Complement is one of those Step questions that feels “too fast to miss”… until you blank on which pathway uses what and where C3/C5 convertases differ. Here’s a 5‑second, shareable rule set that lets you ID the classical, alternative, and lectin pathways instantly, then lock in the convertases, triggers, and board‑relevant pearls.
The 5‑Second Rule (Ultra-High Yield)
All complement pathways:
- Meet at C3 → make C3 convertase
- Then C5 convertase → MAC (C5b-9)
One-liner:
Different starts, same finish: three ways to activate C3 → C5 → MAC.
The Visual: “Three Doors, One Hallway”
Think of complement as a building:
- Door 1: Classical = Antibody door
- Door 2: Lectin = Sugar door
- Door 3: Alternative = Microbe surface door
All doors dump you into the same hallway: C3 → C5 → MAC
Pathway Snapshots (Triggers + Key Proteins)
| Pathway | What triggers it? (5-sec ID) | Early key proteins | High-yield one-liner |
|---|---|---|---|
| Classical | IgG or IgM bound to antigen | C1 (C1q, C1r, C1s) → C4, C2 | “Antibody activates C1; IgM is best at complement.” |
| Lectin | Mannose on microbes | MBL (mannose-binding lectin) + MASP → C4, C2 | “Lectin acts like classical without antibody.” |
| Alternative | Spontaneous C3 activation on microbial surfaces | C3, Factor B, Factor D, Properdin | “No C1/C2/C4—just C3 + B, D, properdin.” |
The Money Mnemonic (Shareable)
Classical: “C1 sees antibodies”
- C1q binds Fc region of antibody
- Needs antibody already bound to antigen
- IgM > IgG for complement activation (pentamer = efficient Fc clustering)
One-liner: “Classical = immune complexes (IgG/IgM) → C1.”
Lectin: “Same as classical, but sugar instead of antibody”
- MBL binds mannose
- MASP cleaves C4 and C2 (same downstream setup as classical)
One-liner: “Lectin = classical pathway cosplay—MBL/MASP replace C1.”
Alternative: “C3 ticks over, microbes pay the price”
- Low-level “tickover” generates C3b that can stick to surfaces
- Stabilized on microbial surfaces by properdin
- Uses Factor B + Factor D
One-liner: “Alternative = C3b + Factor B/D (+ properdin) on microbial surfaces.”
Convertases in 5 Seconds (Classic Step 1 Table)
C3 convertases
| Pathway | C3 convertase |
|---|---|
| Classical | C4b2a |
| Lectin | C4b2a |
| Alternative | C3bBb |
C5 convertases
(Add a C3b to the C3 convertase.)
| Pathway | C5 convertase |
|---|---|
| Classical | C4b2a3b |
| Lectin | C4b2a3b |
| Alternative | C3bBb3b |
One-liner memory trick:
- Classical/Lectin: “4-2 makes C3” → C4b2a
- Alternative: “B’s alternative” → Bb shows up: C3bBb
What Complement DOES (USMLE Favorites)
OIL RIG (the classic)
- Opsonization: C3b (also iC3b) coats bacteria → easier phagocytosis
- Inflammation: C5a (strongest) and C3a = anaphylatoxins → mast cell degranulation, ↑ vascular permeability
- Lysis: C5b-9 (MAC) punches holes, especially important for Neisseria
Rapid recall:
- C5a = chemotaxis + neutrophil activation (big-time test favorite)
- C3b = opsonin
- C5b-9 = MAC
Clinical Correlations You’re Expected to Know
Neisseria infections (MAC deficiency)
- C5–C9 deficiency → recurrent Neisseria gonorrhoeae/meningitidis
- Mechanism: can’t form MAC
C1 esterase inhibitor deficiency → Hereditary angioedema
- Uncontrolled bradykinin → swelling, no urticaria, poor response to antihistamines/epinephrine
- (High yield tie-in: complement regulation is clinically relevant.)
Low C3 vs Low C4 clue
- Low C3 + low C4: think classical activation (e.g., immune complex disease like lupus)
- Low C3 with normal C4: can suggest alternative pathway activation
(These patterns show up in Step vignettes and help you “pathway-localize” fast.)
5-Second Vignette Triggers (Mini Drill)
- “After strep infection, immune complexes, low C3/C4” → Classical
- “Mannose-binding lectin binds bacteria” → Lectin
- “C3 deficiency → severe recurrent pyogenic infections” → affects all pathways (C3 is central)
- “Recurrent Neisseria” → C5–C9 (MAC)
Final 5-Second Summary (Screenshot-Ready)
- Classical: IgG/IgM → C1 → C4b2a
- Lectin: MBL/MASP (mannose) → C4b2a
- Alternative: C3b + B/D (+ properdin) → C3bBb
- All roads: C3 → C5 → MAC (C5b-9)
- Big effects: C3b opsonizes, C5a chemotaxis, C5b-9 lyses