Complement and systemic lupus erythematosus

PURPOSE OF REVIEW: It is well recognized that the complement system plays multiple roles in systemic lupus erythematosus. Activation of the classical pathway by immune complexes leads to the generation of inflammatory mediators, thus promoting tissue injury. Complement activation also plays an important role in the maintenance of tolerance to self-antigens. This review discusses recent insights in the role of complement in the pathogenesis of systemic lupus erythematosus. RECENT FINDINGS: The antiphospholipid syndrome is a major feature of systemic lupus erythematosus. New findings have clearly demonstrated that the prothrombotic effects seen in a mouse model of this syndrome depend on complement activation, whereas the protective effects of heparin are due to its anticomplementary effects rather than its anticoagulant action. Secondly, a potential mechanism explaining the association of anti-C1q autoantibodies with lupus glomerulonephritis has been elucidated in a mouse model system. SUMMARY: New findings have helped to reinforce the role of complement in the etiology and tissue damage of systemic lupus erythematosus. These findings point to more precise, mechanism-based therapies for autoimmune and inflammatory disease.     

Apoptosis and autoimmunity: Complement deficiency and systemic lupus erythematosus revisited

Apoptosis may have a dual role in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. First, this process may be integral in the clonal deletion of self-reactive lymphocytes and maintenance of peripheral tolerance. Second, apoptosis generates altered self-antigens with the potential for breaking self-tolerance. This review will discuss these two aspects of apoptosis and autoimmunity, and explore the potential role of the classical complement pathway in this context.     

Apoptosis and autoimmunity: Complement deficiency and systemic lupus erythematosus revisited

Apoptosis may have a dual role in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. First, this process may be integral in the clonal deletion of self-reactive lymphocytes and maintenance of peripheral tolerance. Second, apoptosis generates altered self-antigens with the potential for breaking self-tolerance. This review will discuss these two aspects of apoptosis and autoimmunity, and explore the potential role of the classical complement pathway in this context.     

Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus.

OBJECTIVE: To determine whether variant alleles in the coding portion of the mannose-binding lectin (MBL) gene are associated with increased susceptibility to systemic lupus erythematosus (SLE) and concomitant infections. METHODS: MBL alleles and serum concentrations were determined by polymerase chain reaction and enzyme-linked immunosorbent assay, respectively, in 91 Danish patients with SLE and in 250 controls. RESULTS: Homozygosity for MBL variant alleles was observed in 7.7% of the SLE patients compared with 2.8% of the controls (P = 0.06), while no difference was seen for heterozygosity (33.0% versus 34.4%). Homozygotes had an increased risk of acquiring serious infections compared with patients who were heterozygous or homozygous for the normal allele (odds ratio 8.6, 95% confidence interval 1.5-47.6, P = 0.01). The time interval from the diagnosis of SLE to the first infectious event was shorter (P = 0.017), and the annual number of infectious events was 4 times higher, among homozygotes (P = 0.00002). They were especially prone to acquire pneumonia (P = 0.00004). CONCLUSION; Homozygosity for MBL variant alleles may explain much of the increased risk of complicating infections seen in SLE patients. Additionally, it is a minor risk factor for acquiring SLE.     

Selective C4 deficiency, systemic lupus erythematosus, and Whipple''s disease.

A 45-year-old female with selective deficiency of C4 and systemic lupus erythematosus developed puzzling gastrointestinal and systemic symptoms in the last 6 months of her life. Extensive investigation of the gastrointestinal tract did not yield any diagnosis, and the patient died shortly afterwards. Autopsy revealed evidence of a typical Whipple's disease of the jejunum and lymph nodes. This association has not been previously described. The disease is reviewed with emphasis on its being an opportunistic infection in an immunosuppressed host with a complement deficiency and SLE.     

Complement activation in patients with systemic lupus erythematosus without nephritis.

OBJECTIVE: To study the association between disease activity and complement activation prospectively in patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Twenty-one SLE patients were examined monthly for 1 yr. Disease activity, autoantibodies, conventional complement tests and the following complement activation products were investigated: C1rs-C1inh complexes, C4bc, Bb, C3a, C3bc, C5a and the terminal SC5b-9 complement complex (TCC). RESULTS: Modest variation in disease activity was noted. None of the patients had nephritis. Flare was observed at 27 visits. Four patients had anti-C1q antibodies in conjunction with modestly low C1q concentrations. The complement parameters were rather constant during the observation period. Slightly to moderately decreased C4 (0.05-0.10 g/l) was found in 10 patients and severely decreased C4 (<0.05 g/l) in seven patients. Decreased C4 was not associated with increased complement activation. Complement activation products were either normal or slightly elevated. TCC was the only activation product correlating significantly with score for disease activity at flare. None of the variables tested predicted flares. CONCLUSION: Complement tests are of limited importance in routine examination of SLE without nephritis, although TCC is suggested to be one of the most sensitive markers for disease activity.     

