The competition between DAF or MCP and factor B for binding to surface-bound C3b is an example of the second mechanism for inhibiting complement activation on host cells. By binding C3b and C4b on the cell surface, these proteins competitively inhibit the binding of C2 to cell-bound C4b and of factor B to cell-bound C3b, thereby inhibiting convertase formation. DAF and MCP also mediate protection against complement through a third mechanism, which is to augment the dissociation of C4b2a and C3bBb convertases that have already formed. Like DAF, CR1 is among the host-cell membrane molecules that regulate complement through both these mechanisms—that is, by promoting the dissociation of convertase and exhibiting cofactor activity. All the proteins that bind the homologous C4b and C3b molecules share one or more copies of a structural element called the short consensus repeat (SCR), the complement control protein (CCP) repeat, or (especially in Japan) the sushi domain.
In addition to the mechanisms for preventing C3 convertase formation and C4 and C3 deposition on cell membranes, there are also inhibitory mechanisms that prevent the inappropriate insertion of the membrane-attack complex (MAC) into membranes. We saw in Section 2-15 that the membrane-attack complex polymerizes onto C5b molecules created by the action of C5 convertase. The MAC complex mainly inserts into cell membranes adjacent to the site of the C5 convertase, that is, close to the site of complement activation on a pathogen. However, some newly formed membrane-attack complexes may diffuse from the site of complement activation and insert into adjacent host-cell membranes. Several plasma proteins, including, notably, vitronectin (also known as S-protein), bind to the C5b67, C5b678, and C5b6789 complexes and thereby inhibit their random insertion into cell membranes. Host-cell membranes also contain an intrinsic protein, CD59, or protectin, that inhibits the binding of C9 to the C5b678 complex (see Fig. 2.37, bottom row). CD59 and DAF are both linked to the cell surface by a glycosylphosphatidylinositol (GPI) tail, like many other peripheral membrane proteins. One of the enzymes involved in the synthesis of GPI tails is encoded by a gene, PIGA, on the X chromosome. In people with a somatic mutation in this gene in a clone of hematopoietic cells, both CD59 and DAF fail to function. This causes the disease paroxysmal nocturnal hemoglobinuria, which is characterized by episodes of intravascular red blood cell lysis by complement. Red blood cells that lack only CD59 are also susceptible to destruction as a result of spontaneous activation of the complement cascade.
2-17 Pathogens produce several types of proteins that can inhibit complement activation.
Bacterial pathogens have evolved various strategies to avoid activation of complement, and thereby to avoid elimination by this first line of innate defense (Fig. 2.38). One strategy that many pathogens employ is to mimic host surfaces by attracting host complement regulators to their own surfaces. A mechanism to achieve this is for the pathogen to express surface proteins that bind to soluble complement-regulatory proteins such as C4BP and factor H. For example, the Gram-negative pathogen Neisseria meningitidis produces factor H binding protein (fHbp), which recruits factor H (see Section 2-10), and the outer
Fig. 2.38 Complement evasion proteins produced by various pathogens.
membrane protein PorA, which binds to C4BP. By recruiting factor H and C4BP to the pathogen membrane, the pathogen is able to inactivate C3b that is deposited on its surface and thereby avoid the consequences of complement activation. Complement is important in defense against Neisseria species, and several complement deficiencies are associated with increased susceptibility to this pathogen.