membrane attack complex
Summary
The membrane attack complex (MAC, C5b-9) is the terminal product of the complement cascade, formed by sequential binding of C5b, C6, C7, C8, and multiple C9 molecules. It creates a pore in the target cell membrane, leading to osmotic lysis and cell death. It is a key effector of innate immunity, particularly important for defense against gram-negative bacteria like Neisseria species.
Detail
MAC formation begins when C5 convertase (formed via classical, alternative, or lectin pathways) cleaves C5 into C5a and C5b. C5b binds sequentially to C6, C7, and C8, forming the C5b-8 complex on the cell membrane. This complex then recruits and polymerizes multiple C9 molecules (typically 10-16), which insert into the lipid bilayer to form a transmembrane pore approximately 10 nm in diameter. This pore disrupts the osmotic gradient, allowing water and ions to flow freely, ultimately causing cell lysis (particularly effective against gram-negative bacteria and some parasites).
Clinical significance: Deficiencies in terminal complement components (C5-C9) result in increased susceptibility to recurrent Neisseria meningitidis and Neisseria gonorrhoeae infections, as these organisms are particularly vulnerable to complement-mediated lysis due to their thin peptidoglycan layer and outer membrane structure. This is a classic board exam association - think 'complement deficiency = Neisseria infections.'
Regulation: Host cells protect themselves from complement-mediated damage via regulatory proteins including CD59 (protectin/MIRL), which inhibits C9 polymerization, and other regulators like decay-accelerating factor (DAF/CD55). Paroxysmal nocturnal hemoglobinuria (PNH) results from a deficiency in GPI-anchored proteins (including CD55 and CD59) due to a PIGA gene mutation, leading to unregulated MAC formation and complement-mediated hemolysis of RBCs, particularly at night when blood is slightly more acidic and complement activity increases.
Eculizumab, a monoclonal antibody that inhibits C5 cleavage, is used therapeutically in PNH and atypical hemolytic uremic syndrome (aHUS) to prevent MAC formation and reduce hemolysis, but increases susceptibility to Neisseria infections (patients require meningococcal vaccination).
Sources
- First Aid for the USMLE Step 1
- Kuby Immunology
- Robbins and Cotran Pathologic Basis of Disease
- Janeway's Immunobiology
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