Complement activation: pathways and convergence on C3
THE CONTEXT
The complement system comprises soluble proteins and membrane receptors involved mainly in antimicrobial defense and pathological inflammatory reactions.
Organization of the complement cascade
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There are more than 20 complement proteins, some numbered C1 through C9.
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Complement proteins circulate as proforms that become activated during inflammatory reactions.
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Activation proceeds through an enzymatic cascade capable of tremendous amplification.
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Proteolytic cleavage of C3, the most abundant complement component, is the critical activation step.
Three activation pathways
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The classical pathway begins when C1 binds to IgM or IgG that has combined with antigen.
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The alternative pathway is triggered without antibody by microbial surface molecules, including endotoxin or lipopolysaccharide, complex polysaccharides, and other substances.
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In the lectin pathway, plasma mannose-binding lectin binds microbial carbohydrates and activates C1 without a role for antibody.
Common endpoint
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All three pathways generate C3 convertase.
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C3 convertase splits C3 into the functionally distinct fragments C3a and C3b; C3a is released.