Elsevier

Molecular Immunology

Volume 40, Issue 18, April 2004, Pages 1333-1346
Molecular Immunology

Complement inhibitor C4b-binding protein—friend or foe in the innate immune system?

https://doi.org/10.1016/j.molimm.2003.12.002Get rights and content

Abstract

The complement system constitutes an important component of the defence against foreign organisms, functioning both in innate and adaptive immune systems. It is potentially harmful also to the own organism and is therefore tightly regulated by a number of membrane-bound and soluble factors. C4b-binding protein (C4BP) is a potent circulating soluble inhibitor of the classical and lectin pathways of complement. In recent years, the relationships between the structure of C4BP and its functions have been elucidated using a combination of computer-based molecular analysis and recombinant DNA technologies. Moreover, two novel functions have recently been ascribed to C4BP. One is the ability of C4BP to localize complement regulatory activity to the surface of apoptotic cells via its interaction with the membrane-binding vitamin K-dependent protein S. The other is the ability of C4BP to act as a survival factor for B cells due to an interaction with CD40. The complement regulatory activity of C4BP is not only beneficial because it is also explored by pathogens such as Neisseria gonorrhoeae, Bordetella pertussis, Streptococcus pyogenes, Escherichia coli K1, and Candida albicans, that bind C4BP to their surfaces. This contributes to the serum resistance and the pathogenicity of these bacteria. In this review, the structural requirements and functional importance of the interactions between C4BP and its various ligands are discussed.

Section snippets

Regulators of the complement system

The innate immune system is able to provide protection against pathogens without previous exposure and immunization. The complement system is a key component of the innate immune system. It consists of more than 30 proteins and not only guards against invading microorganisms with the help of its opsonic, inflammatory and lytic activities, but it also enhances the adaptive immunity (Fearon, 1998, Fearon and Locksley, 1996, Hoffmann et al., 1999) and participates in the process of clearance of

C4BP—from gene to protein

C4BP is a large glycoprotein (570 kDa) with an estimated plasma concentration of 200 mg/l (Dahlbäck, 1983). C4BP exists in several isoforms having different combinations of α- and β-chains. The major isoform, which constitutes about 75–80% of C4BP in plasma, is composed of seven identical α-chains and one β-chain, the chains being linked together in their C-terminal parts (Fig. 2) (Hillarp and Dahlback, 1990, Scharfstein et al., 1978). Other less abundant forms are composed of six α-chains and

C4BP in other species

C4BP was analyzed at the cDNA level in several species. Perhaps the most relevant, due to existence of knock-out technology, was analysis of mouse C4BP. Mouse C4BP α-chain is relatively similar to its human counterpart but lacks two CCP domains (five and six) and the two cysteine residues in the C-terminal region (Fig. 3) (Kristensen et al., 1987). However, the protein is able to form non-covalent polymers (Kaidoh et al., 1981), similar to what we have observed for human α-chains in which the

Inhibition of complement by C4BP—relationships between structure and function

C4BP is best known as inhibitor of the classical, antibody-dependent complement pathway where it controls C4b-mediated reactions in at least three ways. First, C4BP acts as a cofactor to the serine proteinase factor I, in the proteolytic inactivation of C4b, which prevents the formation and reconstitution of the classical C3-convertase (C4bC2a) (Scharfstein et al., 1978). The mechanism by which C4BP operates as a cofactor to FI is not fully understood but it appears that C4b changes its

Localization of the protein S-binding site on the β-chain of C4BP

The binding site for PS on C4BP is fully contained in the β-chain (Hillarp and Dahlbäck, 1988). Using chimeric molecules composed of a variable number of β-chain CCP domains expressed together with CCP domains from the α-chains it was shown that the binding site for PS is located on the β-chain CCP1 (Fig. 5) (Hardig and Dahlback, 1996, Hardig et al., 1993). Later on, some contribution from CCP2 was also demonstrated (van de Poel et al., 1999). To elucidate the structural background for the

Interaction of the C4BP–PS complex with apoptotic cells

In plasma, all β-chain containing C4BP circulates in a high affinity complex with PS and the molar excess of PS (about 30% of total PS) constitutes the free form (Dahlback, 1983, Dahlback and Stenflo, 1981). PS is a 75 kDa glycoprotein synthesized mainly by hepatocytes, but also endothelial cells and testicular Leydig cells (Fair and Marlar, 1986, Fair et al., 1986, Malm et al., 1994). PS is a multidomain protein beginning at the N-terminus with a Gla domain (contains γ-carboxyglutamic acid),

Activation of B cells by C4BP–CD40 interaction

CD40 is a cell surface receptor that belongs to the tumor necrosis factor (TNF) receptor family and was first identified and functionally characterized on B cells but it is also present on monocytes, dendritic cells, endothelial and epithelial cells. The classical activator of CD40 is the CD40 ligand (CD40L), which is present on activated CD4+ T-cells, mast cells, basophils, eosinophils and in some conditions of B cells, NK cells, monocytes and dendritic cells. CD40–CD40L has a pivotal role in

Binding of C4BP to pathogenic bacteria renders them resistant to complement attack

Infectious agents such as viruses, bacteria and parasites are constantly developing strategies to avoid clearance and destruction by the complement system. When the strategy to avoid recognition by the complement fails, a number of pathogens employ complement inhibitors for protection. Some pathogens are able to hijack host’s complement regulators such as C4BP and FH and subsequently down regulate complement activation. Others produce their own regulators with remarkable similarity to the

Concluding remarks

C4BP is a fascinating protein with a number of important functions some of which are probably still waiting to be discovered. C4BP is important for inhibition of unwanted or excessive complement activation, controlled removal of apoptotic cells without evoking inflammatory reactions as well as survival of B cells. However, a number of human pathogens have developed the ability to capture C4BP to their surface and protect themselves from adverse effects of complement system.

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