Complement questions love to look “vague” (recurrent Neisseria, angioedema, lupus-like disease) and then turn into easy points if you can map which arm is broken—classical vs alternative vs terminal vs regulation. This quick-hit guide is designed to be screenshot-friendly for your notes and fast to recall on test day.
The 10-second map: what complement does (and where it breaks)
Think of complement as 3 roads that merge into one highway:
- Classical pathway (C1, C2, C4): triggered by immune complexes (IgG/IgM)
- Alternative pathway (Factor D, Factor B, Properdin): triggered by microbial surfaces
- Lectin pathway (MBL): triggered by mannose
All three converge on C3, then proceed to:
- C5–C9 (MAC) = membrane attack complex that pokes holes in bacteria (especially Neisseria)
Visual mnemonic (shareable): “4 C’s” + “MAC attack” + “angioedema switch”
1) Early classical: C1, C2, C4 = “C’s for Complexes”
- Mnemonic: C1/C2/C4 → immune Complexes
- One-liner: Early classical deficiency causes immune-complex disease (SLE-like) and recurrent pyogenic infections.
2) C3 = “C3 is the Center”
- Mnemonic: C3 = Central opsonin
- One-liner: C3 deficiency is the worst: no opsonization → recurrent severe pyogenic infections + type III hypersensitivity.
3) C5–C9 = “MAC attack”
- Mnemonic: C5–C9 = MAC → Neisseria
- One-liner: Terminal complement deficiency → recurrent Neisseria (meningitidis/gonorrhoeae).
4) C1 esterase inhibitor = “brake on bradykinin”
- Mnemonic: C1-INH inhibits kallikrein → ↓ bradykinin
- One-liner: C1-INH deficiency → hereditary angioedema (no urticaria; ACE inhibitors can worsen).
Comparison table: Complement deficiencies (high-yield)
| Deficiency | Pathway/Function | Classic clinical clue | Organisms / associations | Labs (common patterns) | USMLE one-liner |
|---|---|---|---|---|---|
| C1q, C2, C4 | Early classical (immune complex clearance) | SLE-like disease, recurrent sinopulmonary infections | Encapsulated pyogenic bacteria (due to impaired opsonization via downstream effects); immune complex disease | ↓ CH50, normal AH50 (alternative intact) | “Early classical = immune complexes → lupus-like + infections.” |
| C3 | Central convergence; opsonization (C3b) and amplification | Recurrent severe pyogenic infections, otitis/sinusitis/pneumonia; can have GN | Encapsulated bacteria (e.g., Strep pneumo, H. flu), plus immune complex disease | ↓ CH50, ↓ AH50 (both rely on C3) | “C3 is the center—if it’s gone, everything gets worse.” |
| C5–C9 | MAC formation (lysis) | Recurrent Neisseria infections | N. meningitidis, N. gonorrhoeae | ↓ CH50, normal AH50 or can be abnormal depending on assay design; classic teaching: CH50 low, AH50 often low too in terminal defects (both end in MAC) | “No MAC → Neisseria keeps coming back.” |
| Factor D | Alternative pathway activation | Recurrent respiratory infections; can see Neisseria susceptibility | Neisseria and some pyogenic infections | Normal CH50, ↓ AH50 | “Alternative pathway broken → AH50 low.” |
| Factor B | Alternative pathway C3 convertase component | Recurrent infections similar to other alt pathway defects | Pyogenic infections; sometimes Neisseria | Normal CH50, ↓ AH50 | “B for ‘Broken alternative’.” |
| Properdin | Stabilizes alternative C3 convertase | Recurrent Neisseria, fulminant meningococcemia | Neisseria (notably high yield) | Normal CH50, ↓ AH50 | “Properdin props up alternative—without it, Neisseria wins.” |
| DAF (CD55) ± CD59 (often acquired in PNH) | Protects host cells from complement (DAF blocks C3 convertase; CD59 blocks MAC) | Intravascular hemolysis, thrombosis (PNH) | Not primarily infections; complement-mediated RBC lysis | Complement assays variable; flow cytometry: ↓ CD55/CD59 | “No shield on RBCs → complement punches holes.” |
| C1 esterase inhibitor (C1-INH) | Inhibits complement + kallikrein (↓ bradykinin) | Hereditary angioedema: episodic swelling, laryngeal edema, abdominal pain | Not an infection problem | Normal C3, low C4 common; CH50 may be low | “Angioedema without hives; treat by blocking bradykinin pathway.” |
| MBL (mannose-binding lectin) | Lectin pathway initiation | Often mild; recurrent childhood infections | Pyogenic infections in infants/young children | CH50/AH50 often normal (lectin not captured well) | “Lectin deficiency is usually subtle.” |
Test-day note on CH50 vs AH50:
- CH50 screens the classical → terminal pathway.
- AH50 screens the alternative → terminal pathway.
- If both are low, think C3 (or a shared terminal component depending on lab), but the highest-yield pattern is:
- Early classical defects: ↓ CH50, normal AH50
- Alternative defects: normal CH50, ↓ AH50
- C3: both ↓
- Terminal (C5–C9): classically ↓ CH50; AH50 may also be abnormal since it also requires terminal components—know the clinical clue (Neisseria) first.
Rapid-fire “name that deficiency” (USMLE style)
- Recurrent Neisseria meningitis in a teen → C5–C9 (or properdin if AH50 selectively low)
- SLE-like disease + recurrent infections → C1/C2/C4
- Severe recurrent pyogenic infections starting early → C3 deficiency
- Angioedema, abdominal pain, no urticaria; triggered by stress/trauma; worsened by ACE inhibitor → C1-INH deficiency
- Intravascular hemolysis + thrombosis; pancytopenia → PNH (CD55/CD59)
Micro-associations worth memorizing
Encapsulated bacteria love complement defects (especially when opsonization is impaired)
- Strep pneumoniae
- H. influenzae
- Neisseria meningitidis (especially terminal/alternative pathway)
Why: Loss of C3b opsonization (and downstream effects) reduces clearance of encapsulated organisms.
High-yield treatments (when asked)
- Hereditary angioedema (C1-INH deficiency):
- Acute: C1-INH concentrate, icatibant (bradykinin B2 antagonist), ecallantide (kallikrein inhibitor)
- Avoid: ACE inhibitors (increase bradykinin)
- Terminal complement deficiency:
- Prevention: meningococcal vaccination + consider prophylactic antibiotics in select cases
Take-home screenshot summary
- C1/C2/C4 → SLE-like + infections
- C3 → severe pyogenic infections (worst)
- C5–C9 → Neisseria
- Properdin/Factor D/B → alternative pathway; Neisseria risk
- C1-INH → angioedema without urticaria
- CD55/CD59 → PNH hemolysis