There are many links between the complement system and the autoimmune disease systemic lupus erythematosus (SLE). Soon after the identification of antinuclear antibodies, the major serological hallmark of the disease, it was discovered that complement proteins are deposited in the tissues of patients. An association was found between the degree of complement activation in blood samples from patients and the level of disease activity. Complement proteins were discovered to be co-located with antibodies in inflamed tissues, such as the glomeruli of patients with glomerulonephritis. These data suggested that the formation or deposition of immune complexes in tissues leading to complement and leukocyte activation could cause the pathogenesis of the tissue injury of SLE. However, it was also discovered that the presence of antibodies and complement in tissues was not sufficient to cause inflammatory injury. Clinically normal tissues from patients with SLE (e.g., the skin) also contained deposited antibodies and complement proteins. Indeed, the presence of these proteins at the dermoepidermal junction in nonlesional skin was found to be a moderately specific diagnostic test for SLE, named the lupus band test. As the spectrum of autoantibodies characterized in SLE increased, it was discovered that about one third of patients with the disease have autoantibodies to complement proteins, especially to C1q. A reduction was also discovered in the expression of a complement receptor on erythrocytes, CR1, which plays a role in binding immune complexes in the circulation. Each of these links between complement and SLE, which we discuss in detail below, may be explained on the basis that the autoantibodies of SLE, on binding autoantigen, activate complement. Downstream events following complement activation could explain the development of autoantibodies to complement and to erythrocyte CR1 consumption. However, the links between complement and SLE are much more complicated and curious. It was found that inherited complement deficiency is strongly associated with the development of SLE. Indeed, the very rare inherited homozygous deficiency of the first protein of the classical

Systemic lupus erythematosus, complement deficiency, and apoptosis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which multiple genes appear to play important roles in pathogenesis. Hereditary deficiencies, both complete and partial, of several components of the complement system clearly predispose to lupus. HLA class II alleles appear to mediate specific autoantibodies, many of which are pathogenic. Modern molecular techniques are now providing insight into the specific major histocompatibility complex class II polymorphisms that are associated with different autoantibodies in SLE. Other genetic systems also may be important.

Genetics of systemic lupus erythematosus

The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 × 10−8, permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 × 10−8, permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies.

/pdf/identification-of-two-independent-risk-factors-for-lupus-3n0tqlqmx5.pdf

Identification of two independent risk factors for lupus within the MHC in United Kingdom families

Objective. To determine whether an allelic form of mannose-binding protein (MBP) incapable of activating complement is associated with susceptibility to systemic lupus erythematosus (SLE).



Methods. MBP allele frequencies were determined by amplification refractory mutation system–polymerase chain reaction in 102 white SLE patients and 136 controls.



Results. The MBP allele that is unable to activate complement was present in 42 SLE patients (41%) and in 41 controls (30%) (P = 0.08, odds ratio [OR] = 1.6, 95% confidence interval [95% CI] 1.0–2.8). The gene frequency of this allele was 0.25 in SLE patients and 0.19 in controls (P = 0.08, OR = 1.5, 95% CI 1.0–2.3).



Conclusion. Our results suggest that this allele of the MBP gene represents a minor risk factor for SLE.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780380117

Mannose-binding protein gene polymorphism in systemic lupus erythematosus.

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

Links between complement abnormalities and systemic lupus erythematosus

Susceptibility to systemic lupus erythematosus (SLE) is known to be governed by genes in the HLA region of the 6th chromosome. From previous studies it has not been possible to distinguish between the effects of null genes for the complement component C4 and HLA-DR3, because of the marked linkage disequilibrium between DR3 and a null allele of C4A (C4A QO) in caucasoid populations. We report here an immunogenetic study of 44 cases of SLE, selected because they were DR3 negative. Eighteen of the 30 Caucasoid cases (60%) had extended HLA haplotypes with a C4 null allele, compared with 22 of 60 (37%) of a control panel of 60 DR3 negative normal Caucasoid subjects. This difference is significant (chi 2 = 4.41; 0.05 greater than P greater than 0.01). Of 14 non-caucasoid patients analysed, 10 had a C4 null allele. It is concluded that the null alleles of the C4 A and B genes are themselves directly responsible for conferring susceptibility to SLE.

Family study of the major histocompatibility complex in HLA DR3 negative patients with systemic lupus erythematosus.

The well known HLA/disease associations have often in the past been attributed to the effects of Class 1 or 11 MHC products on an individual’s immune responsiveness. However there are reasons for thinking that more than one mechanism may be responsible for these associations. In this paper, we will outline the evidence which leads us to conclude that the Class 111 genes, encoding polymorphisms for the complement system proteins of C4A, C4B, and C2 govern susceptibility to systemic lupus erythematosus (SLE).

https://link.springer.com/content/pdf/10.1007%2F978-1-4612-5014-2_23.pdf

Class III HLA Genes and Systemic Lupus Erythematosus

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Family study of the major histocompatibility complex in HLA DR3 negative patients with systemic lupus erythematosus.

Class III HLA Genes and Systemic Lupus Erythematosus