Core concept2 exam ›
Three activation pathways, one common terminal pathway
| Pathway | Trigger | Recognition |
|---|---|---|
| Classical | Antigen-antibody complexes (IgM > IgG3 > IgG1) | C1q -> C1r/C1s -> C4, C2 |
| Lectin | Microbial mannose | MBL / ficolins -> MASP -> C4, C2 |
| Alternative | Spontaneous C3 tickover on any surface lacking regulators | C3b, factor B, factor D, properdin (the only positive regulator) |
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All three -> C3 convertase -> C3a + C3b
- -> C5 convertase -> C5a + C5b
- C5b + C6 + C7 -> inserts into membrane
- + C8 -> initiates pore
- + 10-16 C9 -> membrane attack complex C5b-9
- -> transmembrane pore -> Na and water influx
- -> osmotic lysis
```
- MAC assembly is the critical event in complement-dependent cytotoxicity; C5b-9 is the whole terminal pathway in one label
- The other outputs matter more day to day: C3b = opsonisation, C5a = the most potent anaphylatoxin and chemotaxin (C3a, C4a weaker)
Key detail
Deficiency maps onto a specific infection risk
| Deficient | Consequence |
|---|---|
| C1q, C2, C4 (early classical) | SLE-like disease - failure to clear immune complexes and apoptotic debris. C1q deficiency has the highest penetrance for lupus of any single gene |
| C3 | Severe pyogenic infection, glomerulonephritis |
| C5-C9 (terminal / MAC) | Recurrent NEISSERIA infection - meningococcal, often with unusual serogroups and milder disease |
| Properdin (X-linked) | Fulminant meningococcal disease |
| C1 inhibitor | Hereditary angioedema (bradykinin, not complement lysis) |
| CD55/CD59 (GPI-anchored) | PNH - unregulated MAC on red cells -> intravascular haemolysis |
| Factor H / I, MCP (CD46) | Atypical HUS - alternative pathway dysregulation on endothelium |
- Screening: CH50 tests the classical + terminal pathway (abnormal in any classical or terminal deficiency); AH50 tests alternative + terminal
- Both low -> terminal/common pathway defect; CH50 low alone -> classical; AH50 low alone -> alternative
- Consumption patterns: low C3 and low C4 = classical activation (SLE, post-infectious GN, cryoglobulinaemia, endocarditis); low C3 with normal C4 = alternative (C3 glomerulopathy, aHUS)
Clinical relevance
- Therapeutic C5 blockade: eculizumab and ravulizumab in PNH, atypical HUS, refractory myasthenia gravis, AQP4+ NMOSD
- They create an acquired terminal complement deficiency -> meningococcal vaccination (ACWY + B) at least 2 weeks before, plus penicillin prophylaxis, and a patient alert card
- Any fever in a patient on a C5 inhibitor is meningococcal sepsis until disproved
- Recurrent or unusual-serogroup meningococcal disease -> measure CH50 and AH50, not just immunoglobulins
- Complement-dependent cytotoxicity is the mechanism of the crossmatch in transplantation, and of ABO-incompatible transfusion haemolysis
- Therapeutic antibodies that kill by CDC: rituximab (CDC + ADCC + apoptosis); obinutuzumab is glyco-engineered for ADCC over CDC
Correlations
- Hereditary angioedema - diagnostic testing (C4, C1-inhibitor)
- Paroxysmal nocturnal haemoglobinuria; markers of intravascular haemolysis
- Neisseria meningitidis - presentation and mortality
- Antibody effector mechanisms; monoclonal antibody mechanisms
- ABO blood group compatibility
4 of 4 sections written · drafted 2026-09-04