Links between complement abnormalities and systemic lupus erythematosus

Abstract

Systemic Lupus Erythematosus/Series Editors: D. Isenberg and C. Gordon Complement is an important effector pathway of innate immunity. In this review the role of complement in the pathogenesis of systemic lupus erythematosus (SLE) is described. There are important associations between both inherited and acquired complement component deficiencies and SLE. These have focused attention on identifying the relevant physiological role of the classical pathway of complement activation that appears to protect against the development of SLE. There is also unequivocal evidence that major histocompatibility complex (MHC) genes play an important role in determining both disease susceptibility and phenotype in SLE and its subsets. Accordingly, the role of complement genes located in the class III region (C4A, C4B and C2) in the genetic susceptibility to SLE is reviewed. The utility of the measurement of complement levels in monitoring disease activity and the clinical significance of hypocomplementaemia are discussed. Homozygous C1q deficiency is the strongest genetic susceptibility factor for SLE that has been identified in humans, but, paradoxically, SLE causes C1q consumption and is commonly associated with anti‐C1q antibodies. The role of complement in the pathogenesis of lupus, with particular emphasis on the role of C1q, is discussed in order to explain this paradox. Homozygous hereditary deficiency of each of the classical pathway components (C1q, C1r, C1s, C4, and C2) is associated with an increased susceptibility to SLE [1]. Both the severity of disease and the strength of this association is greatest for homozygous C1q deficiency followed in turn by homozygous C4 and C2 deficiency. Thirty‐eight of the 41 patients with homozygous C1q deficiency reported to date have developed a clinical syndrome closely similar to SLE (recently reviewed in [2]). In the affected patients rash occurred in 36, glomerulonephritis in 16, and cerebral disease in seven. Antinuclear antibodies (ANA) were reported in 24 and antibodies to extractable nuclear antigens in 15 of these patients, but notably, the incidence of anti‐double‐stranded DNA antibodies was low, positive in only five of the 24 patients tested. Hereditary deficiency of C1s and C1r is rarer than that of C1q deficiency and, in the majority of cases, deficiencies of both components coincide [3–5]. In such cases C1r levels are usually absent with levels of C1s below 50% of normal. As in homozygous C1q deficiency, SLE occurs in the majority of these individuals (seven of the 11 reported cases). Selective C1s deficiency, i.e. with normal C1r levels, has been reported in association with SLE [6]. In homozygous C4 deficiency, the prevalence of SLE is approximately 75% and the lupus illness is of moderate severity [7]. Homozygous C2 deficiency is the commonest inherited classical pathway complement deficiency with an approximate prevalence in Western European Caucasoid populations of 1:20 000. In contrast to homozygous C1q deficiency, the majority of affected individuals are probably healthy. SLE may occur in up to 33%, although this figure may be an overestimate due to ascertainment artefact, and the severity of the illness is comparable to that seen in SLE patients without homozygous complement deficiency. In contrast to the classical pathway components, homozygous C3 deficiency predisposes to recurrent pyogenic infections and membranoproliferative glomerulonephritis (MPGN), but SLE is rare [8]. What do the clinical observations in individuals with homozygous classical pathway component deficiency teach us about the pathogenesis of SLE? They suggest that there is a physiological function of the classical pathway of complement activation that protects against the development of SLE. Furthermore, the hierarchy of susceptibility and the severity of lupus, according to the missing classical pathway protein (C1q > C4 >> C2), suggest that the early part of the classical pathway plays a key protective role against the disease. Since one of the major roles of the classical pathway is that of host defence against infectious disease, one hypothesis is that classical pathway component deficiency predisposes to SLE because of impaired resistance to an infectious trigger. There is little evidence in favour of this hypothesis. Classical pathway complement deficiencies are not associated with an overt increase in susceptibility to viral or fungal infections. Although complement deficiency is strongly associated with the development of pyogenic bacterial infections, such infectious agents are not strong candidates for the induction of SLE. Other immunodeficiencies associated with increased susceptibility to pyogenic bacterial infections are not associated strongly with the development of SLE. Complement plays a key role in the clearance and processing of immune complexes and cellular debris and the evidence will be summarized that it is the role of the classical pathway that protects against