A 35-year-old woman from Bangalore presents with a 6-month history of recurrent meningitis caused by *Neisseria meningitidis* (serogroup B). She recovered fully from each episode after antibiotic therapy. Complement serum levels (C3, C4, C1q) are all normal. Flow cytometry of blood granulocytes shows absent CD55 and CD46 expression. Which complement regulatory protein deficiency explains her recurrent meningococcal disease?

Explanation

## Clinical Presentation Analysis This patient has: 1. **Recurrent meningitis caused by *Neisseria meningitidis*** (classic terminal pathway defect pattern) 2. **Normal serum complement levels** (C3, C4, C1q all normal) 3. **Absent CD55 and CD46 on granulocytes** (flow cytometry finding) ## Membrane Complement Regulatory Proteins | Protein | Abbreviation | CD Number | Function | Deficiency Pattern | |---------|--------------|-----------|----------|--------------------| | **Decay-accelerating factor** | DAF | CD55 | Accelerates C3/C5 convertase decay (classical & alternative) | Recurrent *Neisseria*, normal serum levels | | **Membrane cofactor protein** | MCP | CD46 | Cofactor for Factor I-mediated C3b/C4b inactivation | Recurrent *Neisseria*, normal serum levels | | **CD59 (MIRL)** | MIRL | CD59 | Inhibits C5b-9 (MAC) assembly | Paroxysmal nocturnal hemoglobinuria (PNH) | | **C1-inhibitor** | C1-INH | — | Inhibits C1r, C1s, kallikrein | Hereditary angioedema | | **Factor H** | FH | — | Negative regulator of alternative pathway | Marked C3 depletion | | **Properdin** | Factor P | — | Positive regulator of alternative pathway | Mild *Neisseria* susceptibility | ## Why DAF/CD55 and MCP/CD46 Deficiency? **Key Point:** DAF and MCP are **membrane-bound regulators** of complement. Their deficiency causes: - **Uncontrolled local C3/C5 convertase activation** on cell surfaces (especially *Neisseria*) - **Serum complement levels remain normal** (because the defect is local, not systemic) - **Selective susceptibility to *Neisseria meningitidis*** (terminal pathway activation → MAC-mediated lysis) **High-Yield:** Patients with DAF/MCP deficiency have **normal serum complement levels but impaired cell-surface regulation**. This distinguishes them from Factor H deficiency (marked C3 depletion) and C1-INH deficiency (angioedema, not meningococcal disease). **Clinical Pearl:** Combined DAF/CD55 and MCP/CD46 deficiency is rare but well-documented. Some patients have isolated CD55 or CD46 deficiency; combined deficiency confers the highest risk of recurrent meningococcal disease. **Mnemonic:** **"MEM-BRANE BUGS"** — **MEM**brane-bound regulators (DAF, MCP) deficiency → susceptibility to **BRANE**-associated bacteria (*Neisseria*), with normal serum complement levels. ## Why Not C1-INH Deficiency? C1-INH deficiency causes **hereditary angioedema** (recurrent angioedema, not meningitis). It is not associated with recurrent meningococcal disease. Flow cytometry would be normal. ## Why Not Factor H Deficiency? Factor H deficiency causes **marked C3 depletion** (C3 level would be low, not normal). It is associated with *Neisseria* susceptibility but also with membranoproliferative glomerulonephritis and C3 glomerulopathy. The normal C3 level rules this out. ## Why Not Properdin (Factor P) Deficiency? Properdin deficiency causes **mild *Neisseria* susceptibility** (not recurrent meningitis). Serum complement levels are normal. Properdin is a positive regulator (not a negative regulator like DAF/MCP), so its deficiency has a milder phenotype. Flow cytometry would be normal (properdin is not a membrane protein).