Review
Regulation of complement activation by C-reactive protein

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Abstract

C-reactive protein (CRP) is an acute-phase serum protein and a mediator of innate immunity. CRP binds to microbial polysaccharides and to ligands exposed on damaged cells. Binding of CRP to these substrates activates the classical complement pathway leading to their uptake by phagocytic cells. Complement activation by CRP is restricted to C1, C4, C2 and C3 with little consumption of C5-9. Surface bound CRP reduces deposition of and generation of C5b-9 by the alternative pathway and deposition of C3b and lysis by the lectin pathway. These activities of CRP are the result of recruitment of factor H resulting in regulation of C3b on bacteria or erythrocytes. Evidence is presented for direct binding of H to CRP. H binding to CRP or C3b immobilized on microtiter wells was demonstrated by ELISA. Attachment of CRP to a surface was required for H binding. H binding to CRP was not inhibited by EDTA or phosphocholine, which inhibit ligand binding, but was inhibited by a 13 amino acid CRP peptide. The peptide sequence was identical to the region of CRP that showed the best alignment to H binding peptides from Streptococcus pyogenes (M6) and Neisseria gonorrhoeae (Por1A). The results suggest that CRP bound to a surface provides secondary binding sites for H resulting in greater regulation of alternative pathway amplification and C5 convertases. Complement activation by CRP may help limit the inflammatory response by providing opsonization with minimal generation of C5a and C5b-9.

Introduction

C-reactive protein (CRP) is an acute phase serum protein with roles in host defense and inflammation (reviewed by Steel and Whitehead, 1994; Gewurz et al., 1995; Szalai et al., 1997). During the acute phase response, the serum concentration of CRP increases rapidly from less than one to several hundred micrograms per milliliter due to increased synthesis by hepatocytes in response to cytokines. Experimental evidence supports two major functions for CRP: one in innate immunity against infection (Mold et al., 1981b; Szalai et al., 1995; Weiser et al., 1998) and the second in removal of membrane and nuclear material from necrotic cells (reviewed by Du Clos, 1996). CRP is a member of the pentraxin family of proteins, which share cyclic pentameric structure, sequence homology, and calcium-dependent ligand binding. On one face of CRP are five calcium-dependent binding sites through which it recognizes phosphocholine (PC) on pneumococcal C-polysaccharide (Volanakis and Kaplan, 1971) and other bacterial products. The same sites react with components of damaged cells including phosphatidylcholine and sphingomyelin on damaged cell membranes (Volanakis and Wirtz, 1979; Li et al., 1994), and with nuclear antigens, notably histones H1, H2A, H2B, and the U1 70K and Sm D proteins of small nuclear ribonucleoprotein complexes (Du Clos, 1989; Du Clos et al., 1991). CRP activates the classical complement pathway and reacts with Fcγ receptors (Crowell et al., 1991; Marnell et al., 1995) and possibly other receptors (Kilpatrick and Volanakis, 1985; Tebo and Mortensen, 1990) on phagocytic cells. Binding sites on CRP for C1q (Agrawal and Volanakis, 1994) and FcγRI (Marnell et al., 1995) have been identified by site-directed mutagenesis.

Section snippets

Complement activation by CRP

Activation of the classical complement pathway by CRP was first described in 1974 by Kaplan and Volanakis using C-polysaccharide and phospholipid ligands (Kaplan and Volanakis, 1974), and by Siegel et al. using CRP-protamine complexes (Siegel et al., 1974). These and subsequent studies established that CRP, complexed with polyvalent ligand or chemically cross-linked, binds to C1q and activates the classical complement pathway. Despite the overall similarity in classical pathway activation by

Inhibition of alternative pathway activation by CRP

Studies of the effect of CRP on alternative pathway activation helped clarify the limited classical pathway activation by CRP. These experiments (Mold and Gewurz, 1981a; Mold et al., 1984) used either Streptococcus pneumoniae or positively charged liposomes as particles that activate the alternative pathway and also bind CRP. Complement activation was restricted to the alternative pathway by using MgCl2–EGTA to chelate calcium or using C2-deficient serum. Initial experiments established a

Inhibition of lectin pathway lysis by CRP

Complement activation initiated by another acute phase protein, mannan-binding lectin (MBL), has recently been defined as a third complement pathway (reviewed by Reid et al., 1998). The MBL pathway is activated when MBL with associated serine proteases, MASP-1 and -2, binds to ligands, including mannans and bacterial lipopolysaccharides. MBL has a structure similar to C1q and its binding activates MASP-1 and -2 resulting in cleavage of C4 and C2 and formation of a C3 convertase identical to

CRP regulation of complement is mediated by recruitment of factor H

Further experiments using both the alternative pathway and the MBL pathway indicate that the inhibitory effects of CRP are mediated by factor H. H binding to C3b on bacteria, and erythrocytes was increased approximately two-fold in the presence of CRP (Table 2) (Mold et al., 1984; Suankratay et al., 1998a). Increased H binding required both CRP and C3b to be present. Factor H binds to C3b to promote its degradation by factor I, and binds to the alternative pathway C3 convertase and both C5

Evidence for direct binding of factor H to CRP

For S. pneumoniae, liposomes or appropriately sensitized erythrocytes, CRP increases the binding of factor H in the presence of C3b. This is reminiscent of the effects of surface bound sialic acid and other polyanions that increase the affinity of H for bound C3b (Carreno et al., 1989; Meri and Pangburn, 1990). The enhancing effect of polyanions on H binding to C3b occurs through specific polyanion-binding sites on factor H (Pangburn et al., 1991; Blackmore et al., 1996; Ram et al., 1998b).

To

Comparison of CRP and bacterial factor H binding proteins

Several binding sites for factor H have been identified on C3 (Lambris et al., 1988; Lambris et al., 1996). Direct competition experiments in the ELISA, as well as studies using bacteria and sensitized erythrocytes indicate that CRP and C3b do not compete for factor H binding. In addition, competition between CRP and C3b for H binding would not result in the observed CRP enhancement of H activity. Thus, the binding site on CRP for factor H is likely to be distinct from those on C3.

Several

Significance of CRP recruitment of factor H

Acute phase proteins are produced by the liver in response to inflammatory cytokines, notably interleukin (IL)-6, IL-1, and tumor necrosis factor-α (Steel and Whitehead, 1994). Several of the acute phase proteins including C3, factor B, properdin and MBL are important in host defense against infection. Other acute phase proteins such as α-1 anti-trypsin and ceruloplasmin, are inhibitors of neutrophil proteases and reactive oxygen intermediates, and help limit the inflammatory response (Tilg et

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