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Complement. Complement: History. Discovered in 1894 by Bordet It was used to refer to a heat-labile serum component Its lytic activity destroyed when heated at 56°C for 30 min However it is now known that complement contributes to many other functions. Complement Functions. Host benefit:

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Complement history
Complement: History

Discovered in 1894 by Bordet

It was used to refer to a heat-labile serum component

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

However it is now known that complement contributes to many other functions


Complement functions
Complement Functions

  • Host benefit:

    • opsonization to enhance phagocytosis

    • phagocytes attraction and activation

    • lysis of bacteria and infected cells

    • regulation of antibody responses

    • clearance of immune complexes

    • clearance of apoptotic cells

  • Host detriment:

    • Inflammation, anaphylaxis


Proteins of the complement system
Proteins of the complementsystem

  • Complement comprises over 20 different serum proteins

  • These proteins are produced by a variety of cells:

  • Hepatocytes, macrophages, gut epithelial cells

  • Some components can bind to Immunoglobulins

  • While others are proenzymes that when activated can cleave and activate other components


Proteins of the complement system nomenclature
Proteins of the complementsystem (nomenclature)

  • C1(q r s), 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)


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 a standardized suspension of Ab-coated R.B.Cs

  • 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


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 into 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)

EXCEPTION: C2 (the larger, membrane-binding moiety is C2a; the smaller one 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 convertase

C4a

C1r

C1s

C1q

b

Ca++

Classical Pathway Generation of C3-convertase

C4


Classical pathway generation of c3 convertase1

C2b

C1r

C1s

a

C1q

Ca++

C2

a

Classical Pathway Generation of C3-convertase

C2

C4a

_____

C4b2a is C3 convertase

Mg++

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




Components of mannose binding lectin pathway
Components of mannose-binding (lectin) pathway

  • Mannose Binding Lectin (MBL),

  • which binds to bacterial surface with mannose-containing polysaccharides

  • MBL associated serine proteases (MASP-1 MASP-2)


Components of mannose binding lectin pathway1

MBL

Components of mannose-binding lectin pathway

C4

MASP2

C2

MASP1


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


Components of the alternative pathway
Components of thealternative pathway

  • C3

  • factors B & D

  • properdin (P)


Control and regulation of the alternative pathway
Control and regulation of the alternative pathway

  • Factor I & H

  • DAF

  • Complement receptor 1


The alternative pathway can be activated by:

  • Many gram-negative bacteria:

    Neisseria meningitidis and N. gonorrhoea

  • Some gram-positive bacteria

  • Certain viruses and parasites

  • Aggregated immunoglobulina(particularly IgA)

the result is lysis of these organisms


Activation of the alternative pathway
Activation of the alternative pathway

  • Spontaneous hydrolysis of C3 to produce C3i

  • C3i cleaves Factor B into Bb

  • The C3iBb complex acts as C3 convertase(has very short half life)

  • Once C3b is formed Factor B binds to it and becomes susceptible to cleavage by Factor D

  • C3bBb is a more stable C3 convertase which continues to generate more C3b(amplfication loop)


Components of the alternative pathway1
Components of thealternative pathway

D

C3

B

P


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
C3b stabilization andC5 activation

  • When C3b finds the appropriate surface it binds to factor B, which is cleaved by Factor D to produce C3 convertase(C3bBb) (which is more stable)

  • C3 convertase(C3bBb) is further stabilized by Poperdin


C3b stabilization and c5 activation1

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


Lytic pathway

Generation of C5 convertase leads to the activation of the

Lytic pathway


Components of the lytic pathway

C8

C7

Components of the lytic pathway

C6

C5

C

9


Lytic pathway
Lytic pathway

  • C5-convertase (of the Classical and lectin Pathways or the Alternative Pathway) cleaves C5 into C5a & C5b

  • C5b associates with C6 &C7 and insrets into the cell membrane

  • Then C8 binds, followed by several molecules of C9

  • C9 molecules form a pore in the membrane

  • C5bC6C7C8C9 is MAC



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-B (C3-INA)

C5b67

chemotaxis, attaches to other membranes

protein-S

Biological properties of C-activation products





Complement deficiencies and disease alternative pathway cont
Complement Deficiencies and DiseaseAlternative Pathway cont.


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