Regulation of Complement Activation

Activation of the complement cascade and the stability of active complement proteins are tightly regulated to prevent complement activation on normal host cells and to limit the duration of complement activation even on microbial cells and antigen-antibody complexes. Regulation of complement is mediated by several circulating and cell membrane proteins (Table 12-9). Many of these proteins as well as several proteins of the classical and alternative pathways belong to a family called regulators of complement activity (RCA) and are encoded by homologous genes that are located adjacent to one another in the genome.

Complement activation needs to be regulated for two reasons. First, low-level complement activation goes on spontaneously, and if such activation is allowed to proceed, the result can be damage to normal cells and tissues. Second, even when complement is activated where needed, such as on microbial cells or antigen-antibody complexes, it needs to be controlled because degradation products of complement proteins can diffuse to adjacent cells and injure them. Different regulatory mechanisms inhibit the formation of C3 convertases in the early steps of complement activation, break down

TABLE 12-9 Regulators of Complement Activation

Receptor

Structure

Distribution

Interacts with

Function

C1 inhibitor (C1 INH)

104 kD

Plasma protein; conc. 200 |g/mL

C1r, C1s

Serine protease inhibitor; binds to C1r and C1s and dissociates them from C1q

Factor I

88-kD dimer of 50- and 38- kD subunits

Plasma protein; conc. 35 |g/mL

C4b, C3b

Serine protease; cleaves C3b and C4b by using factor H, MCP, C4BP, or CR1 as cofactors

Factor H

150 kD; multiple CCPRs

Plasma protein; conc. 480 |g/mL

Cofactor for factor I-mediated cleavage of C3b

C4-binding protein (C4BP)

570 kD; multiple CCPRs

Plasma protein; conc. 300 |g/mL

Cofactor for factor I-mediated cleavage of C4b

Membrane cofactor for protein (MCP CD46)

45-70 kD; four CCPRs

Leukocytes, epithelial cells, endothelial cells

C3b, C4b

Cofactor for factor I-mediated cleavage of C3b and C4b

Decay-accelerating factor (DAF)

70 kD; GPI linked, four CCPRs

Blood cells, endothelial cells, epithelial cells

C4b2a, C3bBb

Displaces C2b from C4b and Bb from C3b (dissociation of C3 convertases)

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