Regulation of the Complement System

Because many elements of the complement system are capable of attacking host cells as well as foreign cells and microorganisms, elaborate regulatory mechanisms have evolved to restrict complement activity to designated targets. A general mechanism of regulation in all complement pathways is the inclusion of highly labile components that undergo spontaneous inactivation if they are not stabilized by reaction with other components. In addition, a series of regulatory proteins can inactivate various complement components (Table 13-2). For example, the glycoprotein C1 inhibitor (C1Inh) can form a complex with C1r2s2, causing it to dissociate from C1q and preventing further activation of C4 or C2 (Figure 13-9a(1)).

The reaction catalyzed by the C3 convertase enzymes of the classical, lectin, and alternative pathways is the major amplification step in complement activation, generating hundreds of molecules of C3b. The C3b generated by these enzymes has the potential to bind to nearby cells, mediating damage to the healthy cells by causing their opsonization by phagocytic cells bearing C3b receptors or by induction of the membrane-attack complex. Damage to normal host cells is prevented because C3b undergoes spontaneous hydrolysis by the time it has diffused 40 nm away from the C4b2a or C3bBb convertase enzymes, so that it can no longer bind to its target site. The potential destruction of healthy host cells by C3b is further limited by a family of related proteins that regulate C3 conver-tase activity in the classical and alternative pathways. These regulatory proteins all contain repeating amino acid sequences (or motifs) of about 60 residues, termed short consensus repeats (SCRs). All these proteins are encoded at a single location on chromosome 1 in humans, known as the regulators of complement activation (RCA) gene cluster.

In the classical and lectin pathways, three structurally distinct RCA proteins act similarly to prevent assembly of C3 convertase (Figure 13-9a(2)). These regulatory proteins include soluble C4b-binding protein (C4bBP) and two membrane-bound proteins, complement receptor type 1 (CR1) and membrane cofactor protein (MCP). Each of these regulatory proteins binds to C4b and prevents its association with C2a. Once C4bBP, CR1, or MCP is bound to C4b, another regulatory protein, factor I, cleaves the C4b into bound C4d and soluble C4c (Figure 13-9a(3)). A similar regulatory sequence operates to prevent assembly of the C3 convertase C3bBbin the alternative pathway. In this case CR1, MCP, or a regulatory component called factor H binds to C3b and prevents its association with factor B (Figure 13-9a(4)). Once CR1, MCP, or factor H is bound to C3b, factor I cleaves the C3b into a bound iC3b fragment and a soluble C3f fragment. Further cleavage of iC3b by factor I releases C3c and leaves C3dg bound to the membrane (Figure 13-9a(5)). The molecular events involved in regulation of cell-bound C4b and C3b are depicted in Figure 13-10 (page 310).

Proteins that regulate the complement system

Protein

Type of protein

Pathway affected

Immunologic function

C1 inhibitor (C1Inh)

C4b-binding protein (C4bBP)*

Factor H*

Complement-receptor type 1 (CR1)*

Membrane-cofactor protein (MCP)*

Decay-accelerating factor (DAE or CD55)*

Factor-I

S protein

Homologous restriction factor (HRF)

Membrane inhibitor of reactive lysis (MIRL or CD59)*

Anaphylatoxin inactivator

Soluble Soluble

Soluble

Membrane bound

Membrane bound

Soluble

Soluble

Membrane bound

Soluble

Classical

Classical and lectin Alternative

Classical, alternative, and lectin

Classical, alternative, and lectin

Classical, alternative, and lectin

Terminal

Terminal

Effector

Serine protease inhibitor: causes C1r2s2 to dissociate from C1q

Blocks formation of C3 convertase by binding C4b; cofactor for cleavage of C4b by factor I

Blocks formation of C3 convertase by binding C3b; cofactor for cleavage of C3b by factor I

Block formation of C3 convertase by binding C4b or C3b; cofactor for factor I-catalyzed cleavage of C4b or C3b C3bBb

Accelerates dissociation of C4b2a and C3bBb (classical and alternative C3 convertases)

Serine protease: cleaves C4b or C3b using C4bBP, CR1, factor H, DAE, or MCP as cofactor

Binds soluble C5b67 and prevents its insertion into cell membrane

Bind to C5b678 on autologous cells, blocking binding of C9

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-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 anchored 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 activity (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 component, irreversibly inactivating the convertase (Figure 13-9b).

Regulatory proteins also operate at the level of the membrane-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 membrane 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 membrane proteins that block MAC formation. These two proteins, 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 protect cells from nonspecific complement-mediated lysis by binding to C8, preventing assembly of poly-C9 and its insertion 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.

Association of C4b and C2a is blocked by binding C4b-binding protein (C4bBP), complement receptor type I, or membrane cofactor protein (MCP)

Inhibitor-bound C4b is cleaved by Factor 1

C4bBP, CRI, or MCP

Factor 1

C3 convertase

In alternative pathway, CR1, MCP, or Factor H prevent binding of C3b and Factor B

Inhibitor-bound C3b is cleaved by Factor 1

CRI, MCP, Factor H

Factor B

Factor 1

C3 convertase

(b) After assembly of convertase

C3 convertases are dissociated by C4bBP, CR1, Factor H, and decay-accelerating Factor (DAF)

C4bBP, CR2 Factor H, DAF

Dissociation of convertase; remaining C4b or C3b cleaved by Factor 1

(c) Regulation at assembly of membrane-attack complex (MAC)

S protein prevents insertion of C5b67 MAC component into the membrane

C5b67

—I I—> Cannot attack nearby cells S protein

Homologous restriction factor (HRF) and membrane inhibitor of reactive lysis (MIRL or CD59) bind C81, preventing assembly of poly-C9 and blocking formation of MAC

C4bbp Complement System

Membrane attack complex

FIGURE 13-9

Regulation of the complement system by regulatory proteins (black)

Cell membrane

Bound C4b

C4bBP or CR1 or MCP

Factor I

NH 0C

C3dg Fragment

Cell membrane

Bound C3b

Factor H or

Factor I

iC3b

Factor I

C3dg

FIGURE 13-10

Inactivation of bound C4b and C3b by regulatory proteins of the complement system. (a) In the classical pathway, C4bBP (C4b-binding protein), CR1 (complement receptor type 1), or MCP (membrane cofactor protein) bind to C4b and act as cofac-tors for factor I-mediated cleavage of C4b. (b) In the alternative pathway, factor H, CR1, or MCP bind to Ccb and act as cofactors for factor I-mediated cleavage of C4b. Free diffusible fragments are shown in dark shades; membrane bound components in light shades.

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