<$ ;?5 *,
: #*+"- ')#/($) -$<"()/#/")
3K@5 '('
: *T$/#/. 6445 )-(
: !B E!E1 0*)<#/") S@5 ,'
: &00 #$&1 ^O4f I <$11.a ^O?f I
<$11.
IA=$1&$- BIUF <$11. 3@5 >@4
: '11$-(/< '.#=+' 634
: '#"&/< G$-+'#/#/. 6@45 )2(
: ^O4 3;5 '.
: G/',$#$. +$11/#*. 6>@5 )+'
: G/00$-$)#/'#/") /)#" IU 3 ')G
IU6 <$11. 6@5 )'
: (1*#$)A.$)./#/T$
$)#$-"&'#=9 6@?
: U'.=/+"#"R. #=9-"/G/#/.
66?5 )),
: +'#$-)"0$#'1 #"1$-')<$
64?5 )-,
: +"G*1'#/") ,9 +")"<9#$.
465 -+
: +*1#/&1$ .<1$-"./. 6>45 )+(
: -$.&").$ &"1'-/X'#/") 4;5
-.
: #-').&1')# -$P$<#/") 3;45
'*(
#'<-"1/+*. 6K?5 )(,
I'H'9'.*R. '-#$-/#/. 3S?5 ',,3
6;;
#'&'-/) K;5 (.
#$'- 01*/G 6465 )-+
#$+&"-'1 '-#$-/#/. 3S?5 ',,
#$#')*. T'<</)$ 6K@5 )('
#$#-'/"G"#=9-")/)$ BI4F 66?5
)),
#$#-'+$- .#'/)/)( S4
#='1'..$+/' 3;@5 '*'
#=-"+,"<9#"&$)/'5 /++*)$
36;5 ').3 64?5 )-,
#=-"+,"<9#"&$)/< &*-&*-'5
/++*)$ BNICF 64?5 )-,
#=-"+,".&")G/) BIDCF L45 .(
#=9+/#/.5 19+&="0"11/<*1'-
6>?5 )+,
#=9+"<9#$. ;
: G$T$1"&+$)# 3@5 ''
: IA<$11 .$1$<#/") 365 '+
#=9+"+' 6>?5 )+,
#=9+*. 45 (3 ;
: 'G*1# .
: ')'#"+9 ;5 .
: G$T$1"&+$)# ;5 .
: =9&"&1'./' 3@65 '2+
: 19+&="<9#$. ;
: )$")'#$ .
: I <$11.
: +'#*-'#/") 3@5 ''
: .$1$<#/") 365 '+
#=9-"/G G/.$'.$
!"#$%
: '*#"/++*)$ 6>@5 )+'
: &00 #$&1 =9&$-#=9-"/G/.+a
=9&"#=9-"/G/.+
#=9-"/G (1')G '*#"')#/($).
66?5 )),
#=9-"/GA.#/+*1'#/)( ="-+")$
BIDUF 66?5 )),
#=9-"/GA.#/+*1'#/)( ="-+")$
BIDUF -$<$&#"-
'*#"')#/,"G/$. 66?5 )),
#=9-"/GA.#/+*1'#/)( /++*)"A
(1",*1/) BIDNF 66?5 )),3
64?5 )-,
#=9-"/G/#/. &00 U'.=/+"#"R.
#=9-"/G/#/.
#/)(/,1$ ,"G/$. 64
#/..*$ /)01'++'#/") 465 -+
: G$)G-/#/< <$11 +/(-'#/") ;45
*(
#"1$-')<$ 35 >@4
: <$)#-'1 3
: U[2A76L /)
.&")G91'-#=-"&'#=/$.
3L?5 '.,
: &$-/&=$-'1 3
: I <$11. ;?5 *,
I"11A1/H$ -$<$&#"-. ;65 *+3 66@
#")./1. ?
#"W/< +$('<"1") 63@
#"W"/G. 6K@
#"W"&1'.+"./. 6445 )-(
#-').($)/< +/<$ ;?5 *,
#-').&1')#'#/")
: '11"($)$/< 3;65 '*+
: '*#"1"("*. 3;65 '*+
: /++*)"($)/</#9 3;45 '*(
: /++*)"1"(9 3K?:;K
: H/G)$9 3;65 '*+
: "-(') -$+"T'1 <-/#$-/' 3;65
'*+
: -$P$<#/") 3;65 3;45 '*(
: .9)($)$/< 3;65 '*+
: #9&$. 3;65 '*+
: &00 #$&1 ,")$ +'--"]
#-').&1')#'#/")a .#$+
<$11.5 =$+'#"&"/$#/<5
#-').&1')#'#/")
!
#-').&"-#$- '.."</'#$G ]/#=
')#/($) &-"<$../)( BI2CF
K;5 (.3 3K65 '(+
: #-').&1')#
/++*)"($)/</#9 3;45 '*(
: #*+"- ')#/($) -$<"()/#/")
3K@5 '(' &+*
"
#-'.#*X*+', 3K;5 6;@
 !"#$%
#-//"G"#=9-")/)$ BI>F 66?5
)),
M?1=D0?><# ND!==0$! 6@?5
)2,
#-"&=",1'.# 64?5 )-,
M?>=#B1&1<# %?AH! 6>65 )++
IDU ,/)G/)(A/)=/,/#/)( /+A
+*)"(1",*1/). BI7NNF
66?5 )),3 64?5 )-,
#*,$-<*1"./. 66@5 ))'
: (-')*1"+' 66@
: /++*)$ -$.&").$ 66@5 ))'
: T'<</)$ 6K@5 )('
#*,*1"/)#$-.#/#/'1 )$&=-/#/.
