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Core concept7 exam ›

Pathway	Trigger	Recognition molecule	C3 convertase
Classical	IgM (most efficient), IgG1/IgG3, immune complexes, CRP, apoptotic cells, some bacteria directly	C1q (with C1r/C1s)	C4b2a
Lectin	Microbial mannose/GlcNAc	MBL, ficolins 1-3, collectins + MASP-1/2	C4b2a (identical - bypasses C1)
Alternative	Spontaneous C3 "tick-over" amplified on any surface lacking regulators - bacterial polysaccharide, IgA immune complexes, C3 nephritic factor	C3(H2O) + factor B	C3bBb (stabilised by properdin)

-> C3 convertase cleaves C3 -> C3a + C3b
-> C5 convertase (C4b2a3b or C3bBb3b) -> C5a + C5b
-> C5b + C6,7,8, then multiple C9 -> membrane attack complex (C5b-9)
The alternative pathway is also the amplification loop for all three - any C3b deposited feeds back into it

Four functions

Opsonisation - C3b (and iC3b) binding CR1/CR3 on phagocytes - quantitatively the most important function
Anaphylatoxins - C3a, C5a (C5a most potent): mast cell degranulation, smooth muscle contraction, inc vascular permeability, inc adhesion molecules; C5a is also a powerful neutrophil chemoattractant
Lysis - MAC - only really matters for Neisseria**
Immune complex clearance and B-cell priming - C3b/C4b on complexes bind CR1 on erythrocytes -> transport to liver/spleen; C3d + CR2 (CD21) lowers the B-cell activation threshold ~1,000-fold

Regulators - and what happens when they fail

Regulator	Action	Deficiency
C1 inhibitor	Inhibits C1r/C1s, MASP, kallikrein and factor XIIa	Hereditary angioedema - bradykinin-mediated, so low C4 but no urticaria and no response to adrenaline/antihistamine
Factor H	Cofactor for C3b cleavage, decay-accelerating, binds host sialic acid/glycosaminoglycans	aHUS, C3 glomerulopathy, age-related macular degeneration
Factor I	Serine protease cleaving C3b/C4b (needs H, MCP, C4BP)	aHUS, recurrent infection
CD46 (MCP)	Membrane cofactor	aHUS
CD55 (DAF)	Accelerates convertase decay	PNH (with CD59)
CD59	Blocks C9 insertion into C5b-8	PNH
C4-binding protein	Classical pathway regulator	Rare

*Host cells are protected because they carry regulators and sialic acid; microbes are not - that is the entire basis of self/non-self discrimination by the alternative pathway*

Reading the complement profile

C3	C4	Interpretation
Low	Low	Classical pathway consumption - active SLE (especially class IV lupus nephritis), cryoglobulinaemia, MPGN, serum sickness, subacute bacterial endocarditis
Normal/low	Low, C3 relatively preserved	Classical pathway deficiency, or hereditary angioedema (low C4, low C1-INH, normal C3)
Low	Normal	Alternative pathway - post-streptococcal GN, infection-related GN, C3 glomerulopathy / dense deposit disease (C3 nephritic factor), aHUS, PNH-related
Normal	Normal	Does not exclude complement-mediated disease at the tissue level

CH50 tests the classical + terminal pathway; AH50 tests alternative + terminal
- Both zero -> terminal pathway (C5-C9) defect; CH50 zero with normal AH50 -> C1/C2/C4; AH50 zero with normal CH50 -> factor B/D/properdin
A completely absent CH50 in a well patient suggests a deficiency; a low-but-detectable CH50 suggests consumption

C3a/C5a explain non-IgE "anaphylactoid" reactions - radiocontrast, vancomycin, liposomal drugs, dialysis membranes - clinically identical to anaphylaxis but complement-mediated, no prior sensitisation needed
Complement is consumed in active disease - serial C3/C4 track lupus nephritis activity
Therapeutic complement inhibition (all raise Neisseria risk -> vaccinate + prophylaxis)
- C5: eculizumab, ravulizumab, crovalimab - PNH, aHUS, gMG, NMOSD, AMR
- C3: pegcetacoplan; factor B: iptacopan; factor D: danicopan - PNH, C3 glomerulopathy
- C1s: sutimlimab - cold agglutinin disease
- C1-INH concentrate, icatibant (B2 antagonist), lanadelumab (anti-kallikrein) - hereditary angioedema
Complement fixation is why IgM causes intravascular haemolysis (cold agglutinins, ABO-incompatible transfusion) while IgG causes extravascular splenic clearance
Do not send complement studies during an acute severe illness and expect a clean answer - both consumption and acute-phase rise occur

4 of 4 sections written · drafted 2026-09-04