THE CONTEXT
Following C3 cleavage, complement activation produces mediators of inflammation, opsonins for phagocytosis, and a membrane attack complex that lyses cells.
Progression to the membrane attack complex
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C3b becomes covalently attached to the cell or molecule where complement is activated.
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Additional C3b binds previously generated fragments to form C5 convertase. This enzyme cleaves C5, releasing C5a and leaving C5b attached to the cell surface.
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C5b binds C6–C9, culminating in formation of the membrane attack complex (MAC), which is composed of multiple C9 molecules.
Inflammation and opsonization
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C5a, and to a lesser extent C4a and C3a, stimulate recruitment of neutrophils and other leukocytes.
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These fragments may trigger mast-cell histamine release, increasing vascular permeability and causing vasodilation. They are termed anaphylatoxins because their effects resemble those of mast-cell mediators involved in anaphylaxis.
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C3b and its cleavage product iC3b, or inactive C3b, act as opsonins when fixed to microbial walls.
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Neutrophils and macrophages possess receptors for these complement fragments, allowing enhanced phagocytosis.
Cell lysis and infection susceptibility
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MAC assembly creates membrane holes through which intracellular water and ions leak, causing cell lysis. Thin-walled microbes such as Neisseria are especially susceptible.
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Inherited deficiencies of terminal complement components and treatment with complement inhibitors increase the risk of disseminated Neisseria infections, including meningococcal and gonococcal infections.
Control of activation
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Cell-associated and circulating regulatory proteins tightly control complement activation, including by inhibiting production of active complement fragments.