Mannose-binding lectin and susceptibility to infection in Chinese patients with systemic lupus erythematosus

OBJECTIVE: To test the hypothesis that low serum mannose-binding lectin (MBL) levels, as a result of the single-nucleotide polymorphisms in the promoter region (-221 X/Y) and exon 1 (codon 54 A/B) of the MBL2 gene, predispose to infection in Chinese patients with systemic lupus erythematosus (SLE). METHODS: Two hundred forty-five patients with SLE were prospectively followed for the development of major infective episodes that required hospitalization and antibiotic treatment during 1992-2005. MBL genotypes were determined by polymerase chain reaction and serum MBL levels were measured by ELISA. RESULTS: In total, 254 major infections developed in 130 patients. Serum MBL levels were shown to correlate inversely with the number of bacterial infections (r = -0.13, p = 0.03). The distribution of MBL genotypes was similar in patients with and without major infection (p = 0.84). Patients with major infection also had more major lupus exacerbations that required daily prednisolone dose > or = 15 mg. Logistic regression showed that log MBL level (odds ratio 0.516, 95% confidence interval 0.305-0.873; p = 0.01) and major lupus exacerbation (OR 1.382, 95% CI 1.154-1.654; p < 0.001) were independent risk factors to major bacterial infection after adjustment for age and disease duration. Multiple regression analysis showed an increase in risk of bacterial infection by 34.2% for every decrease in serum MBL level by one log, and by 22.8% for each increase in number of major lupus exacerbations. CONCLUSION: Low serum MBL level predisposes Chinese patients with SLE to more major infections, in particular bacterial ones.     

Genetics of susceptibility and severity in systemic lupus erythematosus

PURPOSE OF REVIEW: The genetic basis of systemic lupus erythematosus, a complex genetic trait, may provide important insights into autoimmune disease. Innovation in both practical and theoretical approaches will assist in accelerating the pace of discovery and our understanding of pathogenesis. RECENT FINDINGS: Significant progress has been made in the last year with respect to the refinement of genetic intervals to promising candidate genes involved in systemic lupus erythematosus pathogenesis and specific phenotype susceptibility. This review highlights these discoveries and suggests platforms that may affect the future of analysis of this complex disease. SUMMARY: Understanding the genetic basis for systemic lupus erythematosus disease and sub-phenotype susceptibility will have a substantial effect on the therapeutic interventions used to care for patients.     

Factor xii deficiency with systemic lupus erythematosus

A patient with Factor XII (Hageman) deficiency and fulminant systemic lupus erythematosus is presented. The Factor XII deficiency was noted prior to the onset of clinical systemic lupus erythematosus and persisted throughout the patient's course without associated hemorrhagic manifestations. There was no evidence for a circulating anticoagulant. The patient had a rapidly progressive fatal course unresponsive to corticosteroid therapy. Factor XII levels did not increase during therapy with steroids. Despite absence of Hageman factor, evidence for activation of complement by the classic pathway and thromboembolic phenomenon was observed. The role of Factor XII in coagulation and inflammatory pathways and the influence of the factor deficiency on the course of the patient's illness are discussed.     

Kidney disease in systemic lupus erythematosus

Summary Glomerulonephritis is a major determinant of outcome in patients with systemic lupus erythematosus. Persistently active lupus nephritis imposes serious threats of end-stage renal failure and cardiovascular morbidity. Sustained corticosteroid treatment has been characterized as having an uncertain net benefit on the control of lupus nephritis, mainly because these drugs have relatively weak efficacy and they have been shown to confer their own set of cardiovascular risk factors. Controlled trials of corticosteroids, azathioprine and cyclophosphamide have demonstrated that the best control of clinical activity of proliferative lupus nephritis is attained with cyclophosphamide. To date, intermittent pulse cyclophosphamide treatment has produced the most facorable balance of efficacy and toxicity in patients with lupus nephritis.