A 35-year-old Indian man with a history of recurrent Neisseria meningitidis and Neisseria gonorrhoeae infections presents to the immunology clinic. Serum complement levels are measured: C3 95 mg/dL (normal 80–160), C4 28 mg/dL (normal 15–45), C5 <1% (normal 5–10%), C6 <1%, C7 <1%, C8 <1%, C9 <1%. CH50 (total hemolytic complement) is undetectable. Which complement component deficiency best explains this clinical presentation, and what is the mechanism of increased susceptibility to Neisseria species?

Explanation

## Terminal Complement Deficiency and Neisseria Susceptibility ### Clinical Presentation of Terminal Complement Deficiency **Key Point:** Selective deficiency of terminal complement components (C5–C9) is the most common complement deficiency associated with recurrent meningococcal and gonococcal infections. The patient's lab values show normal C3 and C4 but absent C5–C9, confirming terminal pathway deficiency. ### Mechanism of Increased Neisseria Susceptibility Terminal complement deficiency impairs two critical defense mechanisms: 1. **Impaired Membrane Attack Complex (MAC) Formation** - C5–C9 are required for MAC assembly on bacterial cell membranes - MAC creates osmotic lysis and direct bactericidal activity - Without MAC, Neisseria species can survive complement-mediated killing 2. **Reduced C5a Generation** - C5 cleavage generates C5a, a potent anaphylatoxin and neutrophil chemoattractant - C5a is essential for neutrophil recruitment and activation at sites of infection - Deficiency results in impaired local inflammatory response **Clinical Pearl:** Patients with C5–C9 deficiency have a 200–1000-fold increased risk of meningococcal disease, yet maintain relatively normal responses to encapsulated bacteria (pneumococcus, H. influenzae) because opsonization via C3b and antibody-mediated phagocytosis remain intact. ### Why Neisseria Species Are Particularly Vulnerable Neisseria meningitidis and N. gonorrhoeae are highly susceptible to MAC-mediated lysis because: - Their outer membranes are relatively fragile compared to gram-negative rods - They lack robust lipopolysaccharide (LPS) O-antigen side chains that protect other gram-negatives - They depend on complement-mediated killing as a primary defense mechanism **Mnemonic:** **NEISSERIA = Needs Excellent Immune System (especially C5–C9)** ### Laboratory Findings in Terminal Complement Deficiency | Parameter | Finding | Interpretation | |-----------|---------|----------------| | C3, C4 | Normal | Classical and alternative pathways intact | | C5–C9 | Absent or <1% | Terminal pathway defective | | CH50 | Undetectable | No hemolytic complement activity | | AP50 | Normal | Alternative pathway functional | | Opsonization | Normal | C3b deposition and phagocytosis preserved | ### Differential Diagnosis of Complement Deficiencies ```mermaid flowchart TD A[Recurrent Neisseria Infection]:::outcome --> B{Complement Profile?}:::decision B -->|C3 & C4 normal, C5-C9 absent| C[Terminal Pathway Deficiency]:::outcome B -->|C3 low, C4 normal| D[Alternative Pathway Defect]:::outcome B -->|C3 & C4 low| E[Classical Pathway Defect]:::outcome C --> F[MAC formation impaired<br/>C5a generation reduced]:::action D --> G[Factor H/I deficiency<br/>or C3 deficiency]:::action E --> H[C1q, C2, C4 deficiency]:::action F --> I[Meningococcal & gonococcal<br/>susceptibility]:::urgent G --> J[Encapsulated bacteria<br/>& autoimmune disease]:::urgent E --> K[SLE, GN, vasculitis]:::urgent ``` **High-Yield:** Terminal complement deficiency (C5–C9, properdin) → recurrent Neisseria; C3 deficiency → recurrent encapsulated bacteria + autoimmune disease; C1q/C2/C4 deficiency → SLE-like syndrome. [cite:Harrison 21e Ch 310; Robbins 10e Ch 6]