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Disease activity in systemic lupus erythematosus correlates with expression of the transcription factor AT-rich-interactive domain 3A.

ABSTRACT: Systemic lupus erythematosus (SLE) is a complex and multifactorial autoimmune disease with striking clinical, immunologic, and genetic heterogeneity, despite nearly ubiquitous antinuclear antibody (ANA) production. Multiple gene polymorphisms have been associated with the disease, but these individually account for only a very small percentage of overall SLE risk. In earlier studies, constitutive expression of the DNA-binding protein AT-rich-interactive domain 3A (ARID3a) in transgenic mouse B lymphocyte lineage cells led to spontaneous ANA production and preferential development of B cells associated with production of polyreactive antibodies. Therefore, we undertook this study to determine whether ARID3a was overexpressed in B lymphocytes of SLE patients and whether ARID3a expression was associated with disease severity.A cross-section of SLE patients, rheumatoid arthritis patients, and age- and sex-matched controls was analyzed longitudinally for lupus disease activity, numbers of ARID3a+ peripheral blood mononuclear B cells from multiple B cell subsets, and immunoglobulin and cytokine levels.Fifty of 115 SLE patients (43%) had dramatically increased numbers of ARID3a+ B cells compared to healthy controls. ARID3a was not expressed in naive B cells of healthy controls, but was abundant in these precursors of antibody-secreting cells in SLE patients. Total numbers of ARID3a+ B cells correlated with increased disease activity as defined by SLE Disease Activity Index scores in individuals assessed at 3 time points.These findings identify B cell anomalies in SLE that allow stratification of patient samples based on ARID3a expression and implicate ARID3a as a potential marker of CD19+ B lymphocytes correlated with disease activity.

SUBMITTER: Ward JM

PROVIDER: S-EPMC4245462 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Disease activity in systemic lupus erythematosus correlates with expression of the transcription factor AT-rich-interactive domain 3A.

Ward Julie M JM Rose Kira K Montgomery Courtney C Adrianto Indra I James Judith A JA Merrill Joan T JT Webb Carol F CF

Arthritis & rheumatology (Hoboken, N.J.) 20141201 12

<h4>Objective</h4>Systemic lupus erythematosus (SLE) is a complex and multifactorial autoimmune disease with striking clinical, immunologic, and genetic heterogeneity, despite nearly ubiquitous antinuclear antibody (ANA) production. Multiple gene polymorphisms have been associated with the disease, but these individually account for only a very small percentage of overall SLE risk. In earlier studies, constitutive expression of the DNA-binding protein AT-rich-interactive domain 3A (ARID3a) in tr ...[more]

PMID: 25185498

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Project description:BackgroundFactor H (FH) is a major soluble inhibitor of the complement system and part of a family comprising five related proteins (FHRs 1-5). Deficiency of FHR1 was described to be linked to an elevated risk of systemic lupus erythematosus (SLE). As FHR1 can partially antagonize the functionality of FH, an altered FHR1/FH ratio could not only enhance SLE vulnerability but also affect the disease expression. This study focuses on the analysis of FH and FHR1 at a protein level, and the occurrence of anti-FH autoantibodies (anti-FH) in a large cohort of SLE patients to explore their association with disease activity and/or expression.MethodsWe assessed FH and FHR1 levels in plasma from 378 SLE patients compared to 84 healthy controls (normal human plasma, NHP), and sera from another cohort of 84 healthy individuals (normal human serum, NHS), using RayBio® CFH and CFHR1 ELISA kits. Patients were recruited by the Swiss SLE Cohort Study (SSCS). Unmeasurable FHR1 levels were all confirmed by Western blot, and in a subgroup of patients by PCR. Anti-FH were measured in SLE patients with non-detectable FHR1 levels and matched control patients using Abnova's CFH IgG ELISA kit.ResultsOverall, FH and FHR1 levels were significantly higher in healthy controls, but there was no significant difference in FHR1/FH ratios between SLE patients and NHPs. However, SLE patients showed a significantly higher prevalence of undetectable FHR1 compared to all healthy controls (35/378 SLE patients versus 6/168 healthy controls; p= 0.0214, OR=2.751, 95% CI = 1.115 - 8.164), with a consistent trend across all ethnic subgroups. Levels of FH and FHR1, FHR1/FH ratios and absence of FHR1 were not consistently associated with disease activity and/or specific disease manifestations, but absence of FHR1 (primarily equivalent to CFHR1 deficiency) was linked to the presence of anti-FH in SLE patients (p=0.039).ConclusionsDeficiency of FHR1 is associated with a markedly elevated risk of developing SLE. A small proportion of FHR1-deficient SLE patients was found to have autoantibodies against FH but did not show clinical signs of microangiopathy.

Project description:ObjectivesThis study aims to correlate subclinical echocardiographic features with the clinical, laboratory, and therapeutic profiles of the patients to characterize risks for systemic lupus erythematosus (SLE) cardiac diseases.MethodsThe study included 59 SLE patients. Demographic data, disease characteristics, and current therapies were recorded, and the anthropometric measurements and routine laboratory tests were performed. The disease activity by the SLE Disease Activity Index-2K (SLEDAI2K) and the presence of metabolic syndrome (MetS) were assessed. Two-dimensional echocardiography was performed.ResultsThe mean age of the patients was 31.3 ± 10.5 years, and the disease duration was 5.18 ± 4.1 years. 86.4% of the patients were females. Cardiac presentations by echocardiography were mainly mitral regurgitation (33.9%), tricuspid regurgitation (32.2%), mitral thickening (18.6%), aortic thickening (13.6%), pericardial effusion (13.6%), and pulmonary hypertension (8.5%) in order of frequency. The frequency of different echocardiographic findings with respect to other clinical phenotypes showed peaks with renal disease, MetS, and leukopenia. Components of MetS (triglycerides, high systolic blood pressure) and avascular necrosis were significant predictors for pericardial diseases (OR=1.011 CI 95% 1-1.022, p=0.046, OR=1.157 CI 95% 1.025-1.307, p=0.018, and OR=74.78 CI 95% 2.52-2215.76, p=0.013, respectively), and it is likely that hydroxychloroquine was protective against them. Age of the patients was a significant predictor for tricuspid regurgitation (OR=1.063 CI 95% 1.004-1.126, p=0.036). Mucosal ulcers were negative predictors for mitral thickening and regurgitation (OR=0.2 CI 95% 0.059-0.673, p=0.009). The use of corticosteroids appeared to protect against a number of valve lesions especially tricuspid regurgitation (OR=0.299 CI 95% 0.088-1.019, p=0.054).ConclusionThis study highlighted different echocardiographic features and identified clinical predictors of different cardiac pathologies aiming to determine patients at risk and improve the prognosis of SLE cardiac diseases.

Dataset Information

Disease activity in systemic lupus erythematosus correlates with expression of the transcription factor AT-rich-interactive domain 3A.

Publications

Disease activity in systemic lupus erythematosus correlates with expression of the transcription factor AT-rich-interactive domain 3A.

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