complement system done

COMPLEMENT SYSTEM

DR. MALEEHA ASLAM

Complement system (nomenclature)

• Protective cascading system- composed of 25 proteins

• Can be activated via Classical and Alternate pathways

• Culminates in three useful results– phagocytosis, lysis and inflammation

• Classical pathway C1- C9= C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9

• Alternate pathway = factors B, D, and IF, properdin (P)

• C3b inactivator, anaphylotoxin inhibitors

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 microenvironmentLetter “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 one is C2b)

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

GENERAL PROPERTIES OF COMPLEMENT SYSTEM

• PRESENT IN NORMAL SERA• DOES NOT INCREASE ON IMMUNIZATION• DESTROYED AT 56oC IN 30 MINUTES• NOT A SINGLE SUBSTANCE- COMPLEX• IN CLASSICAL PATHWAY- 9 PROTEINS COMPLEX• IN ALTERNATE PATHWAY- 13 PROTEINS

COMPLEX• IgM, IgG-1,2,3 REACT WITH COMPLEMENT• ACTIVATION BY ANTIGEN ANTIBODY COMPLEX• ACTIVATION BY POLYSAC/ ENZYMES –

ALTERNATE PATHWAY• INACTIVATORS AND INHIBITORS PRESENT IN

SERUM

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 apoptotic cells

• Host detriment:– Inflammation, anaphylaxis

Pathways of complement activation

CLASSICALPATHWAY

ALTERNATIVEPATHWAY

activationof C5

LYTIC ATTACKPATHWAY

antibodydependent

LECTINPATHWAY

antibodyindependent

Activation of C3 andgeneration of C5 convertase

CLASSICAL PATHWAY

3 GROUPS

• RECOGNITION UNIT

CI( C1q, C1r, C1s)

•ACTIVATION COMPLEX

C4,C2,C3

•MEMBRANE ATTACK COM

C5,C6,C7,C8,C9

ALTERNATE PATHWAY

IMPORTANT PROTEINS

•FACTOR B- C3 PROACTIVATOR

•FACTOR D- C3 PROACTIVATOR

CONVERTASE – SPLIT FACTOR B

Ba & Bb •FACTOR P- PROPERDIN

Activation of Complement

THE CLASSICAL AND ALTERNATE PATHWAYS

Components of the Classical Pathway

C4C2 C3

C1 complex

Ca++

C1r C1s

C1q

Ca++

C1r C1s

C1q

C4

C4a

b

Classical Pathway Generation of C3-

convertase

Generation of C3-convertase

C4b

Mg++

C4a

Ca++

C1r C1s

C1q

C2

C2ba

C2a

_____

C4b2a is C3 convertase

Classical Pathway Generation of C5-convertase

C4b

Mg++

C4a

Ca++

C1r C1s

C1q

C2b

C2a

C3

C3a

b

________

C4b2a3b is C5 convertase; it leads into the Membrane

Attack Pathway

ALTERNATE PATHWAY

Components of thealternative pathway

C3 B

D

P

Spontaneous C3 activation

C3

H2O

i B

D

Generation of C3 convertase

C3iBb 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

C3a BbC3b

C3bC3 BbB

D

bb

C3a


loop

C3b

C3a

C3a BbC3b

BbBbC3b

C3a


loop

C3bC3b

Control of spontaneousC3 activation via DAF

C3b

DAF prevents

the binding of

factor B to C3b

B

Autologous cell membrane

DA

F

CR1

Control of spontaneousC3 activation via DAF

DAF dislodges

C3b-bound

factor Bb

B 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

PThis 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

Generation of C5 convertase leads to the activation of the

Lytic pathway

Lytic pathway

Components of the lytic pathway

C6

C9

C8

C7C5

Lytic pathwayC5-activation

C3b C2 aC4b

C5 b

C5a

Lytic pathwayassembly of the lytic

complex

C5 b

C6

C7

Lytic pathway:insertion of lytic complex into cell

membrane

C5 b

C6

C7C8

C9

C9

C9

C9C9

C9 C

9C9

C9

Products and their Control FactorsFragment Activity Effect Control Factor (s)

C2a Prokinin, accumulation of fluids Edema C1-INHIBITOR

C3a

Basophil and mast cells degranulation; enhanced vascular permeability, smooth muscle contraction

Anaphylaxis C3a-INACTIVATOR

C3b Opsonin, phagocyte activation Phagocytosis Factors H and I

C4a


Anaphylaxis(least potent)

C3a-INACTIVATOR

C4b Opsonin Phagocytosis C4-BP and Factor I

C5a


Anaphylaxis(most potent)

C3a-INACTIVATORChemotaxis, stimulation of respiratory burst, activation of phagocytes, stimulation of inflammatory cytokines

Inflammation

C5bC6C7Chemotaxis Inflammation

Protein S (vitronectin)Attaches to other membranes

Biological Activities of Classical Pathway ComponentsComponent Biological ActivityC2b Prokinin; cleaved by plasmin to yield

kinin, which results in edemaC3a 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 AnaphylaotoxinC4b Opsonin

Product Biological Effects Regulation

Biological properties of C-activation products

anaphylactic as C3, but much more potent;attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release

C5a (chemotactic factor)

carboxy-peptidase-B (C3-INA)

C5b67 protein-Schemotaxis, attaches to other membranes

Biological effects of C5a

Control of Classical Pathway Components

Component RegulationAll C1-inhibitor (C1-INH); dissociates C1r

and C1s from C1qC3a C3a-inactivator (C3a-INA;

Carboxypeptidase B)C3b Factors H and I; Factor H facilitates the

degradation of C3b by Factor IC4a C3a-INHC4b 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

Complement deficiencies and diseasePathway/Component Disease Mechanism

Classical Pathway

C1INH Hereditary angioedema Overproduction of C2b (prokinin)

C1, C2, C4 Predisposition to SLE

Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation

Alternative Pathway

Factors B or D Susceptibility to pyogenic (pus-forming) bacterial infections

Lack of sufficient opsonization of bacteria

C3 Susceptibility to bacterial infectionsLack of opsonization and inability to

utilize the membrane attack pathway

C5, C6, C7 C8, and C9 Susceptibility to Gram-negative infections

Inability to attack the outer membrane of Gram-negative bacteria

Properdin (X-linked) Susceptibility meningococcal meningitis Lack of opsonization of bacteria

Factors H or I C3 deficiency and susceptibility to bacterial infections

Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3

C1-inhibitor deficiency:hereditary angioedema

complement system done

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