Genetics and Deficiencies of the Soluble Regulatory Proteins of the Complement System

Abstract

Int Rev Immunol Downloaded from informahealthcare.com by McMaster University on 11/03/14 For personal use only. 66 R. B. SIM et ul.The activation and regulation of the complement system are presented in more detail in several reviews [2-41. Complement activation via the classical pathway ( Fig. 1) is initiated by the binding of the Cl complex to complement activators, such as immune complexes. This results in activation of the serine proteases Clr and Cls, within Cl. Activated Cls then cleaves and activates C4 and C2: the number of molecules of C4 and C2 cleaved is regulated by theaction of C1-inhibitor on Cls. When C4 is activated, the major fragment, C4b, has an exposed, activated thiolester, which reacts rapidly with any nearby electron-donating (nucleophilic) species. C4b may react with an amine or hydroxyl group on the surface of the complement activator, and thus becomes covalently bound, by an ester or amide linkage, to the activator. Most of the C4b generated, however, simply reacts with water, and diffuses away from the site of complement activation. C2 binds to C4b, and if the C2 is appropriately oriented towards Cls, Cls cleaves C2, forming a complex consisting of C4b and C2a, the major fragment of C2. Since in physiological conditions Cls is bound to the complement activator, within the C1 complex, only C4b molecules which bind to the activator, very close to the C1 complex, will take part in formation of C4b2a. The C4b2a complex is a protease ("C3 convertase"), with its active site in C2a, which cleaves and activates C3. The activity of C4b2a is regulated by 3 mechanisms: firstly, the C4b2a complex is unstable, and dissociates irreversibly with a half-life of about 5 minutes. Secondly, C4bp binds to C4b in competition with C2, and can therefore inhibit formation of the C4b-C2 complex, and also accelerates the dissociation of C2a from C4b. The latter activity is named the "decay-acceleration'' activity of C4bp (Fig. 2): the membrane-bound regulatory proteins DAF and CR1 also possess this activity. Thirdly, C4b which is bound to C4bp is a substrate for factor I, which cleaves C4b to form two products, C4c (140kD) and C4d (45kD). This activity of C4bp is termed "factor I-cofactor" activity ( Fig. 2): CR1 and MCP also have this activity. C4c and C4d are not known to have any biological activity. Thus C4b, which mediates immune adherence and functions as part of the C3 and C5 convertase enzymes, is broken down to inactive products by the factor I + cofactor system. Once C3 is activated by C4b2a, the major fragment, C3b, behaves like C4b: via a thiolester, it may bind covalently to the surface of the complement activator, or it may react with water and diffuse away. One molecule of C3b binds directly to the C4b in C4b2a, forming C4b2a3b ("C5 convertase"): the C4b and C3b subunits of this complex bind C5, orienting it for cleavage by C2a [5-71. Cleavage of C5 to C5b initiates the assembly of the C5b, C6, C7, C8, C9 complex (C5b-9, also called MAC (membrane attack complex) or TCC (terminal complement complex...

Clinical Significance of Complement Deficiencies

“…42 Factor H deficiency classically presents with MPGN or other renal disease. 35,[95][96][97] It has also been associated with most inherited cases of HUS. 95,[98][99][100][101] Factor H deficiency has also been associated with increased susceptibility to infection in general.…”

The role of Fcγreceptor polymorphisms and C3 in the immune defence againstNeisseria meningitidisin complement-deficient individuals

“…Properdin acting as a stabilizer of the alternative pathway C3 convertase has been postulated to increase C3b deposition onto bacterial surfaces [14,15]. Stabilization of the C3 convertase may be essential for meningococci since sialic acid containing capsules and lipopolysaccharides (LPS) of the meningococcal surface are strong down‐regulators of the alternative pathway activity [16]…”

“…Properdin acting as a stabilizer of the alternative pathway C3 convertase has been postulated to increase C3b deposition onto bacterial surfaces [14,15]. Stabilization of the C3 convertase may be essential for meningococci since sialic acid containing capsules and lipopolysaccharides (LPS) of the meningococcal surface are strong downregulators of the alternative pathway activity [16] The present study aims to assess whether PMN FcgR allotypes are associated with the risk of contracting meningococcal disease in either properdin-deficient or LCCD persons. In addition, we determined the role of meningococcal C3 deposition in PMN phagocytosis.…”

Two Human Gene Families Display Preferences for Different Nucleotides and Have Distinct Codon Usage Patterns

“…All members of the factor H gene family are located in a gene cluster on human chromosome 1 termed regulators of complement activation (RCA) [33]. The genes encoding factor H [33], FHL-1 [34], and FHR-1 to -4 have been mapped to this region in human chromosome 1 [35,36] and the genomic structure of the human FHR-2 gene [35] and a partial structure of the human factor H gene has been described [34]. Thus, the proposed chromosomal linkage of all members of the factor H gene family to a region which includes additional SCR-containing genes is a strong indication for duplication events which resulted in the evolution of this gene cluster.…”