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 56C 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
PATHWAY
antibody
dependent

LECTIN
PATHWAY

ALTERNATIVE
PATHWAY
antibody
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

C1 complex
C1s is an enzyme and cleaves C4 and C2

C4

Classical Pathway
Generation of C3-convertase
C1r

C1s

Ca++
C1q

C4
b

C4a

Cleavage of C4 by C1s
produces C4a and C4b

Classical Pathway
Generation of C3-convertase
C4a

C1r

C1s

Ca++

C2

C2b
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

C1q
Mg++

C4b

C2 a

Classical Pathway
Generation of C5-convertase
C4a

C1r

Ca++
C1q
Mg++

C3a

C2b

C1s

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

C3

C4b

C2 a

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

C4
MASP2

Pathogen

MBL

C2

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

C2b

C4a

MASP1

MASP2

MBL

C4b
C4
C2
C2a
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

C4b

C2a

C3b

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

C3

C3

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

C3

C3-activation
the amplification loop
D

C3

C3a
C3a

C3b

Bb

C3b

C3-activation
the amplification loop

Bb

C3a
C3a

C3a

Bb

C3b

C3b

Bb

C3b

Control of spontaneous
C3 activation via DAF
DAF prevents
the binding of
C3b

B
DAF

factor B to

C3b

CR1

Autologous cell membrane

Control of spontaneous
C3 activation via DAF
DAF dislodges
factor Bb

C3b

b
DAF

C3b-bound

CR1

Autologous cell membrane

C3b stabilization and

C5 activation
C3a

C3b finds an activator

(protector) membrane
P
C3b

This is stable C5 convertase of

the alternative pathway

C3

C5-convertase of the two

pathways
C5-convertase of the
Classical and lectin
Pathways

C4b

C2a

C3b

C5-convertase of the
Alternative Pathway

C3b

Bb

C3b

Pathways of complement
activation
CLASSICAL
PATHWAY
antibody
dependent

LECTIN
PATHWAY

ALTERNATIVE
PATHWAY
antibody
independent

Activation of C3 and
generation of C5 convertase
activation
of C5
LYTIC ATTACK
PATHWAY

Complement System

Components of the lytic pathway

C7

C6

C8

C5

C
9

Lytic pathway
C5-activation
C5a

C5

C4b

C2

C3b

Lytic pathway
assembly of the lytic complex
C5b first binds C6 and then C7
from the plasma. Membrane bound
C5b67 recruits C8 and C9 to form
the Membrane Attack Complex (MAC)

C6

C7

C5

Lytic pathway:

insertion of lytic complex into cell membrane

C6

C7
9 C
9 C
C
9C
9
C
C
9
9
C
C
9 C
9 9

C5

Soluble Pattern Recognition ReceptorsComplement activation pathways

Biological effects of C5a

Links to Specific Immunity

Phagocytosis continues to be common way to kill pathogenic
cells in both specific and non-specific response
Inflammation works to allow both specific and non-specific
immune response to accelerate
Fever also allows for better performance in both specific and
non-specific function
Specific immune response and antigen presentation further
stimulates non-specific actions like phagocytosis,
complement.