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Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus is a severe autoimmune disease that affects multiple organ systems resulting in diverse symptoms and outcomes. It is characterized by antibody production to a variety of self-antigens, but it is specifically associated with those against anti-dsDNA. Anti-dsDNA antibodies are present before the onset of clinical disease and are associated with severe manifestations of lupus such as glomerulonephritis. Their levels fluctuate with changes in disease activity and, in combination with the levels of complement proteins C3 and C4, are strong indicators of disease flare and treatment response in patients with lupus. The decreased complement levels that are noted during flares of lupus activity are believed to be secondary to increased autoantibody production and immune complex formation that results in tissue damage; however, recent data suggest that complement activation can also drive development of these pathogenic autoantibodies. This review will explore the various roles of complement in the development and pathogenesis of anti-dsDNA antibodies.

SUBMITTER: Giles BM

PROVIDER: S-EPMC4018221 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus.

Giles Brendan M BM Boackle Susan A SA

Immunologic research 20130301 1-3

Systemic lupus erythematosus is a severe autoimmune disease that affects multiple organ systems resulting in diverse symptoms and outcomes. It is characterized by antibody production to a variety of self-antigens, but it is specifically associated with those against anti-dsDNA. Anti-dsDNA antibodies are present before the onset of clinical disease and are associated with severe manifestations of lupus such as glomerulonephritis. Their levels fluctuate with changes in disease activity and, in com ...[more]

PMID: 22941560

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Project description:Evidence about the relevance of the complement system, a highly conserved constituent of the innate immunity response that orchestrates the elimination of pathogens and the inflammatory processes, has been recently accumulated in many different rheumatologic conditions. In rheumatoid arthritis, complement, mainly the classical pathway, contributes to tissue damage especially in seropositive subjects, with complement activation occurring in the joint. Data about complement pathways in psoriatic arthritis are dated and poorly consistent; among patients with Sjögren syndrome, hypocomplementemia exerts a prognostic role, identifying patients at risk of extra-glandular manifestations. Hints about complement involvement in systemic sclerosis have been recently raised, following the evidence of complement deposition in affected skin and in renal samples from patients with scleroderma renal crisis. In vasculitides, complement plays a dual role: on one hand, stimulation of neutrophils with anti-neutrophil cytoplasmic antibodies (ANCA) results in the activation of the alternative pathway, on the other, C5a induces translocation of ANCA antigens, favouring the detrimental role of antibodies. Complement deposition in the kidneys identifies patients with more aggressive renal disease; patients with active disease display low serum levels of C3 and C4. Even though in dermatomyositis sC5b-9 deposits are invariably present in affected muscles, data on C3 and C4 fluctuation during disease course are scarce. C3 and C1q serum levels have been explored as potential markers of disease activity in Takayasu arteritis, whereas data in Behçet disease are limited to in vitro observations. Pregnancies in women with rheumatologic conditions are still burdened by a higher rate of pregnancy complications, thus the early identification of women at risk would be invaluable. A fine-tuning of complement activation is required from a physiological progression of pregnancy, from pre-implantation stages, through placentation to labour. Complement deregulation has been implicated in several pregnancy complications, such as recurrent abortion, eclampsia and premature birth; low complement levels have been shown to reliably identify women at risk of complications. Given its physiologic role in orchestrating pregnancy progression and its involvement as pathogenic effector in several rheumatologic conditions, complement system is an attractive candidate biomarker to stratify the obstetric risk among women with rheumatologic conditions.

Project description:BackgroundSystemic Lupus Erythematosus (SLE) is a complex and heterogeneous autoimmune disease mediated by quantities of autoantibodies in which anti-double-stranded DNA (anti-dsDNA) antibodies are important. Besides, glycosylation is one of the most commonly post-translational modifications of antibodies. The association of anti-dsDNA antibodies glycosylation and SLE disease activity is still unknown.MethodsWe enrolled 101 consecutive treatment-naïve SLE patients with positive anti-dsDNA antibodies from the Department of Rheumatology and Immunology at Ruijin Hospital, Shanghai, between 2017 and 2019. Serum samples were used in this study. We analysed the glycosylation of anti-dsDNA IgG and total IgG subclasses according to systemic lupus erythematosus disease activity index (SLEDAI) scores. Statistical analysis and machine learning were performed to assess the correlation between glycosylation of anti-dsDNA IgG and total IgG with disease activity.FindingsSerum samples from 86 patients could be detected with anti-dsDNA IgG glycopeptide and subclass of IgG glycoform. Cluster analysis showed that glycosylation of anti-dsDNA IgG and total IgG subclasses were different in SLE patients. Fucosylation, galactosylation, and sialylation levels of anti-dsDNA IgG1 were increased with SLEDAI scores (all p<0.05). The results of machine learning showed that all the glycoforms of anti-dsDNA IgG1 had better performance with lower standardised square error (SSE) than that of total IgG1, with anti-dsDNA IgG1 fucosylation level having the lowest SSE (0.009).InterpretationOur study indicated that glycosylation of anti-dsDNA IgG was different from that of total IgG and fucosylation of anti-dsDNA IgG1 correlated best with SLE disease activity.FundingThis work is supported by the National Key Research and Development Program of China (2018YFC0910303), National Natural Science Foundation of China (81801592, 82101876), Clinical Research Plan of SHDC (SHDC2020CR4011), Ruijin Hospital Youth Incubation Project (KY2021607) and Shanghai Pujiang Young Rheumatologists Training Program (SPROG202006).

Project description:Anti-phospholipid (aPL) antibodies are important contributors to development of thrombosis in patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE). The underlying mechanism of aPL antibody-mediated thrombosis is not fully understood but existing data suggest that platelets and the complement system are key components. Complement activation on platelets is seen in SLE patients, especially in patients with aPL antibodies, and has been related to venous thrombosis and stroke. The aim of this study was to investigate if aPL antibodies could support classical pathway activation on platelets in vitro as well as in SLE patients. Furthermore, we investigated if complement deposition on platelets was associated with vascular events, either arterial or venous, when the data had been adjusted for traditional cardiovascular risk factors. Finally, we analyzed if platelet complement deposition, both C1q and C4d, was specific for SLE. We found that aPL antibodies supported C4d deposition on platelets in vitro as well as in SLE patients (p?=?0.001 and p<0.05, respectively). Complement deposition on platelets was increased in SLE patients when compared with healthy individuals (p<0.0001). However, high levels of C4d deposition and a pronounced C1q deposition were also seen in patients with rheumatoid arthritis and systemic sclerosis. In SLE, C4d deposition on platelets was associated with platelet activation, complement consumption, disease activity and venous (OR?=?5.3, p?=?0.02), but not arterial, thrombosis, observations which were independent of traditional cardiovascular risk factors. In conclusion, several mechanisms operate in SLE to amplify platelet complement deposition, of which aPL antibodies and platelet activation were identified as important contributors in this investigation. Complement deposition on platelets was identified as a marker of venous, but not arterial thrombosis, in SLE patients independently of traditional risk factors and aPL antibodies. Further studies are needed to elucidate the role of complement deposition on platelets in development of venous thrombosis.

Dataset Information

Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus.

Publications

Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus.

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