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Figure 2. The classical pathway of complement activation.

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Figure 3. Complement split products in an inflammatory response. Fc regions. By contrast, one pentameric IgM molecule attached to a cell surface may interact with Clq to initiate the classical pathway. Binding of Clq activates C Ir to become activated C I r*. This, in tum, activates Cis. To create the activation unit, C 1s* splits C4 to produce C4a and C4b and C2 to form C2a and C2b. The ability of a single recognition unit to split numerous C2 and C4 molecules represents an amplification mechanism in the cascade. The union of C4b and C2a produces C4b2a which is known as C3 convertase. C4b2a binds to the cell membrane and splits C3 into C3a and C3b fragments. The ability of C4b2a to cleave multiple C3 molecules represents another amplification mechanism. The interaction of C3b with C4b2a bound to the cell membrane produces a complete activation unit,

THE COMPLEMENT SYSTEM

209

C4b2a3b, which is termed C5 convertase. It splits C5 into C5a and C5b fragments and represents yet another amplification mechanism because a single molecule of C5 convertase may cleave multiple C5 molecules. The terminal stage of the classical pathway involves creation of the membrane attack unit, which is also called the lytic unit exclusive of the recognition and activation units, C5b binds to the cell membrane. This is followed by the successive interaction of single molecules of C6, C7 and C8 with the membrane-bound C5b. Finally, further interaction with several C9 molecules finishes formation of the lytic unit through non-covalent interactions without enzymatic alteration. Formation of a membrane attack unit or membrane attack complex (MAC) leads to a cell membrane lesion that permits loss of K+ and ingress of Na+ and water leading to hypotonic lysis of cells. Not all C3b produced in classic complement activation unites with C4b2a to produce C5 convertase. Some of it binds directly to the cell membrane and acts as an opsonin which makes the cell especially delectable to phagocytes such as neutrophils and macrophages that have receptors for C3b. Complement fragments C3a and C5a serve as powerful anaphalatoxins that stimulate mast cells to release histamine that enhances vascular permeability and smooth muscle contraction. Neutrophils release hydrolytic enzymes and platelet aggregate leading to microthrombosis, blood stasis, edema formation and local tissue injury/destruction. C5a not only acts as an anaphylatoxin but is also chemotactic for PMNs and macrophages. Nonimmunologic classical pathway activators are selected microorganisms such as Escherichia coli and low virulence S