The Complement Cascade: From Three Triggers to One Pore

A blood-borne alarm that amplifies itself

The complement system is roughly 30 proteins circulating inertly in blood plasma, waiting to be triggered. It is part of innate immunity — fast, non-specific, no memory required — and its defining trick is proteolytic amplification: each activated enzyme cleaves and activates many copies of the next protein in line, so a handful of trigger molecules can generate an overwhelming, second-scale response. That cascading multiplication is the same design principle blood clotting uses, and it is why complement can go from undetectable to fully mobilised on a pathogen's surface within moments of first contact.

Three doors into the same cascade

Complement can be triggered three separate ways, and all three converge on the same downstream machinery. The classical pathway starts when antibodies (IgG or IgM) bind a pathogen and the C1 complex recognises the bound antibody — this is where complement meets adaptive immunity. The lectin pathway starts when mannose-binding lectin recognises specific sugar patterns on microbial surfaces directly, no antibody needed. The alternative pathway is always ticking over at a low, spontaneous rate — C3 slowly hydrolyses on its own — and is normally suppressed on healthy host cells by regulatory proteins, but runs unchecked once it lands on a pathogen surface lacking that protection, making it a built-in self/non-self discriminator.

classical:   antigen-antibody complex  -> C1  -> C4, C2
lectin:      microbial surface sugars  -> MBL -> C4, C2
alternative: spontaneous C3 hydrolysis -> factor B, D  (amplification loop)

all three converge on:  C3 convertase  -> massive C3 -> C3b cleavage

C3: the hinge the whole system turns on

Every pathway builds a C3 convertase enzyme complex, and C3 convertase is where the real amplification happens: each convertase molecule cleaves many C3 molecules into C3a and C3b, and — critically — the alternative pathway convertase is itself built partly from C3b, so newly generated C3b feeds back to create more convertase, more C3b, more convertase. This positive feedback loop is why the alternative pathway is often described as complement's amplification loop, and it means even a small classical- or lectin-pathway trigger can be massively boosted once it seeds this loop.

What C3b actually does once it's made

C3b's main job is opsonisation: it coats the pathogen surface, and phagocytic cells (macrophages, neutrophils) carry complement receptors that recognise C3b-tagged particles and engulf them far more efficiently than uncoated ones — complement essentially paints a target for the phagocyte's benefit. A separate branch of C3b builds a C5 convertase, which cleaves C5 into C5a and C5b. C5a and its smaller cousin C3a are anaphylatoxins: small fragments that diffuse away and recruit and activate immune cells, trigger mast-cell degranulation, and drive local inflammation and increased vascular permeability — the redness and swelling of an inflammatory response, chemically.

The membrane attack complex: a literal hole

C5b left behind on the pathogen surface recruits C6, C7, C8 and multiple copies of C9, which polymerise into a ring that inserts directly into the pathogen's lipid membrane — the membrane attack complex (MAC), a genuine transmembrane pore roughly 10 nm across. That pore destroys the osmotic gradient the cell depends on, water and ions flood through uncontrolled, and the cell lyses. This is complement's most direct killing mechanism, most effective against Gram-negative bacteria whose outer membrane the MAC can reach; Gram-positive bacteria's thick peptidoglycan wall generally blocks MAC insertion, which is why opsonisation and phagocytosis matter more for those.

Keeping an amplifying weapon pointed outward

A cascade this explosive needs equally aggressive brakes, because unchecked complement would attack the body's own cells. Host cells carry regulatory proteins — CD55 (decay-accelerating factor) speeds the breakdown of convertases, CD46 helps inactivate C3b, CD59 directly blocks MAC assembly on the host membrane — and their absence is not hypothetical: paroxysmal nocturnal haemoglobinuria is a disease caused specifically by a genetic loss of CD55 and CD59 on red blood cells, leaving them undefended against the patient's own complement system and destroyed by their own MAC pores.

Frequently asked questions

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