No abstract

The fifth component of guinea pig complement, with a sedimentation coefficient 7.8S, is cleaved by sensitized sheep erythrocytes treated with the first four components of complement into two fragments with sedimentation coefficients of 7.4S and 1.5S. The smaller fragment, with a molecular weight of about 15,000, possesses chemotactic activity for rabbit polymorphonuclear leukocytes, as well as anaphylatoxic activity for guinea pig ileum.

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 leakypatch 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.Recent studies of complement (C) have focused attention on the late-acting components, C5-C9, which make up the cytolytic part of the system (1-8). It has been shown that the C4, 2, 3 enzyme activates C5 by cleavage (2, 3) and that the resulting C5b fragment combines with C6, which serves as a stabilizer (4). In turn, the C5b, 6 complex combines with C7 (5, 6) yielding C5b, 6, 7, which appears to be the foundation of the lytic attack mechanism (1). After uptake of C8 by this complex, partial membrane damage is produced as evidenced by slow lysis of erythrocytes in the state erythrocyte-antibody-complement components 1-8 (EAC1-8) on incubation at 370 (7). When the terminal complement component, C9, joins the attack system, rapid lysis ensues indicating overt membrane damage. Recent studies of the reaction of EAC1-8 with C9 (8) have reaffirmed the one-hit theory in its strict sense, namely, that a single membrane Abbreviations: C, C1, C2, C3, etc.-C refers to complement, and the numbers indicate the components of the complement system. The letters "a" or "b", as in C5b, refer to fragments. 935-938. lesion at the C5-C9 locus suffices for lysis, and this has led to an examination of possible mechanisms for producing this lesion. These are described in the present paper in relation to newer concepts of membrane structure.The fluid mosaic model of membrane structure Physicochemical studies of the proteins and lipids in cell membranes have led to a new concept of membrane structure, termed the fluid mosaic model (9, 10). As in the DavsonDa...