A 28-year-old man with recurrent Neisseria meningitidis infections is found to have a deficiency in the membrane attack complex (MAC). Which finding would best distinguish his condition from C3 deficiency?

Explanation

## MAC Deficiency vs. C3 Deficiency: Clinical Distinction ### Overview Both MAC deficiency (C5–C9) and C3 deficiency cause recurrent *Neisseria* infections, but the **mechanisms and clinical presentations differ significantly**. ### MAC Deficiency (C5–C9 Deficiency) **Key Point:** MAC deficiency specifically impairs the lytic phase of complement but preserves all upstream complement functions (C3 activation, opsonization, anaphylatoxin generation). #### Preserved Functions - **C3 activation** remains intact → C3b deposition on pathogens - **Opsonization** is normal → phagocytes recognize C3b-coated bacteria - **Phagocytosis** proceeds normally - **C3a and C5a** generation is normal → chemotaxis and inflammation intact - **Classical and alternative pathways** activate normally up to C5 #### Impaired Function - **Bacteriolysis** is absent → cannot directly kill gram-negative bacteria - **Neisseria meningitidis** (gram-negative, encapsulated) is particularly vulnerable to MAC-mediated lysis #### Clinical Features - Recurrent **meningococcal meningitis** (often recurrent, but not fulminant) - **Gonococcal infections** (disseminated) - Relatively preserved immunity to other infections - Infections often **less severe** than in C3 deficiency ### C3 Deficiency **Key Point:** C3 deficiency eliminates the central hub of complement—both opsonization AND lysis are impaired. #### Impaired Functions - **No C3b deposition** → no opsonization - **No phagocytosis enhancement** → bacteria evade innate immunity - **No C3a generation** → impaired chemotaxis - **No C5 activation** → no anaphylatoxins, no MAC formation #### Clinical Features - Recurrent infections with **encapsulated bacteria** (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) - **Severe, recurrent, life-threatening** infections - Increased susceptibility to **pyogenic bacteria** - Often presents in **infancy/early childhood** ### Comparison Table | Feature | MAC Deficiency (C5–C9) | C3 Deficiency | | --- | --- | --- | | **Opsonization** | Preserved (C3b intact) | Absent (no C3b) | | **Phagocytosis** | Normal | Severely impaired | | **Bacteriolysis** | Absent | Absent | | **C3a/C5a generation** | Normal | Absent | | **Chemotaxis** | Normal | Impaired | | **Infection severity** | Moderate (recurrent meningitis) | Severe (life-threatening) | | **Pathogen spectrum** | *Neisseria* spp. (gram-negative) | Encapsulated bacteria (broad) | | **Age of onset** | Variable (can be adult) | Usually infancy | | **Opsonin-mediated killing** | Intact | Absent | ### Why Opsonization Distinguishes Them **High-Yield:** In MAC deficiency, the **complement cascade proceeds normally through C3**, depositing C3b on bacterial surfaces. Phagocytes (macrophages, neutrophils) recognize C3b via complement receptors (CR1, CR3, CR4) and engulf the bacteria efficiently. This is why patients with MAC deficiency can still mount an immune response to most pathogens. In C3 deficiency, there is **no C3b to deposit**, so opsonization fails entirely. Bacteria are not recognized by phagocytes and disseminate unchecked. **Clinical Pearl:** A patient with MAC deficiency who develops meningitis may respond to antibiotics and supportive care because phagocytosis is intact. A patient with C3 deficiency has a much higher mortality rate because even antibiotics cannot overcome the lack of opsonization-enhanced clearance. ### Why Other Options Are Wrong - **Option B (Encapsulated bacteria only):** C3 deficiency predisposes to recurrent infections with encapsulated bacteria. MAC deficiency also causes recurrent *Neisseria* infections, but the spectrum is narrower (primarily gram-negative diplococci). This is not a clear discriminator. - **Option C (Elevated C3a/C5a):** In MAC deficiency, C3a and C5a levels are normal or elevated (complement is activated). In C3 deficiency, these cannot be generated. This is actually **opposite** to what the question implies. - **Option D (Impaired classical pathway):** Both MAC and C3 deficiency have normal classical pathway activation up to the point of their respective defects. This does not distinguish them. [cite:Robbins 10e Ch 6; Harrison 21e Ch 310]