C5b9

C5b-9, commonly referred to as the membrane attack complex (MAC), is the final assembly of the vertebrate complement system that forms pores in lipid membranes to induce cell lysis. It results from the terminal steps of complement activation and is composed of the C5b fragment bound to C6, C7, C8, and multiple C9 molecules.

Formation occurs after activation of the classical, lectin, or alternative pathways, which cleave C5 into C5a and C5b. C5b rapidly binds C6 and C7, then associates with C8 and multiple C9 molecules to create a ring-shaped, transmembrane pore. The MAC inserts into target cell membranes, disrupting ionic and molecular gradients and leading to cell death. The C5a fragment serves as a potent inflammatory mediator, recruiting immune cells to the site of activation.

Functionally, C5b-9 is a key effector of terminal complement activity, providing defense against certain pathogens, particularly encapsulated bacteria, by enabling direct lysis. However, unregulated MAC formation can damage host tissues, contributing to pathology in various diseases.

Regulation is achieved by host proteins that inhibit or prevent MAC assembly. CD55 (decay-accelerating factor) and CD46 (membrane cofactor protein) limit upstream activation and convertase formation, while CD59 (protectin) inhibits C9 polymerization. Soluble regulators such as vitronectin and clusterin can sequester MAC components. Defects in regulation or excessive activation are implicated in conditions like paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and certain inflammatory diseases.

In research and clinical settings, soluble C5b-9 in serum (sC5b-9) serves as a biomarker of terminal pathway activation and MAC turnover.