art 1 Immune effector mechanisms TABLE 13.2 Proteins that requlate the complement system Type of Protein Immunologic function Cl inhibitor(ClInh) Soluble Classical Serine protease inhibitor: causes Clr.S2 to dissociate from C1q C4b-binding pro Soluble Classical and lectin Blocks formation of C3 convertase by (C4bBP) binding C4b: cofactor for cleavage of C4b by factor I Factor H Soluble Alternative Blocks formation of C3 convertase by binding C3b; cofactor for cleavage Complement-receptor Block formation of C3 convertase by type 1(CRT) Membrane Classical, alternative binding C4b or C3b: cofactor for Membrane-cofactor and lectin factor I-catalyzed cleavage of C4b protein(MCP) Decay-accelerating Membrane Classical, alternative Accelerates dissociation of c b2a and factor(DAE or CD55) bound and lectin C3bBb(classical and alternative C3 Factor-I Soluble Serine protease: cleaves C4b or C3b lectin using C4bBP, CRl, factor H, DAE Sprotein Soluble Terminal luble C5b67 and prevents its insertion into cell membrane Homologous restriction factor(HRF) Termina Bind to C5b678 on autologous cells, Membrane inhibitor of blocking binding of C9 reactive lysis( MIRL or CD59 Anaphylatoxin inactivate Soluble Effector Inactivates anaphylatoxin activity of C3a C4a, and C5a by carboxypeptidase N removal of C-terminal Arg An RCA (regulator of complement activation) protein In humans, all RCA proteins are encoded on chromosome 1 and contain short consensus repeats. Several rCa proteins also act on the assembled C3 con- tein can bind to C5b67, inducing a hydrophilic transition vertase, causing it to dissociate; these include the previously and thereby preventing insertion of C5b67 into the mem- mentioned C4bBP, CRl, and factor H. In addition, decay- brane of nearby cells(Figure 13-9c(1)) accelerating factor(DAF or CD55), which is a glycoprotein an- Complement-mediated lysis of cells is more effective if chored covalently to a glycophospholipid membrane protein, the complement is from a species different from that of the has the ability to dissociate C3 convertase. The consequences cells being lysed. This phenomenon depends on two mem- of daF deficiency are described in the Clinical Focus section. brane proteins that block MAC formation. These two pro- Each of these RCa proteins accelerates decay(dissociation) of teins, present on the membrane of many cell types, are C3 convertase by releasing the component with enzymatic ac- homologous restriction factor(HRF)and membrane inhibitor tivity( C2a or Bb)from the cell-bound component( CAb or of reactive lysis(MIRl or CD59). Both HRF and mirl pro- C3b). Once dissociation of the C3 convertase occurs, factor I tect cells from nonspecific complement-mediated lysis by cleaves the remaining membrane-bound C4b or C3b compo- binding to C8, preventing assembly of poly-C9 and its inser nent, irreversibly inactivating the convertase(Figure 13-9b). tion into the plasma membrane(Figure 13-9c(2)).However, Regulatory proteins also operate at the level of the mem- this inhibition occurs only if the complement components brane-attack complex. The potential release of the C5b67 are from the same species as the target cells. For this reason, complex poses a threat of innocent-bystander lysis to healthy MIRL and hrf are said to display homologous restriction, cells. A number of serum proteins counter this threat by for which the latter was named. As discussed in Chapter 21 binding to released C5b67 and preventing its insertion into homologous restriction poses a barrier to the use of organs the membrane of nearby cells. A serum protein called S pro- from other species for clinical transplantationSeveral RCA proteins also act on the assembled C3 con￾vertase, causing it to dissociate; these include the previously mentioned C4bBP, CR1, and factor H. In addition, decay￾accelerating factor (DAF or CD55), which is a glycoprotein an￾chored covalently to a glycophospholipid membrane protein, has the ability to dissociate C3 convertase. The consequences of DAF deficiency are described in the Clinical Focus section. Each of these RCA proteins accelerates decay (dissociation) of C3 convertase by releasing the component with enzymatic ac￾tivity (C2a or Bb) from the cell-bound component (C4b or C3b). Once dissociation of the C3 convertase occurs, factor I cleaves the remaining membrane-bound C4b or C3b compo￾nent, irreversibly inactivating the convertase (Figure 13-9b). Regulatory proteins also operate at the level of the mem￾brane-attack complex. The potential release of the C5b67 complex poses a threat of innocent-bystander lysis to healthy cells. A number of serum proteins counter this threat by binding to released C5b67 and preventing its insertion into the membrane of nearby cells. A serum protein called S pro￾tein can bind to C5b67, inducing a hydrophilic transition and thereby preventing insertion of C5b67 into the mem￾brane of nearby cells (Figure 13-9c(1)). Complement-mediated lysis of cells is more effective if the complement is from a species different from that of the cells being lysed. This phenomenon depends on two mem￾brane proteins that block MAC formation. These two pro￾teins, present on the membrane of many cell types, are homologous restriction factor (HRF) and membrane inhibitor of reactive lysis (MIRL or CD59). Both HRF and MIRL pro￾tect cells from nonspecific complement-mediated lysis by binding to C8, preventing assembly of poly-C9 and its inser￾tion into the plasma membrane (Figure 13-9c(2)). However, this inhibition occurs only if the complement components are from the same species as the target cells. For this reason, MIRL and HRF are said to display homologous restriction, for which the latter was named. As discussed in Chapter 21, homologous restriction poses a barrier to the use of organs from other species for clinical transplantation. 308 PART III Immune Effector Mechanisms TABLE 13-2 Proteins that regulate the complement system Type of Pathway Protein protein affected Immunologic function C1 inhibitor (C1Inh) Soluble Classical Serine protease inhibitor: causes C1r2s2 to dissociate from C1q C4b-binding protein Soluble Classical and lectin Blocks formation of C3 convertase by (C4bBP)* binding C4b; cofactor for cleavage of C4b by factor I Factor H* Soluble Alternative Blocks formation of C3 convertase by binding C3b; cofactor for cleavage of C3b by factor I Complement-receptor Block formation of C3 convertase by type 1 (CR1)* Membrane Classical, alternative, binding C4b or C3b; cofactor for Membrane-cofactor bound and lectin factor I-catalyzed cleavage of C4b protein (MCP)* or C3b C3bBb Decay-accelerating Membrane Classical, alternative, Accelerates dissociation of C4b2a and factor (DAE or CD55)* bound and lectin C3bBb (classical and alternative C3 convertases) Factor-I Soluble Classical, alternative, Serine protease: cleaves C4b or C3b and lectin using C4bBP, CR1, factor H, DAE, or MCP as cofactor S protein Soluble Terminal Binds soluble C5b67 and prevents its insertion into cell membrane Homologous restriction factor (HRF) Membrane Terminal Bind to C5b678 on autologous cells, Membrane inhibitor of bound blocking binding of C9 reactive lysis (MIRL or CD59)* Anaphylatoxin inactivator Soluble Effector Inactivates anaphylatoxin activity of C3a, C4a, and C5a by carboxypeptidase N removal of C-terminal Arg *An RCA (regulator of complement activation) protein. In humans, all RCA proteins are encoded on chromosome 1 and contain short consensus repeats. } }