Complement system

Tiana Milanda

Chapter 4

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 opsonizationGram-negative bacteria more susceptible

Pathways of complement activation

CLASSICALPATHWAY

ALTERNATIVEPATHWAY

activationof C5

LYTIC ATTACKPATHWAY

antibodydependent

LECTINPATHWAY

antibodyindependent

Activation of C3 andgeneration of C5 convertase

Classsical Pathway

• Classical pathway– Initiated by antibody –

antigen reaction

Components of the Classical Pathway

C4C2 C3

C1 complex

Ca++

C1r C1s

C1q

C1s is an enzyme and cleaves C4 and C2

Ca++

C1r C1s

C1q

C4

C4a

b

Classical Pathway Generation of C3-convertase

Cleavage of C4 by C1s produces C4a and C4b

Classical Pathway Generation of C3-convertase

C4b

Mg++

C4a

Ca++

C1r C1s

C1q

C2

C2ba

C2 a

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

Classical Pathway Generation of C5-convertase

C4b

Mg++

C4a

Ca++

C1r C1s

C1q

C2b

C2 a

C3

C3a

b

________C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway

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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 OpsoninActivation of phagocytic cells

C4a Anaphylotoxin

C4b Opsonin

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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

C1-inhibitor deficiency:hereditary angioedema

Lectin Pathway

• Lectin pathway– Released by

macrophages ingesting microbes

– Lectins initiate complement

Components of mannose-binding lectin pathway

C4

MBL C2 MASP1

MASP2

Pathogen

• mannose binding lectin (MBL), MBL associated serine proteases (MASP-1, MASP-2)

Mannose-binding lectin pathway

C4

MBL

C4b

C4a

C4b

C2

C2b

C2a

C2a

_____C4b2a is C3 convertase; it will lead to the generation of C5 convertase

MASP1MASP2

Binding to lectins cause autocatalytic activationof MASPs, which then cleave C4 & C2

C5-convertase

C4b C2a C3b

C5-convertase of the Classical and lectin Pathways

Alternative Pathway

• Alternative pathway– Activated between

complement proteins and microbe

Components of thealternative pathway

C3 fB

fD

P

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

Spontaneous C3 activation

C3

H2O

B

D

Generation of C3 convertase

fB activate fD which then cut fB releasingBa, while Bb becomes an active proteaseC3Bb complex has a very short half life

b C3

C3a

b

B

D

bC3b

If spontaneously-generated C3b is not degraded

C3-activationthe amplification loop

C3C3a b

C3a

B

D

BbC3b

C3 b

C3-activationthe amplification loop

C3b

C3a

b

C3a

C3a BbC3b

BbBb

C3a

C3-activationthe amplification loop

C3bC3b

Control of spontaneousC3 activation via DAF

C3b

DAF prevents

the binding of

factor B to C3bB

Autologous cell membrane

DA

F

CR1

Control of spontaneousC3 activation via DAF

DAF dislodges

C3b-bound

factor BbB bb C3b

Autologous cell membrane

DA

F

CR1

B b

C3b stabilization andC5 activation

C3b

C3b finds an activator (protector) membrane

C3

C3a

bB

D

b

P This is stable C5 convertase of the alternative pathway

C5-convertase of the two pathways

C3b Bb C3b

C5-convertase of the Alternative Pathway

C4b C2a C3b

C5-convertase of the Classical and lectin Pathways

Pathways of complement activation

CLASSICALPATHWAY

ALTERNATIVEPATHWAY

activationof C5

LYTIC ATTACKPATHWAY

antibodydependent

LECTINPATHWAY

antibodyindependent

Activation of C3 andgeneration of C5 convertase

Complement System

Components of the lytic pathway

C6

C9

C8

C7

C5

Lytic pathwayC5-activation

C3b C2 aC4b

C5 b

C5a

Lytic pathwayassembly of the lytic complex

C5 b

C6

C7

C5b first binds C6 and then C7from the plasma. Membrane boundC5b67 recruits C8 and C9 to formthe Membrane Attack Complex (MAC)

Lytic pathway:insertion of lytic complex into cell membrane

C5 b

C6

C7C8

C9C9 C9 C9C9C9 C9 C9 C9

Soluble Pattern Recognition Receptors-Complement

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.