Complement and disease: a review - Europe PMC

Journal of the Royal Society of Medicine Volume 75 February 1982

121

Complement and disease: a review M Adinolfi MD PhD J Zenthon BSC Paediatric Research Unit, Prince Philip Research Laboratories Guy's Hospital Medical School, London SE] 9RT

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 of C 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 (C l q, C l 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 (C 1-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 'Accepted 17 November 1981 0 141-0768/82/020121-03/$O 1.00/0

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CLASSICAL ACTIVATION

ALTERNATIVE ACTIVATION

Ag-Ab+Cl (Clq,r,s)

(C3) + Factor B +

Mg2+

4

J, Clr

C3bB + Factor D

C4 + Cls

C4,C2,Mg2I

C-Tb

C4b2b

C

bB-b

e~~nvrtas

v

C3 C4b2b3bb

'

C3b BbP

nvert C5

1 4

+ C6,C7 + C8,C9

C5-9

Figure 1. Classical and alternative pathways of complement (C). The classical activation starts with the interaction between antigen (Ag) and antibody (Ab) complexes and Cl, and it involves the cleavage of C4 and C2. The alternative pathway is activated by aggregated IgA polysaccharides, endotoxins and involves the interaction of Factor B, Factor D and properdin. The activation of the early components of C of both pathways results in the cleavage of C3, the formation of C5 convertase and the reaction of the late components of C

the case of a deficiency of C1-INH associated with episodes of hereditary angio-oedema (Donaldson & Evans 1963). Deficiencies of C3b-INA are also responsible for a continuous activation of C3, reduction of the levels of various components of C and hence repeated severe infections. In man, deficiencies have been observed for all components of C involved in the activation of the 'classical' pathway (Lachmann 1979, Minta & Ward 1979). Low levels or absence of C2 are substantially more common than those of the other components. So far, deficiencies of the proteins of the 'alternative' pathway have not been described. It is of interest that while the deficiency of C1-INH is transmitted as an autosomal dominant trait and the affected individuals are therefore heterozygotes, all the other C deficiencies are transmitted by autosomal recessive or codominant genes. In the latter group of hereditary disorders, bacterial infections and immune complex diseases are the most common clinical complications. Severe Neisseria infections have been observed in patients with C3b-INA, C6 and C8 deficiencies. The immune complex diseases most often found to be associated with deficiencies of the early components of C are systemic lupus erythematosus, Henoch-Shonlein purpura, polymyositis and glomerulonephritis (Lachmann 1979, Minta & Ward 1979). The severity of the syndrome associated with the deficiency of a component of C varies greatly from patient to patient. Pronounced immune deficiencies to bacterial infections are seen, for example, in most patients with low levels of C3; however, occasionally this deficiency is associated with minor illness. In many cases, low serum levels of C2, C6 and C7 have been observed in individuals in apparent good health. High serum levels of some components of C are, on the other hand, useful indices of infections and disease. In fact some components, such as Factor B and C9, behave as sensitive acute phase proteins and their concentrations in blood increase dramatically in association with increased levels of C-reactive protein or alantitrypsin (Adinolfi et al. 1979). The estimation of C9 and Factor B has been found quite useful in young children, and the role of these proteins has been extensively investigated in children with Crohn's disease (Campbell et al. 1982) and in patients with recurrent oral ulceration and Beh9;et's syndrome (Adinolfi et al. 1979).


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The role that acute phase proteins play in disease is not yet clear, but it is feasible that some of these might dampen the immune response of lymphocytes once they are activated by specific antigens. Future work on the functions of this heterogeneous group of plasma proteins, mostly produced in liver, is certainly going to be rewarding. Finally, there is the question of the significance of the polymorphism of C2, C4 and Factor B in disease. Since the discovery by Alper & Propp (1968) of genetic variants of C3, polymorphism of many other components of C has been observed, including C4, C5, Factor B and Factor D (Hobart & Lachmann 1976). When linkage studies were performed, interestingly only those components with C3 convertase properties, C4, C2 and Factor B, were found to be linked to the HLA region on chromosome 6 (Hobart & Lachmann 1976). These findings are particularly interesting in view of the association of some diseases with HLA (Amos & Kostyu 1980). Although the exact position of the C4, C2 and Factor B loci is still unknown, the present evidence suggests that they are located between HLA-B and HLAD/DR. Work on the association between C4, C2 and Factor B haplotypes and disease is in progress (Rittner & Bertrams 1981) and some preliminary data are available. The results indeed suggest that diseases like insulin-dependent diabetes mellitus, multiple sclerosis and idiopathic membranous nephropathy, which are primarily HLA-D/DR-associated, are also related to rare C4, C2 and Factor B alleles and/or with disfunctional genes. Accordingly, Rittner & Bertrams (1981) have advanced the hypothesis that mutant C genes may lead to impaired effector mechanisms in virus neutralization or lysis of virus-infected cells and be responsible, at least in part, for the pathogenesis of these diseases. Components of C are produced at an early stage of fetal life in man and other mammals and with the exception of C9, levels between 50 and 70% of those present in adults are detected in normal newborns (Adinolfi 1977). Adult values are reached within 6 to 12 months after birth. This, and the availability of antisera against various components of C, make it feasible to estimate them in most laboratories. The detection of their polymorphism and association with certain diseases still pertains to the research field, but it is likely that in only a few years' time the value of these tests will be fully appreciated. References Adinolfi M (1977) American Journal of Diseases of Children 131, 1015-1023 Adinolfi M, Beck S E & Lehner T (1979) In: Behqet's Syndrome: Clinical and Immunological Features. Ed. T Lehner and C G Barnes. Academic Press, New York & London; pp 107-126 Alper C A & Propp R P (1968) Journal of Clinical Investigation 47, 2181-2191 Amos D B & Kostyu D D (1980) In: Advances in Human Genetics. Ed. H. Harris and K Hirschhorn. Plenum Press, New York; pp 137-208 Campbell C A, Walker-Smith J A, Hindocha P & Adinolfi M (1982) Acta Paediatrica (in press) Donaldson V H & Evans R R (1963) American Journal of Medicine 35, 37-44 Gotze 0 & Mililer-Eberhard H J (1976) Advances in Immunology 24, 1-35 Hobart M J & Lachmann P J (1976) Transplantation Reviews 32, 26-42 Lachmann P J (1979) In: The Antigens, vol 5. Ed. M Sela. Academic Press, New York & London; pp 283-353 Minta J 0 & Ward P A (1979) In: Inflammation, Immunity and Hypersensitivity: Cellular and Molecular Mechanisms. 2nd edn. Ed. H Z Movat. Harper & Row, New York; pp 445-525 Miller- Eberhard J H (1975) In: The Plasma Proteins, vol 1. 2nd edn. Ed. F W Putnam. Academic Press, New York; p 394 Pepys M B (1976) Transplantation Reviews 32, 93-120 Rittner C (1976) Human Genetics 35, 1-20 Rittner C & Bertrams J (1981) Human Genetics 56, 235-247