Complement questions on Q-banks love to punish “I know the gist” thinking. The pathways overlap just enough to confuse you, and the answer choices are usually designed to test whether you know what starts each pathway, what gets cleaved, what gets deposited, and what actually kills bugs. Let’s walk through a classic-style vignette and then dissect every distractor like you’re doing a post-game review after a missed question.
Clinical Vignette
A 6-year-old boy has a history of recurrent infections with Neisseria meningitidis despite appropriate vaccination. He has had two episodes of meningococcemia requiring hospitalization. His growth and development are normal. Laboratory testing shows normal immunoglobulin levels and normal neutrophil oxidative burst. Further evaluation reveals a mutation causing failure to form the membrane attack complex.
Which complement components are most directly impaired by this mutation?
A. C1 inhibitor (C1 esterase inhibitor)
B. C3
C. C5b–C9
D. Factor H
E. Mannose-binding lectin (MBL)
The Correct Answer: C. C5b–C9
Why?
The membrane attack complex (MAC) is formed by terminal complement components:
- C5b initiates assembly
- C6, C7, C8 bind and insert into membrane
- C9 polymerizes to form the pore
High-yield association: Deficiency of C5–C9 → recurrent Neisseria infections (especially N. meningitidis), because Neisseria are particularly susceptible to MAC-mediated lysis.
Step-friendly memory hooks
- “MAC attacks Neisseria’s back.” (Terminal complement deficiency → Neisseria)
- Classic board phrasing: “Recurrent Neisseria with normal Ig and normal oxidative burst” → think C5–C9 deficiency
Complement Pathways: The Map You Need in Your Head
All pathways converge on C3 convertase, then proceed to C5 convertase, then to MAC.
Initiation & Convertases (High Yield Table)
| Pathway | Trigger | C3 Convertase | C5 Convertase |
|---|---|---|---|
| Classical | IgG/IgM bound to antigen (or CRP) | C4b2a | C4b2a3b |
| Lectin | MBL binds mannose on microbes | C4b2a | C4b2a3b |
| Alternative | Spontaneous C3 “tick-over” on microbial surfaces | C3bBb | C3bBb3b |
Core functions to memorize
- C3b: opsonization (“B” for Bind)
- C5a: neutrophil chemotaxis, inflammation (very potent anaphylatoxin)
- C3a, C4a, C5a: anaphylatoxins (mast cell degranulation; C5a strongest)
- C5b–C9: MAC lysis
Why Each Distractor Is Wrong (and What It Would Cause)
A. C1 inhibitor (C1 esterase inhibitor) — Wrong
What it does: Inhibits C1 (classical pathway) and also regulates kallikrein/bradykinin production.
If deficient → Hereditary angioedema
- Recurrent angioedema (face, lips, airway), abdominal pain
- No urticaria (key differentiator from allergic angioedema)
- Labs: ↓ C4 (often tested), normal/variable C3
Why it’s not this case: The vignette is about recurrent Neisseria and MAC failure, not episodic swelling due to bradykinin.
USMLE pearl: ACE inhibitors can worsen bradykinin-mediated angioedema.
B. C3 — Wrong (but important)
What it does: Central hub of complement:
- Required for opsonization (C3b)
- Amplifies all pathways
- Helps generate C5 convertase → MAC downstream
If deficient →
- Severe, recurrent pyogenic infections (especially encapsulated organisms)
- Think: S. pneumoniae, H. influenzae
- Also immune complex disease risk due to impaired clearance
Why it’s not this case: Terminal complement deficiency is classically linked to Neisseria, while C3 deficiency causes broad susceptibility to encapsulated bacteria, often earlier and more severe.
D. Factor H — Wrong
What it does: Regulatory protein that inhibits the alternative pathway by inactivating C3b on host cells (helps prevent complement from attacking self).
If defective → overactive alternative pathway (uncontrolled complement)
- Associated with atypical hemolytic uremic syndrome (aHUS)
- Can be linked to C3 glomerulopathy
- Mechanism vibe: complement-mediated endothelial injury → microangiopathic hemolysis, thrombocytopenia, AKI
Why it’s not this case: Factor H problems are dysregulation (too much complement activity), not inability to form MAC, and the phenotype is more microangiopathy/renal disease than isolated Neisseria susceptibility.
E. Mannose-binding lectin (MBL) — Wrong (but fair game)
What it does: Initiates the lectin pathway by binding mannose on microbes → activates MASPs → cleaves C4 and C2 → forms C4b2a (same C3 convertase as classical).
If deficient →
- Often asymptomatic
- Can have recurrent infections in childhood, especially if immunocompromised
Why it’s not this case: MBL deficiency affects one initiation pathway; MAC formation can still proceed via classical/alternative pathways. The question stem directly says failure to form MAC, which points to C5b–C9.
Putting It Together: How Q-Banks Test Complement
Pattern recognition stems
- Recurrent Neisseria + otherwise normal immune workup → C5–C9 deficiency
- Recurrent pyogenic/encapsulated infections → C3 deficiency
- Angioedema without urticaria → C1 inhibitor deficiency
- aHUS / complement-mediated renal disease → Factor H / Factor I / MCP (CD46) issues
- Early complement (C1, C2, C4) deficiency → SLE-like disease (impaired immune complex clearance)
Quick “What starts what?” checklist
- Classical: IgM/IgG (immune complexes), CRP
- Lectin: MBL binding mannose
- Alternative: spontaneous activation on microbial surfaces; stabilized by properdin (Factor P)
Micro-High-Yield: Convertase Mnemonics (Worth the Memorization)
- Classical/Lectin C3 convertase: C4b2a
- Alternative C3 convertase: C3bBb
- Add C3b to either C3 convertase → C5 convertase
If you remember nothing else:
All roads lead to C3, and Neisseria fears C5–C9.
Rapid Review Box (Exam-Day Ready)
- C3b = opsonization
- C5a = neutrophil chemotaxis + strongest anaphylatoxin
- C3a/C4a/C5a = anaphylatoxins
- C5b–C9 = MAC
- C5–C9 deficiency = Neisseria
- C1 inhibitor deficiency = hereditary angioedema (↓ C4, no urticaria)
- C3 deficiency = recurrent encapsulated infections
- Factor H deficiency/dysfunction = alternative pathway overactivation → aHUS/C3 glomerulopathy