Mechanism of Cytolysis by Complement

The attack of complement is directed against the lipid moiety of the cell membrane; a single lesion at the site of fixation of complement proteins C5-C9 is responsible for lysis of a cell. There are two hypothetical models for the generation of this membrane lesion. The first of these, designated the leaky-patch model, postulates either direct enzymatic attack or enzymatic generation of a lytic substance by C5-C9. As a result, the phospholipid bilayer of the membrane would be disrupted and a leaky patch permitting passage of water and salt would appear. However, this hole would persist only as long as enzymatic action continues. Thus, the leaky-patch model would not produce a stable hole, and for this reason it is considered an unlikely mechanism. The second hypothesis, termed the doughnut model, describes a structural concept for creating a hydrophilic passage through the hydrophobic phospholipid bilayer of the membrane. In essence, this would be a rigid and hollow structure, like a doughnut, with a hydrophobic exterior, which is inserted into the phospholipid bilayer of the cell membrane in such a way that its hollow hydrophilic core becomes a channel through which salt and water can exchange freely between the interior of the cell and the extracellular environment. The late-acting complement proteins C5-C9 are the most probable source of the structural components of the doughnut. A combination of the leaky-patch and doughnut models may represent the most likely mechanism.