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Complement SystemDr. Tahir Yaqub

Associate Professor 

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Complement system� The complement system is a biochemical

cascade that helps, or ³complements´, theability of antibodies to clear pathogens from anorganism

� It is part of the immune system called theinnate immune system that is not adaptable

and does not change over the course of anindividual's lifetime

� However, it can be recruited and brought intoaction by the adaptive immune system

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� The complement system consists of a number of small proteins found in the blood, generally

synthesized by the liver, and normally circulatingas inactive precursors (pro-proteins)

� When stimulated by one of several triggers, proteases in the system cleave specific proteins to

release cytokines and initiate an amplifyingcascade of further cleavages

� The end-result of this activation cascade ismassive amplification of the response and

activation of the cell-killing membrane attack complex

� Over 25 proteins and protein fragments make upthe complement system, including serum proteins,serosal proteins, and cell membrane receptors

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Functions of Complement

� Lysis of cells, bacteria and viruses.

� Opsonization, which promotes phagocytosis of 

 particular antigens.� Binding to specific complement receptors on thecells of the immune system, triggering specificcell functions, inflammation, and certainimmunoregulatory molecules.

� Immune Clearance, which removes immunecomplexes from immune system and depositsthem in the spleen and liver.

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Pathways� Three biochemical pathways activate the

complement system:

� Classical complement pathway

� Alternative complement pathway

� Mannose-binding lectin pathway

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Classical pathway� The classical pathway is triggered by activation of the C1-complex

(C1q, two molecules of C1r, and two molecules of C1s thus formingC1qr2s2),

� Which occurs when C1q binds to IgM or IgG complexed with antigens(a single IgM can initiate the pathway, while multiple IgGs areneeded),

� The C1r2s2 component now splits C4 into C4a and C4b

� Then C2, producing C4a,C4b,C2a,and C2b.

� C4b and C2b bind to form the classical pathway C3-convertase (C4b2bcomplex), which promotes cleavage of C3 into C3a and C3b;

� C3b later joins with C4bC2a (the C3 convertase) to make C5convertase (C4b2a3b complex).

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Classical Complement Pathway is Triggered by

Antibodies Binding to Foreign Cells

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Alternative pathway

� The alternative pathway is triggered by spontaneous C3 hydrolysisdirectly due to the breakdown of the thioester bond to form C3a andC3b.

� It does not rely on a pathogen-binding antibodies like the other  pathways.

� If there is no pathogen in the blood, the C3a and C3b protein fragmentswill be deactivated by rejoining with each other.

� Upon binding with a cellular membrane C3b is bound by factor B toform C3bB. This complex in presence of factor D will be cleaved intoBa and Bb.

� Bb will remain covalently bonded to C3b to form C3bBb which is thealternative pathway C3-convertase.

� After hydrolysis of C3, C3b complexes to become C3bBbC3b, whichcleaves C5 into C5a and C5b.

� C5b with C6, C7, C8, and C9 (C5b6789) complex to form themembrane attack complex, also known as MAC,

� which is inserted into the cell membrane, "punches a hole," andinitiates cells lysis. C5a and C3a are known to trigger mast cell

degranulation.

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Both Classical and Alternative Complement

Pathways Trigger the Cleavage of C3

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Mannose-binding lectin pathway

� The lectin pathway is homologous to the classical pathway, but with the opsonin, mannose-binding lectin (MBL), andficolins, instead of C1q.

� This pathway is activated by binding mannose-bindinglectin to mannose residues on the pathogen surface, whichactivates the MBL-associated serine proteases, MASP-1,

and MASP-2 (very similar to C1r and C1s, respectively),� Which can then split C4 into C4a and C4b and C2 into C2aand C2b. C4b and C2a then bind together to form the C3-convertase, as in the classical pathway.

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Classical and Alternative Complement Pathways

Cause Inflammation, Opsonization, and Cytolysis

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Cytolysis Caused by Membrane Attack Complex