The Complement Cascade and Where It Breaks | Visual AI Learning Guide

Follow the cascade from left to right. Three routes — classical, lectin, and alternative — all converge on the same step: cutting C3 into C3a and C3b. C3b lands on the microbial surface and acts as an opsonin, the tag that phagocytes grab through their complement receptors. C3b also helps build the C5 convertase, which cuts C5 into C5a, a signal that calls neutrophils in, and C5b, which starts the membrane attack complex. Watch what happens when the animation blocks C3. Opsonization stops and the membrane attack complex never forms, so the patient has severe recurrent pyogenic infection from infancy. Now watch a block at C5 through C9. Opsonization still works, but lysis fails, and the vulnerability narrows to Neisseria. The position of the block, not just its presence, determines the infection pattern.

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Complement is a set of plasma proteins that act in sequence. Three entry routes — the classical pathway (triggered by antibody bound to antigen), the lectin pathway (triggered by mannose-binding lectin binding microbial sugars), and the alternative pathway (triggered by spontaneous C3 hydrolysis on microbial surfaces) — all converge on the cleavage of C3 into C3a and C3b. C3b covalently attaches to the microbial surface, where it acts as an opsonin: phagocytes carry complement receptor 1 (CR1) and CR3, which bind C3b and its degradation product iC3b, and this binding is what drives ingestion. C3b also joins the C5 convertase complex, which cleaves C5 into C5a (a potent neutrophil chemoattractant and anaphylatoxin) and C5b, the seed of the membrane attack complex (MAC). C5b recruits C6, C7, C8, and multiple C9 molecules to form a pore that lyses susceptible organisms, especially Neisseria species.

A deficiency at each step produces a different consequence. Loss of an early classical pathway component (C1q, C1r, C1s, C2, C4) impairs clearance of immune complexes and predisposes to immune-complex disease and encapsulated bacterial infection. Loss of C3 — the central hub — is the most severe, because both opsonization and MAC formation fail; patients have recurrent pyogenic infection from infancy. Loss of a terminal component (C5 through C9) leaves opsonization intact but blocks lysis, and the striking result is a selective vulnerability to Neisseria meningitidis and Neisseria gonorrhoeae. The pattern of infection therefore tells you which part of the cascade is missing.