The Complement Cascade and Its Regulators
Complement is not one pathway. It is three ignition routes into a single amplification loop, and a set of regulators that decide whether your own cells survive it. The classical route needs antibody, the lectin route needs sugar, and the alternative route needs nothing at all — it ticks over continuously on every surface in the body. What separates a pathogen from your own tissue is not whether C3 lands on it, but whether Factor H, CD55 and CD59 are there to take it off again. Nearly every complement disease is a failure of that second layer, not the first. Click any protein for the matching Assay Genie ELISA kit or In Vivo antibody.
Three ways in, and only one of them needs an immune system. The classical route starts when C1q binds clustered IgG or a single IgM pentamer on a surface, activating C1r and then C1s. The lectin route starts when MBL recognises mannose patterns that vertebrate glycoproteins do not display, activating MASP-1 and MASP-2; MASP-2 then does exactly what C1s does. The alternative route starts with nothing: C3 spontaneously hydrolyses in plasma at a low rate — "tick-over" — and Factor D cleaves Factor B on whatever surface that hydrolysed C3 happens to land on. Properdin then stabilises the result. The consequence is important and often missed: the alternative pathway is firing on your own cells right now, continuously, and is being switched off just as continuously.
C3 is the hub, and the amplification loop is the whole point. Both the classical/lectin convertase (built from C4 and C2) and the alternative convertase cleave C3. C3b deposited on a surface can then seed more alternative convertase, so a handful of initiating events becomes thousands of C3b molecules within minutes. That exponential quality is why complement is so fast and so dangerous, and why the regulators have to be constitutive rather than induced. C3a diffuses away as an anaphylatoxin; iC3b, the cleaved and inactivated form, stays on the surface as the dominant opsonin.
The regulators are the actual story in human disease. C1-inhibitor restrains C1r/C1s and MASPs — lose it and you get hereditary angioedema. Factor H discriminates self from non-self by binding host sialic acid and glycosaminoglycans, and accelerating decay of the alternative convertase there; Factor H mutations cause atypical haemolytic uraemic syndrome and drive age-related macular degeneration. Factor I does the cutting, but only with a cofactor: CD46, CR1, C4BP or Factor H. On the membrane, CD55 accelerates convertase decay and CD59 blocks C9 insertion into the forming pore. Both are GPI-anchored, which is precisely why paroxysmal nocturnal haemoglobinuria — a defect in GPI anchoring — presents as complement- mediated haemolysis. The pattern repeats: the cascade is intact, the brake is missing.
Three outputs, and only one of them is lysis. C5b-9, the membrane attack complex, gets the attention, but it is the least important arm for most nucleated cells, which survive sublytic MAC by shedding it. The two arms that matter more are opsonisation — iC3b read by CR3 (CD11b/CD18) and CRIg on tissue macrophages, and CR1 on erythrocytes for immune-complex transport — and anaphylatoxin signalling, where C5a acting through C5aR1 is one of the most potent neutrophil chemoattractants known. C5aR2 is the non-signalling decoy that modulates it. The In Vivo tie-in: the functional-grade layer on this map is deliberately just two nodes, and that reflects the biology rather than the catalogue. Complement is a cascade of soluble plasma proteins: you measure it, you do not usually block it with an antibody at the bench. Where blockade is the right experiment it is on the cells that read the output — anti-CD11b removes CR3-dependent phagocytosis and anti-Ly6G removes the neutrophils C5a recruits. Everything else here is an ELISA, and the panel is deep: C1q, C4, C4d, C3, C3a, iC3b, C5, C5a, C5b-9, Factor H, Factor I, C1-INH and the membrane regulators. For the Fcγ-receptor side of opsonisation, see the Fc receptors map in this library. For research use only; not for use in diagnostic or therapeutic procedures.
Every protein node links to a product — ELISA kit, In Vivo antibody or research antibody.