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
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
C1r
C1s
Ca++
C1q
C2 C3 C4
C1 complex
C1s is an enzyme and cleaves C4 and C2
Classical Pathway
Generation of C3-convertase
C4a C1r
C1s
Ca++
b
C4
C1q
Cleavage of C4 by C1s
produces C4a and C4b
Classical Pathway
Generation of C3-convertase
C4a C1r C2b
C1s
a C1s binds C2 and C2
Ca++ C2 is cleaved by C1s.
C1q C2b is released but
C2a remains bound
Mg++ to C4b on the
surface. C4b2a is C3
Convertase
C4b C2 a
Classical Pathway
Generation of C5-convertase
C4a C1r C2b C3a
C1s
Ca++ ________
C4b2a3b is C5 convertase; it
C1q leads into the Membrane Attack
Pathway
Mg++
C3 b
C4b C2 a
Classsical
Pathway
Lectin
Pathway
• Lectin pathway
– Released by
macrophages ingesting
microbes
– Lectins initiate
complement
Components of mannose-binding
lectin pathway
C4
MASP2
Pathogen
MBL C2 MASP1
• mannose binding lectin (MBL), MBL associated
serine proteases (MASP-1, MASP-2)
Mannose-binding lectin pathway
_____
C2b
C4b2a is C3 convertase; it will
C4a lead to the generation of C5
convertase
MASP1 C4b
C4
C2
MASP2 C2a
MBL C4b C2a
Binding to lectins cause autocatalytic activation
of MASPs, which then cleave C4 & C2
C5-convertase
C5-convertase of the
Classical and lectin
Pathways
C2a C3b
C4b
Lectin Pathway
Alternative
Pathway
• Alternative pathway
– Activated between
complement proteins and
microbe
Components of the
alternative pathway
fD
C3 fB
P
• fB = factors B, fD, H and I, properdin (P)
Spontaneous C3 activation
Generation of C3 convertase
D
H2O
B b
C3 C3 b
C3a
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
C3a C3b B b C3 b
C3-activation
the amplification loop
C3 b B b C3b
C3a C3b Bb
C3a
C3-activation
the amplification loop
Bb C3b
Bb C3b
C3a C3b Bb
C3a
C3a
Control of spontaneous
C3 activation via DAF
DAF prevents
the binding of C3b
B
factor B to C3b
DAF
CR1
Autologous cell membrane
Control of spontaneous
C3 activation via DAF
DAF dislodges
C3b-bound
B b B b C3b
factor Bb
DAF
CR1
Autologous cell membrane
C3b stabilization and
C5 activation
C3a
C3b finds an activator
(protector) membrane
This is stable C5 convertase of
P the alternative pathway
D
C3b
B b
C3 b
C5-convertase of the two
pathways
C5-convertase of the C5-convertase of the
Classical and lectin Alternative Pathway
Pathways
C3b Bb C3b
C2a C3b
C4b
Alternative Pathway
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
C5
C8
C
9
Lytic pathway
C5-activation
C5a
C5 b
C3b
C4b C2 a
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 C5 b
Lytic pathway:
insertion of lytic complex into cell membrane
C6
C8 C7 b
C5
C CC
99 9 C9
C
9 C
9
C
9 C C
9 9
Soluble Pattern Recognition Receptors-
Complement activation pathways
Biological effects of C5a
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
34
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
35
C1-inhibitor deficiency:
hereditary angioedema
Complement System
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