Chapter 4

Complement system

Tiana Milanda
 Complement: History

o Discovered in 1894 by
Bordet
o It represents lytic
activity of fresh serum

o Its lytic activity is

destroyed when
heated at 56ºC for 30
min
 Complement System
• Complement
– Consists of over 30 proteins
• Designated by C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9
• Factors B, D, H and I, properdin (P)
• Mannose binding lectin (MBL), MBL associated serine
proteases (MASP-1, MASP-2)
• C1 inhibitor (C1-INH, serpin), C4-binding protein (C4-BP),
Decay Accelerating Factor (DAF), Complement Receptor 1
(CR1), protein-S (vitronectin)
• Cascade of reactions eventually
– Destroy microorganisms by
• Cytolysis
• Inflammation
• Phagocytosis by opsonization
Gram-negative bacteria more susceptible
 Pathways of complement
activation
CLASSICAL LECTIN ALTERNATIVE
PATHWAY PATHWAY PATHWAY

antibody antibody
dependent independent

Activation of C3 and
generation of C5 convertase

activation
of C5
LYTIC ATTACK
PATHWAY
 Classsical
Pathway
• Classical pathway
– Initiated by antibody –
antigen reaction
 Components of the Classical
Pathway

C3 C4

C1 complex

C1s is an enzyme and cleaves C4 and C2

 Classical Pathway
Generation of C3-convertase

Cleavage of C4 by C1s
produces C4a and C4b
 Classical Pathway
Generation of C3-convertase

C1s binds C2 and C2

is cleaved by C1s.
C2b is released but
C2a remains bound
to C4b on the
surface. C4b2a is C3
Convertase

C4b
 Classical Pathway
Generation of C5-convertase

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

C3 b
C4b
 Biological Activities of
Classical Pathway Components
Component Biological Activity

C2b Prokinin; cleaved by plasmin to yield kinin, which

results in edema
C3a Anaphylotoxin; can activate basophils and mast
cells to degranulate resulting in increased vascular
permeability and contraction of smooth muscle cells,
which may lead to anaphylaxis
C3b Opsonin
Activation of phagocytic cells
C4a Anaphylotoxin

C4b Opsonin
10
 Control of Classical Pathway
Components
Component Regulation

All C1-inhibitor (C1-INH); dissociates C1r and C1s from

C1q
C3a C3a-inactivator (C3a-INA; Carboxypeptidase B)

C3b Factors H and I; Factor H facilitates the degradation

of C3b by Factor I
C4a C3a-INH
C4b C4 binding protein (C4-BP) and Factor I; C4-BP
facilitates degradation of C4b by Factor I; C4-BP
also prevents the association of C2a with C4b thus
blocking formation of C3 convertase
11
C1-inhibitor deficiency:
hereditary angioedema
 Lectin
Pathway
• Lectin pathway
– Released by
macrophages ingesting
microbes
– Lectins initiate
complement
 Components of mannose-binding
lectin pathway

Pathogen

MBL MASP1

• mannose binding lectin (MBL), MBL associated

serine proteases (MASP-1, MASP-2)
Mannose-binding lectin pathway

_____
C4b2a is C3 convertase; it will
lead to the generation of C5
convertase

MASP1

MBL

Binding to lectins cause autocatalytic activation

of MASPs, which then cleave C4 & C2
 C5-convertase

C5-convertase of the
Classical and lectin
Pathways

C3b
C4b
 Alternative
Pathway
• Alternative pathway
– Activated between
complement proteins and
microbe
 Components of the
alternative pathway

C3

• fB = factors B, fD, H and I, properdin (P)

Spontaneous C3 activation

Generation of C3 convertase

b
C3 C3 b

fB activate fD which then cut fB releasing

Ba, while Bb becomes an active protease
C3Bb complex has a very short half life
 C3-activation
the amplification loop

If spontaneously-generated
C3b is not degraded

C3b b C3 b
 C3-activation
the amplification loop

C3 b b C3b

C3b
 C3-activation
the amplification loop

C3b C3b

C3b
 Control of spontaneous
C3 activation via DAF

DAF prevents
the binding of C3b

factor B to C3b
CR1
Autologous cell membrane
 Control of spontaneous
C3 activation via DAF

DAF dislodges
C3b-bound
b C3b
factor Bb
CR1
Autologous cell membrane
 C3b stabilization and
C5 activation

C3b finds an activator

(protector) membrane
This is stable C5 convertase of
the alternative pathway

b
C3b C3 b
 C5-convertase of the two
pathways

C5-convertase of the C5-convertase of the

Classical and lectin Alternative Pathway
Pathways

C3b C3b C3b

C4b
 Pathways of complement
activation
CLASSICAL LECTIN ALTERNATIVE
PATHWAY PATHWAY PATHWAY

antibody antibody
dependent independent

Activation of C3 and
generation of C5 convertase

activation
of C5
LYTIC ATTACK
PATHWAY
Components of the lytic pathway

C7
C6

C
9
Lytic pathway
C5-activation

C3b
C4b
 Lytic pathway
assembly of the lytic complex

C5b first binds C6 and then C7

from the plasma. Membrane bound C6
C5b67 recruits C8 and C9 to form
the Membrane Attack Complex (MAC)
C7 b
 Lytic pathway:
insertion of lytic complex into cell membrane

C6

C7 b

C C C
9 9 C
9 9
C
9C C
9
9 C C
9 9
Soluble Pattern Recognition Receptors-
Complement activation pathways
Biological effects of C5a
Complement System