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Complement. Abdul Ghaffar Microbiology and Immunology. Complement: history. Discovered in 1894 by Bordet It represents lytic activity of fresh serum Its lytic activity destroyed when heated at 56C for 30 min. Complement functions. Host benefit: opsonization to enhance phagocytosis

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slide1

Complement

Abdul Ghaffar

Microbiology and Immunology

complement history
Complement:history

Discovered in 1894 by Bordet

It represents lytic activity of fresh serum

Its lytic activity destroyed when heated at 56C for 30 min

complement functions
Complement functions
  • Host benefit:
    • opsonization to enhance phagocytosis
    • phagocyte attraction and activation
    • lysis of bacteria and infected cells
    • regulation of antibody responses
    • clearance of immune complexes
    • clearance of apoptic cells
  • Host detriment:
    • Inflammation, anaphylaxis
definitions
Definitions
  • C-activation: alteration of C proteins such that they interact with the next component
  • C-fixation: utilization of C by Ag-Ab complexes
  • Hemolytic units (CH50): dilution of serum which lyses 50% of Ab-coated r.b.c in a suspension
  • C-inactivation: denaturation (usually by heat) of an early C-component resulting in loss of hemolytic activity
  • Convertase/esterase: altered C-protein which acts as a proteolytic enzyme for another C-component
proteins of the complement system nomenclature
Proteins of the complementsystem (nomenclature)
  • 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),
  • C1 receptor (CR1), protein-S (vitronectin)
activation product of complement proteins nomenclature

Activated component are usually over-lined: e.g. C1qrs

Activation product of complement proteins (nomenclature)

When enzymatically cleaved, the larger moiety, binds to the activation complex or membrane and the smaller peptide is released in the microenvironment

Letter “b” is usually added to the larger,membrane-binding, peptide and “a” to the smaller peptide (e.g., C3b/C3a, C4b/C4a, C5b/C5a), EXCEPT C2 (the larger, membrane-binding moiety is C2a; the smaller on is C2b)

pathways of complement activation

antibody

independent

antibody

dependent

Activation of C3 and

generation of C5 convertase

activation

of C5

LYTIC ATTACK

PATHWAY

Pathways of complement activation

LECTIN

PATHWAY

ALTERNATIVE

PATHWAY

CLASSICAL

PATHWAY

components of the classical pathway

C1r

C1s

C1q

Ca++

Components of the Classical Pathway

C4

C2

C3

C1 complex

classical pathway generation of c3 convertase1

C2b

C1r

C1s

a

C1q

Ca++

C2

a

Classical Pathway Generation of C3-convertase

C2

C4a

Mg++

C4b2a is C3 convertase

C4b

classical pathway generation of c5 convertase

C1r

C3a

C1s

C1q

Ca++

C2

a

b

Classical Pathway Generation of C5-convertase

C2b

C4a

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

Mg++

C3

C4b

mannose binding lectin pathway

C2a

C2a

C2b

C4a

C4b

C4b

MBL

Mannose-binding lectin pathway

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

C4

C2

MASP2

MASP1

spontaneous c3 activation

b

i

b

C3a

Spontaneous C3 activation

Generation of C3 convertase

D

H2O

B

C3

C3

C3iBb complex has a very short half life

c3 activation the amplification loop

C3b

b

b

C3a

C3-activationthe amplification loop

If spontaneously-generated C3b is not degraded

D

B

C3

c3 activation the amplification loop2

Bb

C3b

C3b

b

b

Bb

C3b

C3a

C3-activationthe amplification loop

D

B

C3

C3a

C3a

c3 activation the amplification loop3

Bb

Bb

C3b

C3b

C3b

Bb

C3b

C3-activationthe amplification loop

C3a

C3a

C3a

control of spontaneous c3 activation via daf

C3b

DAF

CR1

Autologous cell membrane

Control of spontaneousC3 activation via DAF

DAF prevents the binding of factor B to C3b

B

control of spontaneous c3 activation via daf1

B

C3b

b

B

b

b

DAF

CR1

Autologous cell membrane

Control of spontaneousC3 activation via DAF

DAF dislodges C3b-bound factor Bb

control of spontaneous c3 activation via cr1

DAF

B

b

B

b

C3b

C3b

CR1

CR1

iC3b

iC3b

Control of spontaneousC3 activation via CR1

H

I

I

DAF

Autologous cell membrane

degradation of spontaneously produced c3b

C3c

C3c

C3dg

C3dg

C3b

C3b

I

I

iC3b

iC3b

Degradation of spontaneously produced C3b
c3b stabilization and c5 activation

C3a

C3b finds an activator (protector) membrane

C3b

b

b

C3b stabilization andC5 activation

This is stable C5 convertase of the alternative pathway

D

P

B

C3

c5 convertase of the two pathways

C2a

C3b

C4b

C5-convertase of the two pathways

C5-convertase of the Classical and lectin Pathways

C5-convertase of the Alternative Pathway

Bb

C3b

C3b

slide28

Lytic pathway

Generation of C5 convertase leads to the activation of the

Lytic pathway

c1qrs breakdown

C1r

C1r

C1s

C1s

C1q

C1qrs breakdown

C1Inh

biological properties of c activation products

Product

Biological Effects

Regulation

C2b (prokinin)

edema

C1-INH

C3a (anaphylatoxin)

carboxy-peptidase- B (C3-INA)

mast cell degranulation; enhanced vascular permeability; anaphylaxis

Biological properties of C-activation products
biological properties of c activation products1

Product

Biological Effects

Regulation

C3b (opsonin)

opsonization; phagocyte activation

factors H & I

C4a (anaphylatoxin)

as C3, but less potent

(C3-INA)

C4b (opsonin)

opsonization; phagocytosis

C4-BP, factor I

Biological properties of C-activation products
biological properties of c activation products2

Product

Biological Effects

Regulation

C5a (chemotactic factor)

anaphylactic as C3, but much more potent;

attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release

carboxy-peptidase-C (C3-INA)

C5b67

chemotaxis, attaches to other membranes

protein-S

Biological properties of C-activation products