66;5 )).
#*+"- ')#/($). 3K65 '(+
: /G$)#/0/<'#/") 3K@5 '('
: +'-H$-. 6;?
: )$"')#/($). 3K65 '(+
: -$<"()/#/") 3K@5 '('
#*+"- <$11.
: <")#'+/)'#/)( 3K?5 '(,
: /++*)$ -$<"()/#/") $.<'&$
+$<=')/.+. 3K65 '(+
: /--'G/'#$G '*#"1"("*. 3K45
'((
: 19.'#$. 3K45 '((
: #*+"- ')#/($) -$<"()/#/")
3K@5 '('
: T/.*'1/X'#/") ?;5 /.
#*+"- /++*)"1"(9 3K@:L
: $)=')<$+$)# "0 )").&$</0/<
/++*)/#9 3K45 '((
#*+"-A/)0/1#-'#/)( 19+&="A
<9#$. BIN[.F 3K;
#*+"- )$<-"./. 0'<#"- # BI!YA
#F 4@5 -'3 6?4:K
: .9.#$+/< 'G+/)/.#-'#/")
3K45 '((
: #*,$-<*1"./. 66@5 ))'
#*+"- )$<-"./. 0'<#"- %
BI!Y%F 6@5 )'3 6?4:K
#*-,/G/+$#-9 L;5 ..
9 &00 ^O4SG
_3A`!C 3??5 '/,3 6;>
!
*1<$-'#/T$ <"1/#/. 63@5 )''3
6365 )'+
&++
*-'#$ <-9.#'1. 3?@5 '/' T/#'+/) 736 G$0/</$)<9 6@?5
*-#/<'-/' 6@@5 )2' )2,
*T$' 64@5 )-' T/#-/#/. 6445 )-(
*T$/#/. 63;5 )'.3 6445 )-( V"(#:\"9')'(/:U'-'G'
: ')#$-/"- 6445 )-( .9)G-"+$ 64;5 )-.
: 7$=<d$#R. .9)G-"+$ 64;5
)-.
: /)#$-+$G/'#$ 6445 )-( ;
: &='<"($)/< 64;
: &".#$-/"- 6445 )-( i'1G$).#-"Q+R.
: V"(#:\"9')'(/:U'-'G' +'<-"(1",*1/)$+/' 3>?5
.9)G-"+$ 64; 3465 '-+
: : <-9"(1",*1/). 34;5 '-.
: 1/(=# <='/) '+91"/G"./.
34?
: i$($)$-R. (-')*1"+'#"./.
3S;5 ',.3 6;;
T'<</)'#/"). 6K@:> : "<*1'- +')/0$.#'#/"). 64;5
: <'1$)G'- /) <=/1G=""G 6K@5 )-.
)(' i$.#$-) ,1"# ?65 /+
: &$&#/G$ 6;@ i=/&&1$R. G/.$'.$ 6@?5 )2,
T'<</)$. i/G'1 +$#="G ?@
: ($)$#/<'119 $)(/)$$-$G i/.H"##:21G-/<= .9)G-"+$
6K65 )(+ 3@65 '2+
: UNV 3365 ''+
: 1/T$ 6K@
: .&1/#AT/-*. 6K@ <
T'.<*1'- <$11 'G=$./") +"1$A
<*1$ 3 BV^2ZA3F >;5 +. gA1/)H$G
T'.<*1/#/. '('++'(1",*1/)$+/'
: '11$-(/< 6@45 )2( 3@@5 '2'
: '*#"/++*)$ =$&'#/#/. 636 W')#="+'5 <*#')$"*. 6365
: G/'()".#/< ')#/,"G/$. 6;4 )'+
: 1'-($ T$..$1 6;; W$)"#-').&1')#'#/") 3;65 '*+
: +$G/*+A./X$G T$..$1. 6;; W$-"&=#='1+/' 3S@5 ','
: )$<-"#/X/)( W$-".#"+/' 3S@5 ','
1$*H"<9#"<1'.#/< 64;5 )-.
: &')*T$/#/. 64;
: .<1$-/#/. 6465 )-+ =
: .+'11 T$..$1. 6;;
: *-#/<'-/'1 6@@5 )2' j" ')#/($) 6>;5 )+.
: &00 #$&1 .9.#$+/< T'.<*1/#/.
T$)"A"<<1*./T$ G/.$'.$ 3;@5
'*' >
T$-9 1'#$ ')#/($) 4 BV[2A4F
X$#'A'.."</'#$G &-"#$/)
T/)<*1/) 4@5 -' BL@HO'F 3?
T/-'1 ')#/($). 66?5 )),3 6>65 X$#'A'.."</'#$G &-"#$/) H/)'.$
)++ Bb2C H/)'.$F 3?
T/-'1 &-"#$/). 3K65 '(+ X9+"($). K?