MCP and CR1 act as cofactors for Factor Imediated proteolytic cleavage of C3b producing iC3b

FIGURE 12-15 Factor I-mediated cleavage of C3b. In the presence of cell membrane-bound cofactors (MCP or CR1), plasma factor I proteolytically cleaves C3b attached to cell surfaces, leaving an inactive form of C3b (iC3b). Factor H and C4-binding protein can also serve as cofactors for factor I-mediated cleavage of C3b. The same process is involved in the proteolysis of C4.

FIGURE 12-15 Factor I-mediated cleavage of C3b. In the presence of cell membrane-bound cofactors (MCP or CR1), plasma factor I proteolytically cleaves C3b attached to cell surfaces, leaving an inactive form of C3b (iC3b). Factor H and C4-binding protein can also serve as cofactors for factor I-mediated cleavage of C3b. The same process is involved in the proteolysis of C4.

at least partly attributable to unregulated complement activation on the surface of erythrocytes. Recurrent intravascular hemolysis in turn leads to chronic hemolytic anemia and venous thrombosis. An unusual feature of this disease is that the mutation in the defective gene is not inherited but represents an acquired mutation in hematopoietic stem cells.

• Cell-associated C3b is proteolytically degraded by a plasma serine protease called factor I, which is active only in the presence of regulatory proteins (Fig. 12-15). MCP, factor H, C4BP, and CR1 all serve as cofactors for factor I-mediated cleavage of C3b (and C4b). Thus, these regulatory host cell proteins promote proteolytic degradation of complement proteins; as discussed earlier, the same regulatory proteins cause dissociation of C3b (and C4b)-containing complexes. Factor I-mediated cleavage of C3b generates the fragments called iC3b, C3d, and C3dg, which do not participate in complement activation but are recognized by receptors on phagocytes and B lymphocytes.

• Formation of the MAC is inhibited by a membrane protein called CD59. CD59 is a glycophospha-tidylinositol-linked protein expressed on many cell types. It works by incorporating itself into assembling MACs after the membrane insertion of C5b-8, thereby inhibiting the subsequent addition of C9 molecules (Fig. 12-16). CD59 is present on normal host cells, where it limits MAC formation, but it is not present on microbes. Formation of the MAC is also inhibited by plasma proteins such as S protein, which functions by binding to soluble C5b,6,7 complexes and thereby preventing their insertion into cell membranes near the site where the complement cascade was initiated. Growing MACs can insert into any neighboring cell membrane besides the membrane on which they were generated. Inhibitors of the MAC in the plasma and in host cell membranes ensure that lysis of innocent bystander cells does not occur near the site of complement activation.

Much of the analysis of the function of complement regulatory proteins has relied on in vitro experiments, and most of these experiments have focused on assays that measure MAC-mediated cell lysis as an endpoint. On the basis of these studies, a hierarchy of importance for inhibiting complement activation is believed to be CD59 > DAF > MCP; this hierarchy may reflect the relative abundance of these proteins on cell surfaces.

The function of regulatory proteins may be overwhelmed by excessive activation of complement pathways. We have emphasized the importance of these regulatory proteins in preventing complement activation on normal cells. However, complement-mediated phagocytosis and damage to normal cells are important pathogenic mechanisms in many immunologic diseases (see Chapter 18). In these diseases, large amounts of antibodies may be deposited on host cells, generating enough active complement proteins that the regulatory molecules are unable to control complement activation.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment