Links between complement abnormalities and systemic lupus erythematosus

TL;DR: The role of complement in the of the 24 patients tested was low, positive in only five immunity, and it was suggested that the early part of the classical pathway plays followed in turn by homozygous C4 and C2 deficiency a key protective role against the disease.

Abstract: Complement is an important effector pathway of innate stranded DNA antibodies was low, positive in only five immunity. In this review the role of complement in the of the 24 patients tested. pathogenesis of systemic lupus erythematosus (SLE) is Hereditary deficiency of C1s and C1r is rarer than described. There are important associations between that of C1q deficiency and, in the majority of cases, both inherited and acquired complement component deficiencies of both components coincide [3–5]. In such deficiencies and SLE. These have focused attention on cases C1r levels are usually absent with levels of C1s identifying the relevant physiological role of the classical below 50% of normal. As in homozygous C1q deficiency, pathway of complement activation that appears to proSLE occurs in the majority of these individuals (seven tect against the development of SLE. There is also of the 11 reported cases). Selective C1s deficiency, i.e. unequivocal evidence that major histocompatibility with normal C1r levels, has been reported in association complex (MHC) genes play an important role in deterwith SLE [6 ]. In homozygous C4 deficiency, the prevalmining both disease susceptibility and phenotype in SLE ence of SLE is approximately 75% and the lupus illness and its subsets. Accordingly, the role of complement is of moderate severity [7]. genes located in the class III region (C4A, C4B and C2) Homozygous C2 deficiency is the commonest inherited in the genetic susceptibility to SLE is reviewed. The classical pathway complement deficiency with an utility of the measurement of complement levels in approximate prevalence in Western European Caucasoid monitoring disease activity and the clinical significance populations of 1:20 000. In contrast to homozygous C1q of hypocomplementaemia are discussed. Homozygous deficiency, the majority of affected individuals are probC1q deficiency is the strongest genetic susceptibility ably healthy. SLE may occur in up to 33%, although factor for SLE that has been identified in humans, but, this figure may be an overestimate due to ascertainment paradoxically, SLE causes C1q consumption and is artefact, and the severity of the illness is comparable to commonly associated with anti-C1q antibodies. The role that seen in SLE patients without homozygous compleof complement in the pathogenesis of lupus, with parment deficiency. In contrast to the classical pathway ticular emphasis on the role of C1q, is discussed in order components, homozygous C3 deficiency predisposes to to explain this paradox. recurrent pyogenic infections and membranoproliferative glomerulonephritis (MPGN), but SLE is rare [8]. What do the clinical observations in individuals with Homozygous classical pathway component homozygous classical pathway component deficiency deficiency and SLE teach us about the pathogenesis of SLE? They suggest that there is a physiological function of the classical Homozygous hereditary deficiency of each of the claspathway of complement activation that protects against sical pathway components (C1q, C1r, C1s, C4, and C2) the development of SLE. Furthermore, the hierarchy of is associated with an increased susceptibility to SLE [1]. susceptibility and the severity of lupus, according to the Both the severity of disease and the strength of this missing classical pathway protein (C1q>C4>>C2), association is greatest for homozygous C1q deficiency suggest that the early part of the classical pathway plays followed in turn by homozygous C4 and C2 deficiency. a key protective role against the disease. Since one of Thirty-eight of the 41 patients with homozygous C1q the major roles of the classical pathway is that of host deficiency reported to date have developed a clinical defence against infectious disease, one hypothesis is that syndrome closely similar to SLE (recently reviewed in classical pathway component deficiency predisposes to [2]). In the affected patients rash occurred in 36, glomSLE because of impaired resistance to an infectious erulonephritis in 16, and cerebral disease in seven. trigger. Antinuclear antibodies (ANA) were reported in 24 and There is little evidence in favour of this hypothesis. antibodies to extractable nuclear antigens in 15 of these Classical pathway complement deficiencies are not assopatients, but notably, the incidence of anti-doubleciated with an overt increase in susceptibility to viral or fungal infections. Although complement deficiency is Submitted 9 July 1999; revised version accepted 15 July 1999. Correspondence to: M. J. Walport. strongly associated with the development of pyogenic