Cd59

18 kD; GPI linked

Blood cells, endothelial cells, epithelial cells

C7, C8

Blocks C9 binding and prevents formation of the MAC

CCPRs, complement control protein repeats; conc., concentration; GPI, glycophosphatidylinositol; MAC, membrane attack complex.

C1q binds to antigen-complexed antibodies, resulting in activation of C1r2s2

C1 INH prevents C1r2s2 from becoming proteolytically active

C1r2s2/

FIGURE 12-13 Regulation of C1 activity by C1 INH. C1

INH displaces C1r2s2 from C1q and terminates classical pathway activation.

C1r2s2/

FIGURE 12-13 Regulation of C1 activity by C1 INH. C1

INH displaces C1r2s2 from C1q and terminates classical pathway activation.

and inactivate C3 and C5 convertases, and inhibit formation of the MAC in the late steps of the complement pathway.

• The proteolytic activity of C1r and C1s is inhibited by a plasma protein called C1 inhibitor (C1 INH). C1 INH

is a serine protease inhibitor (serpin) that mimics the normal substrates of C1r and C1s. If C1q binds to an antibody and begins the process of complement activation, C1 INH becomes a target of the enzymatic activity of the bound C1r2-C1s2. C1 INH is cleaved by and becomes covalently attached to these complement proteins, and as a result, the C1r2-C1s2 tetramer dissociates from C1q, thus stopping activation by the classical pathway (Fig. 12-13). In this way, C1 INH prevents the accumulation of enzymatically active C1r2-C1s2 in the plasma and limits the time for which active C1r2-C1s2 is available to activate subsequent steps in the complement cascade. An autosomal dominant inherited disease called hereditary angioneurotic edema is due to a deficiency of C1 INH. Clinical manifestations of the disease include intermittent acute accumulation of edema fluid in the skin and mucosa, which causes abdominal pain, vomiting, diarrhea, and potentially life-threatening airway obstruction. In these patients, the plasma levels of C1 INH protein are sufficiently reduced (<20% to 30% of normal) that activation of C1 by immune complexes is not properly controlled and increased breakdown of C4 and C2 occurs. The mediators of edema formation in patients with hereditary angioneurotic edema include a pro-teolytic fragment of C2, called C2 kinin, and bradyki-nin. C1 INH is an inhibitor of other plasma serine proteases besides C1, including kallikrein and coagulation factor XII, and both activated kallikrein and factor XII can promote increased formation of bradykinin.

• Assembly of the components of C3 and C5 convertases is inhibited by the binding of regulatory proteins to C3b and C4b deposited on cell surfaces (Fig. 12-14). If C3b is deposited on the surfaces of normal mammalian cells, it may be bound by several membrane proteins, including membrane cofactor protein (MCP, or CD46), type 1 complement receptor (CR1), decay-accelerating factor (DAF), and a plasma protein called factor H. C4b deposited on cell surfaces is similarly bound by DAF, CR1, and another plasma protein called C4-binding protein (C4BP). By binding to C3b or C4b, these proteins competitively inhibit the binding of other components of the C3 convertase, such as Bb of the alternative pathway and C2b of the classical pathway, thus blocking further progression of the complement cascade. (Factor H inhibits binding of only Bb to C3b and is thus a regulator of the alternative but not the classical pathway.) MCP, CR1, and DAF are produced by mammalian cells but not by microbes. Therefore, these regulators of complement selectively inhibit complement activation on host cells and allow complement activation to proceed on microbes. In addition, cell surfaces rich in sialic acid favor binding of the regulatory protein factor H over the alternative pathway protein factor B. Mammalian cells express higher levels of sialic acid than most microbes do, which is another reason that complement activation is prevented on normal host cells and permitted on microbes.

DAF is a glycophosphatidylinositol-linked membrane protein expressed on endothelial cells and erythrocytes. Genetic deficiency of an enzyme required to form such protein-lipid linkages results in failure to express many glycophosphatidylinositol-linked membrane proteins, including DAF and CD59 (see following), and causes a disease called paroxysmal nocturnal hemoglobinuria. This disease is characterized by recurrent bouts of intravascular hemolysis,

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