Rapid Review·Immunology
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IMMUNE RESPONSES
T1Must knowComplement Disorders & Pathway Testing
P105
Focus on
Which protein is missing determines whether you get infections, lupus, angioedema, or hemolysis.
Key takeaways
Complement deficiencies
Early vs terminal
Early complement deficiencies (C1-C4)
raise the risk of severe, recurrent pyogenic sinus and respiratory infections, and of SLE ("SLEarly"), because C3b is needed to clear antigen-antibody complexes.Terminal complement deficiencies (C5-C9)
raise susceptibility to recurrent Neisseria bacteremia, both meningococcal and gonococcal.Hereditary angioedema
C1 inhibitor deficiency causes hereditary angioedema
Unregulated kallikrein activation raises bradykinin.- ↓ C4 is the screening lab (chronically consumed).
- ACE inhibitors are CONTRAINDICATED, because ACE normally degrades bradykinin.
- Treatment: ecallantide (kallikrein inhibitor) and icatibant (bradykinin B2 receptor antagonist).
Paroxysmal nocturnal hemoglobinuria
What this shows
Paroxysmal nocturnal hemoglobinuria (PNH)
An acquired PIGA mutation causing loss of GPI anchors, and therefore loss of CD55 (DAF) and CD59 (MIRL).- Loss of CD59 → uninhibited MAC formation → INTRAVASCULAR hemolysis (the major mechanism).
- Loss of CD55 → ↑ C3b opsonization → EXTRAVASCULAR hemolysis (the minor mechanism).
- Labs: ↓ haptoglobin, hemoglobinuria, hemosiderinuria, with dark urine that is often worst in the morning.
- Triad: hemolytic anemia, pancytopenia, and atypical venous thrombosis (Budd-Chiari, portal, cerebral, dermal).
- Treatment: eculizumab (anti-C5), which blocks terminal complement and therefore prevents intravascular hemolysis only.
Pathway testing
Pathway testing localizes the defect by which screen is low.
| Test | Pathway Assessed | ↓ In |
|---|---|---|
| CH50 | Classical (C1, C2, C4) | SLE, immune complex disease, C2 or C4 deficiency |
| AH50 | Alternative (factor D, factor B, properdin) | Properdin or factor D/B deficiency, Neisseria infection |
| CH50 + AH50 both ↓ | Terminal / common (C3, C5-C9) | Terminal pathway defect (C5-C9), or complement consumption in sepsis or autoimmune disease |
The naming mnemonic is CAT
CH50 = Classical, AH50 = Alternative, Together = Terminal.A woman has recurrent episodes of facial and laryngeal swelling without hives, and her C4 is low. What is deficient, and which antihypertensive class must she never take?
C1 inhibitor (hereditary angioedema): unregulated kallikrein raises bradykinin, and C4 is chronically consumed. ACE inhibitors are contraindicated, because ACE normally degrades bradykinin.
How it's tested
Hereditary angioedema is a bradykinin disease, not a histamine disease, which is why antihistamines and epinephrine do not work and why the labs show low C4 while C1 inhibitor is deficient. Giving an ACE inhibitor to such a patient is a catastrophic error, because ACE normally degrades bradykinin.
For PNH, the mechanistic split is the exam point. CD59 loss drives the intravascular hemolysis, since MAC punches RBCs directly, so eculizumab blocks C5 and prevents intravascular hemolysis but leaves C3b-mediated extravascular hemolysis intact. And because eculizumab itself blocks MAC formation, patients must be vaccinated against Neisseria meningitidis before starting it.
Go deeper
First Aid 2026 — Immuno (complement disorders) · B&B — Complement deficiencies · Mehlman — HY Immuno (Neisseria; hereditary angioedema)
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