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Core concept1 exam ›

Segment	Components	Infection risk	Other
Early classical	C1q, C1r, C1s, C4, C2	Encapsulated pyogenic - pneumococcus, H. influenzae	*SLE-like autoimmunity - the dominant phenotype*
C3 (the hub)	C3	Severe, recurrent pyogenic infection from infancy	Immune complex GN, MPGN
Alternative	Properdin (X-linked), factor B, factor D	Fulminant Neisseria	Properdin deficiency mimics terminal deficiency
Terminal / MAC	C5, C6, C7, C8, C9	*Recurrent Neisseria - meningococcal and disseminated gonococcal*	Milder disease than in the general population, but recurrent and with unusual serogroups (W, Y, X, 29E)
Lectin	MBL, MASP-2, ficolin	Mild; matters mainly in infancy or with a second immune defect	~5-10% of the population is MBL-deficient and mostly well
Regulators	C1-INH; factor H, I, MCP; CD55/CD59	-	HAE; aHUS/C3G; PNH

The rule: early components -> immune complex disease and pyogenic infection; terminal components -> Neisseria only
- Because C3b opsonisation (early) does the bulk of antibacterial work, while the MAC matters almost exclusively for the thin-walled Neisseria

Why early classical deficiency causes lupus

C1q, C4 and C2 are required to clear apoptotic cells and soluble immune complexes (via CR1 on erythrocytes)
Failure -> persistent nuclear autoantigen exposure -> anti-nuclear autoimmunity
Penetrance ranks with position in the cascade: C1q deficiency -> SLE in >90%, C4 ~75%, C2 ~10-30% (C2 deficiency is the commonest, ~1:20,000)
- Often ANA-positive but dsDNA-negative, with prominent photosensitive rash and relatively little renal disease
C4 gene copy number varies normally (C4A/C4B, 2-6 copies) - low copy number is an SLE risk factor in its own right

Interpreting the screening tests

CH50	AH50	Localises to
Absent	Normal	C1, C2, C4 (classical only)
Normal	Absent	Factor B, factor D, properdin (alternative only)
Absent	Absent	C3 or terminal C5-C9 (shared)
Low but present	Low but present	Consumption, not deficiency

*Both assays need an intact terminal pathway to lyse the indicator red cells - which is why a C5-C9 defect abolishes both*
Follow an abnormal screen with individual component levels and functional assays
Send samples promptly on ice - complement is heat-labile and a delayed or warm sample gives a falsely absent CH50

Hereditary angioedema - the regulator deficiency that is not an infection problem

C1 inhibitor deficiency (type I, low level) or dysfunction (type II, normal level); AD
C1-INH also inhibits kallikrein and factor XIIa -> unopposed bradykinin generation
Recurrent non-pitting, non-pruritic swelling: face, limbs, larynx, and bowel wall (colicky abdominal pain mimicking an acute abdomen)
*No urticaria, normal tryptase, no response to adrenaline, antihistamine or steroid* - the discriminators from anaphylaxis
Low C4 between and during attacks is the best screening test (C4 is normal in the HAE mimics); C1q is low in acquired C1-INH deficiency (lymphoproliferative disease, anti-C1-INH antibody)
ACE inhibitors are absolutely contraindicated; oestrogens trigger attacks

Investigate complement in: a second episode of invasive meningococcal disease, invasive meningococcal disease with an unusual serogroup or in an adolescent/adult, a family history of it, recurrent pyogenic infection, unexplained SLE at a young age or with a strong family history, and recurrent angioedema
Prophylaxis for terminal/alternative pathway deficiency
- Meningococcal ACWY and B vaccination, with boosters; pneumococcal and Hib
- Consider long-term penicillin prophylaxis and give a warning card with instructions to seek care immediately for fever
- Screen and vaccinate household members? No - the defect is in the host, not transmissible; but vaccinate relatives who are found to share the deficiency
*Acquired functional terminal complement deficiency is now iatrogenic and far commoner than the inherited form - eculizumab, ravulizumab, crovalimab, pegcetacoplan, iptacopan* all mandate the same meningococcal precautions
HAE treatment splits by phase
- Acute: C1-INH concentrate, icatibant (bradykinin B2 antagonist), ecallantide; fresh frozen plasma only if nothing else available
- Prophylaxis: lanadelumab (anti-kallikrein), berotralstat (oral kallikrein inhibitor), C1-INH; danazol historically
- Short-term prophylaxis before dental or surgical procedures

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