Lec.8 COMPLEMENT SYSTEM.

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Presentation transcript:

Lec.8 COMPLEMENT SYSTEM

Complement is a plasma proteins (C1-C9) found in the blood synthesized by the liver and play a major role in innate and adaptive immunity,it enhance the ability of antibody and phagocytic cells to clear microbes and damaged cells.

Activation of Pathways

1.Classical pathway: Classical pathway: Activated by Ag-Ab binding (antibody dependent activation, binds C1) The antibody-antigen complex bound to C1 activates C1s, which cleaves C4 and C2 to form C4b2b (C3 convertase). Active C3 convertase, which cleaves C3 molecules into two fragments: C3a and C3b. C3b forms a complex with C4b2b, producing a new enzyme, C5 convertase, which cleaves C5 to form C5a and C5b. C5b binds to C6 and C7 to form a complex. C8 then binds to the C5b/C6/C7 complex, followed by the polymerization of up to sixteen C9 molecules to produce the membrane attack complex that generates a channel or pore in the membrane.

Classical Complement Pathway C1qrs C2 C4 C3 antibody C5 C4b C4a Bacteria

Classical Complement Pathway C1qrs C2 Bacteria antibody C4 C3 C5 C4b C2b C4a C2a

Classical Complement Pathway C1qrs C2 Bacteria antibody C4 C3 C5 C4b C2b C3b C4a C2a C3a

Classical Complement Pathway C1qrs C2 C4 C3 antibody C5 C4b C2b C3b C4a C5b C2a Bacteria C3a C5a Animation complete

Classical Complement Pathway C1qrs antibody C4b C6 C2b C7 C3b C5b C8 Bacteria C6 C9 C7 C8 C9 C9 C9 C9 C9 C9 Animation complete

MAC PORES Source: undetermined Source: undetermined Source: www.wikimedia.org

Activated in the absence of antibody(antibody independent)except(IgA) 2. Alternative pathway: Activated in the absence of antibody(antibody independent)except(IgA) Activated by bacterial lipopolysaccharide, endotoxins, fungal cell wall viruses, parasites (trypanosomes) result in auto-activation of C3) C1, C4 and C2 do not participate. The process begin by binding of C3 to factor B The alternative C3 convertase (C3bBb) which cleaved by factor D to generates more C3b. The additional C3b binds to the C3 convertase to form C5convertase that generates C5b the forming membrane attack complex.

Alternative Complement Pathway B C5 C3b C3a Bacteria

Alternative Complement Pathway B C5 C3b Bb C3a Bacteria

Alternative Complement Pathway B C5 C3b Bb C5b C3a Bacteria C5a Animation complete

Alternative Complement Pathway Bacteria C5b C3b Bb C6 C7 C8 C9 C6 C7 C8 C9 C9 C9 C9 C9 C9 C9 Animation complete

3.Lectin binding pathway: Activation begins when mannan-binding lectin (MBP) binds to the surface of microbes. This complex can activate C4 and C2. The rest of this pathway is the same as the classic pathway of complement activation.

Lectin Binding Complement Pathway Bacteria C4 C2 C3 C5 MBP C4b C4a

Lectin Binding Complement Pathway Bacteria C4 C2 C3 C5 MBP C4b C2b C4a C2a

Lectin Binding Complement Pathway Bacteria C4 C2 C3 C5 MBP C4b C2b C3b C4a C2a C3a

Lectin Binding Complement Pathway Bacteria C4 C2 C3 C5 MBP C4b C2b C3b C4a C5b C2a C3a C5a Animation complete

Lectin Binding Complement Pathway MBP C4b C6 C2b C7 C3b C5b C8 Bacteria C6 C9 C7 C8 C9 C9 C9 C9 C9 C9 Animation complete

SUMMARY OF COMPLEMENT ACTIVATION Classical Pathway Lectin-Binding Pathway Alternative Pathway C1q MBP C3 [C4b2b] [C3bBbP] C3 Convertase anaphylatoxins C3a C3b C3b, C3bi (opsonlzation) C5a C5b C5b-C 9 (membrane attack complex) Cell Injury

Function of complement 1.Anaphylatoxins:C3a and C5a cause mast cell degranulation-------- release of vasoactive mediator (histamine) causing anaphylaxis(allergy). -vascular changes: dilation, increased permeability (edema) 2.Chemotaxis: C5a stimulates movement of neutrophils and monocytes toward sites of antigen deposition. 3.opsonization: C3b (binding to complement receptors and enhanced phagocytosis by neutrophils and macrophages) 4.Cytolysis: Insertion of the membrane attack complex into the cell surface leads to killing or lysis of many types of cells, including erythrocytes, bacteria, and tumor cells. 5. Clearance of circulating immune complexes

Regulation of complement system: C1 inhibitor: it inactivate the protease activity of C1 result in inhibition of classical pathway of complement activation. 2. factor H and Factor I: the alternative pathway is regulated by binding of factor H to C3b forming complex cleaved by Factor I which result in the reduction in the amount of C5 connvertase 3.Decay Accelerating Factor (DAF):Promote decay of C3 Convertases enzymes which is the major amplification step in complement activation result in prevent formation of membrane attack complex.

Complement Deficiencies: early components(C1,C2,C3,C4): auto-immune disease middle and late components( C5, C6, C7,C8,C9) : pyogenic bacterial and Nisseria infections most common congenital deficiency: C2 Hereditary angioedema. Absence of C1-inhibitor  C1 act on C4-C4a  vasoactive (C3a & C5a)  capillary permeability and edema in several organs. Paroxysmal Nocturnal Hemoglubinurea: Episodes of brownish urine (hemoglobin urea) complement-mediated hemolysis caused by deficiency of decay-accelerating factor (DAF).