The Complement

System
 Complement:
Complement:
history
history
Discovered in 1894 by
Bordet

It represents lytic activity

of fresh serum
Its lytic activity destroyed
when heated at 56C
for 30 min
The complement system is the major
effector of the humoral branch of the
immune system.
 The Complement Components

• 1. Complement components are designated by numerals

(C1–C9), by letter symbols (e.g., factor D), or by trivial
names (e.g., homologous restriction factor).
2. Peptide fragments formed by activation of a component
are denoted by small letters. In most cases, the smaller
fragment resulting from cleavage of a component is
designated “a” and the larger fragment designated “b”
(e.g., C3a, C3b; note that C2 is an exception: C2a is the
larger cleavage fragment).
• 3 .Those complexes that have enzymatic activity are
designated by a bar over the number or symbol (e.g.,
C4b2a, C3bBb).
 Complement Activation

• The Classical Pathway

• Alternative pathway

• Lectin pathway
 The Classical Pathway
• Begins with Antigen-Antibody(IgM,IgG) Binding
• The formation of an antigen-antibody complex
induces conformational changes in the Fc portion of
antibody that expose a binding site for the C1
component of the complement system.
• The initial stage of activation involves C1, C2,
C3, and C4.
 Components of the Classical
Pathway

C1r C1s
Ca++
C1q
C2 C3 C4

C1 complex
 Classical Pathway
Generation of C3-convertase
C4a C1r C1s
Ca++

C4 b
C1q
 Classical Pathway
Generation of C3-convertase

C4a C1r C1s

2 a
Ca++ C
C2b
C1q

Mg++
C4b2a is C3 convertase

C4b C2a
 Classical Pathway
Generation of C5-convertase

C4a C1r C1s C3a

Ca++ C2b
C4b2a3b is C5 convertase;
C1q
it leads into the Membrane
Mg++ Attack Pathway

C3
b
C4b C2a
 The Alternative Pathway

• the alternative pathway is a component of the innate

immune system
• The alternative pathway is initiated in most cases by cell-
surface constituents that are foreign to the host
• involve four serum proteins: C3, factor B, factor D, and
properdin.
• serum C3 is subject to slow spontaneous hydrolysis to
yield C3a and C3b.
 Components of the
alternative pathway

C3 B

P
 Spontaneous C3 activation

Generation of C3 convertase
D
H2O

Bb
C3 i C3 b

C3a

This C3b molecule has a very short half life

 C3-activation
the amplification loop

If spontaneously-generated
C3b is not degraded

C3a C3b Bb C3 b
 C3-activation
the amplification loop

C3 b Bb C3b

C3a C3b Bb
C3a
 C3-activation
the amplification loop
D

C3 b Bb Bb C3b
C3b

C3a C3b Bb
C3a
C3a
 C3-activation
the amplification loop

Bb Bb C3b
C3b

C3a C3b Bb
C3a
C3a
 The Lectin Pathway

• The lectin pathway is activated by the binding of

mannose-binding lectin (MBL) to mannose residues
• After MBL binds to the surface of a cell or pathogen,
MBL-associated serine proteases,MASP-1 and MASP-2,
bind to MBL. The active complex formed by this
association causes cleavage and activation of C4 and
C2.
• activating the C2–C4 components to form a C5
convertase doesn,t need for specific antibody
Components of mannose-binding
lectin pathway

C4
MASP2

MBL C2 MASP
Mannose-binding lectin pathway

C4a C4b2a is C3 convertase;

C2b it will lead to the generation
of C5 convertase
MASP C4b
C4
MASP2 2a
CC2
MBL C4b C2a
 The Three Complement Pathways Converge
at the Membrane-Attack Complex
.
• The terminal sequence of complement
activation involves C5b, C6, C7, C8, and
C9, which interact sequentially to form a
macromolecular structure called the
membrane-attack complex (MAC).
 Lytic pathway

Generation of C5 convertase leads

to the activation of the

Lytic pathway
Components of the lytic pathway

C7
C
5 C6

8
C
C
9
Lytic pathway
C5-activation
C5a

5
C b

C3b
C4b C2 a
 Lytic pathway
assembly of the lytic complex

C6

C7 5
C b
 Lytic pathway:
insertion of lytic complex into cell membrane

C6

8
C 5
C b
C7
CC C C
C9 9 9 9C
9C C C9
9 9 9
 The Function of MAC
• MAC forms a large channel through the
membrane of the target cell, enabling ions
and small molecules to diffuse freely across
the membrane.
• So the cell cannot maintain its osmotic
stability and is killed by an influx of water and
loss of electrolytes.
Regulation of the Complement
System
C1qrs breakdown

C1r C1s
C1Inh

C1q
C1r C1s
Biological effects of C5a
Opsonization and phagocytosis
 Biological Consequences of
Complement Activation
• The Membrane-Attack Complex Can Lyse a Broad
Spectrum of Cells
• Cleavage Products of Complement Components Mediate
Inflammation
• C3b and C4b Binding Facilitates Opsonization
• The Complement System Also Neutralizes Viral
Infectivity
• The Complement System Clears Immune Complexes
from Circulation
 The Functions of Complement

• Lysis of cells, bacteria, and viruses

• Opsonization, which promotes phagocytosis of

particulate antigens

• Binding to specific complement receptors on cells of

the immune system, triggering specific cell functions,
inflammation, and secretion of immunoregulatory
molecules

• Immune clearance, which removes immune complexes

from the circulation and deposits them in the spleen and
liver