The Complement System

Complement refers, historically, to fresh serum capable of lysing antibody (Ab)-coated cells. This activity is destroyed (inactivated) by heating serum at 56 degrees C for 30 minutes.

The complement system plays a major role in host defense and the inflammatory process (through innate and acquired immunity). It consists of complex series of at least 25 plasma proteins produced by different tissues and cells including hepatocytes, macrophages and gut epithelial cells are normally functionally inactive.

fibroblast

liver

Synthesis by
MQ

Complement functions
Host benefit:
opsonization to enhance phagocytosis phagocyte attraction and activation lysis of bacteria and infected cells clearance of immune complex

Host detriment:
Inflammation, anaphylaxis

Pathways of Complement Activation

Classical

Alternative (properdin)

Pathways of complement activation

CLASSICAL PATHWAY
antibody dependent

ALTERNATIVE PATHWAY
antibody independent

Activation of C3 and
generation of C5 convertase

activation of C5
LYTIC ATTACK PATHWAY

Components of the Classical Pathway

C3

C4

C1 complex

Classical Pathway Generation of C5-convertase

________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway

C4b

C3b

Classical pathway Normally requires a suitable antibody (Ab) bound to an antigen (Ag), complement components 1, 4, 2 and 3 and Ca++ and Mg++ cations.

C1 activation
Binding of C1 (C1q, C1r & C1s complex), present in normal serum, to Ag-Ab complexes results in the autocatalysis of C1r. The altered C1r cleaves C1s and this cleaved C1s functions as C4-C2 convertase capable of cleaving both C4 and C2.

C4 and C2 activation (generation of C3 convertase)

Activated C1s enzymatically cleaves C4 into C4a and C4b. C4b binds to the Ag-bearing particle or cell membrane while C4a remains a biologically active peptide at the reaction site

C4b binds C2 that becomes susceptible to C1s and is cleaved into C2a and C2b. C2a remains complexed with C4b whereas C2b is released. C4b2a complex is known as C3 convertase.

C3 activation (generation of C5 convertase): C3 convertase, in the presence of Mg++, cleaves C3 into C3a and C3b. C3b binds to the membrane to form C4b2a3b complex; C3a is released. 4b2a3b complex functions as C5 convertase that cleaves C5 into C5a and C5b.

C3 activation (generation of C5 convertase)

C3 convertase, in the presence of Mg++, cleaves C3 into C3a and C3b. C3b binds to the membrane to form C4b2a3b complex; C3a is released. 4b2a3b complex functions as C5 convertase that cleaves C5 into C5a and C5b

Classical Pathway Generation of C3-convertase

Classical Pathway Generation of C3-convertase

_____ C4b2a is C3 convertase

C4b

Classical Pathway Generation of C5-convertase

________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway

C4b

C3b

Alternative Pathway

Alternative pathway begins with the activation of C3 and requires Factors B and D and Mg++ cation, all present in normal serum.

Components of the alternative pathway

C3

Spontaneous C3 activation

Generation of C3 convertase

C3 i

C3b

C3iBb complex has a very short half life

Spontaneous activation of C3: (C3i) is generated by slow hydrolysis of native C3. C3i binds factor B that is cleaved by Factor D to produce C3iBb. C3iBb acts as C3-convertase and cleaves native C3 into C3a and C3b

C3b binds factor B, which is again cleaved by Factor D to produce C3bBb complex (C3 convertase). This C3 convertase will continue to act on C3

Spontaneous C3 activation

Generation of C3 convertase

C3 i

C3b

C3iBb complex has a very short half life

Lytic pathway

Generation of C5 convertase leads to the activation of the

Lytic pathway

Components of the lytic pathway

C7 C6

C 9

Lytic pathway C5-activation

b C4b C3b

Lytic pathway C5-activation

b C4b C3b

Lytic pathway assembly of the lytic complex

C6 b

C7

Lytic pathway:
insertion of lytic complex into cell membrane

C6 b

C7 CC C C C9 9 9 9C 9C C C9 9 9 9

The lytic pathway involves the C5-C9 components. C5 convertase, generated by one of the pathways described above, cleaves C5 into C5a and C5b. C5b instantaneously binds C6 and subsequently C7 to yield C5b67 complex that attaches quickly to plasma membrane

Subsequently, C8 binds to this complex and causes the insertion of several C9 molecules. The insertion of C8(9)n complex causes formation of a hole in the membrane and cell lysis.

Lytic pathway assembly of the lytic complex

C6 b

C7

Lytic pathway:
insertion of lytic complex into cell membrane

C6 b

C7 CC C C C9 9 9 9C 9C C C9 9 9 9

Biologic activities of complement

Triggering inflammation (C5a> C3a>C4a) Chemotactically attracting phagocytes to the infection site (C5a)

Promoting the attachment of antigens to phagocytes via enhanced attachment or opsonization (C3b>C4b) Removing harmful immune complexes from the )C3b>C4b( body

Biological Role of Complement

Inflammation Phagocyte attraction and activation Opsonization to enhance phagocytosis Lysis of bacteria and infected cells Clearance of immune complexes

Functions
C5a C3a C4a

MAC

1- cytotoxicity
4- anaphylatoxins
C5a

2-chemotaxis

5- remove immune complexes

C3b C4b

3- opsonisation

The biologic functions of complement:

1- Opsonization and phagocytosis (C3b, C4b)

The biologic functions of complement (cont.):

2- Anaphylatoxins (Ca 4,2,3,5) and chemotaxis (C5a)

The biologic functions of complement (cont.):

3- Complement-mediated cytotoxicity

Regulatory mechanisms
C1 inhibitor C1qrs
Factor I

Protein H

C3 C3d

Unstable complex C3c

No factor B binding

No C3b production

Regulation of complement activation

Mammalian cells express regulatory proteins that inhibit complement activation, thus preventing complementmediated damage of host cells. Examples:

1- C1 inhibitor (C1 INH):

Stops complement activation early , at the stage of C1 activation. Deficiency of C1 INH hereditary angioneurotic edema.

C1-inhibitor deficiency: angioedema

Regulation of complement activation:

Examples:

(cont.)

2- Factor I: inhibits production of C3b 3- Factor H: prevent production of C3 convertase (C3bBb)

estimation of compl. Components is used in

Indication of Disease activity

Diagnosis&mgmt of -recurrent infections -allergy -autoimmunity