Complement and Disease: A Review

Over the past decade the role of the complement (C) system, as an effector mechanism modulating the consequences of the interaction between antibodies and antigens, has been extended to several other functions. This follows the observation that many components of C have other biological properties besides inducing cell death and lysis. These biological activities include immune-adherence, viral neutralization, chemotaxis, non-cytotoxic lysosomal enzyme release, and the induction of histamine release from basophils and mast cells. Other properties which have been attributed to the C system are related to the metabolism of bone, the production of antibodies and cell proliferation (Miiller-Eberhard 1975, Gotze & Muller-Eberhard 1976, Lachmann 1979, Minta & Ward 1979, Pepys 1976). The discovery that the genes controlling the synthesis of at least three components of C, C4, C2 and Factor B (C3 convertase), are closely linked to the major histocompatibility locus (Rittner 1976), has also raised the possibility of an association among unique variants of these components of C and some diseases, such as insulin-dependent diabetes mellitus, multiple sclerosis, and idiopathic membranous nephropathies (Rittner & Bertrams 1981). Finally, several components ofC have been shown to behave as acute phase proteins, since their serum levels increase markedly during infection; it has been shown that the estimation of these proteins may be useful diagnostic and prognostic indices of disease activities (Adinolfi et al. 1979). On the other hand, deficiencies of various components of C have, for some time now, been known to be associated with recurrent infections and with unique syndromes such as hereditary angio-oedema (Donaldson & Evans 1963). Hence it is necessary to estimate the levels of the components of C and to detect their phenotype in patients, particularly in children with recurrent infections, and with diseases which have been found to be associated with certain HLA haplotypes. Operationally, the C system may be subdivided into two pathways, each comprising several functional units. Almost all components of C are present in serum in non-active form; activation occurs through the reaction with antibody-antigen complexes, fungal or bacterial substances and tryptic enzymes (Miiller-Eberhard 1975, Gotze & Miiller-Eberhard 1976, Lachmann 1979, Minta & Ward 1979). The 'classical' pathway is activated by IgG or IgM antibodies bound to specific antigens; it consists of a recognition unit (Cl q, Cl r and C I s), the 'amplification' unit (C4, C2 and C3) and the attack unit (C5, C6, C7, C8 and C9) (Figure 1). In the 'alternative' pathway, C3 is activated by the interaction of aggregated IgA, naturally occurring polysaccharides or lipopolysaccharides with properdin, Factor B and Factor D (Figure 1); the activation continues with the last components of C from C5 to C9. Once a component of C is rendered active by an enzymatic splitting of the intact molecule, the biologically active fragment must be rendered inactive in a short period of time in order to avoid a permanent state of chain reaction and consequently depletion of C leading to an immunodeficiency state. Inactivation is achieved either by a second breakage of the fragment or by the action of regulatory components of C. Three of these control proteins are: Cl inhibitor (C1-INH), C3b inactivator (C3b-INA) and , I1H. The importance of these regulatory proteins is stressed by the dramatic effects that their deficiencies produce, as for example in