Objective 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 individually account for only a very small percentage of overall SLE risk. In earlier studies, constitutive expression of the DNA-binding protein, A+T rich interacting 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 asked if ARID3a was over-expressed in B lymphocytes of SLE patients and if ARID3a expression was associated with disease severity. Methods A cross section of SLE patients and age and gender-matched controls were analyzed longitudinally for lupus disease activity, numbers of ARID3a+ peripheral blood mononuclear B cells from multiple B cell subsets, immunoglobulin and cytokine levels. Results Fifty of 115 patients (43%) had dramatically increased numbers of ARID3a+ B cells compared to healthy controls. ARID3a is not expressed in naïve 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 three time points. Conclusion 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.
Previously, we determined that enhanced disease activity in patients with systemic lupus erythematosus (SLE) was associated with dramatic increases in numbers of B lymphocytes expressing the transcription factor ARID3a. Our data now indicate ARID3a is important for interferon alpha (IFNa) expression and show a strong association between ARID3a expression and transcription of genes associated with lupus IFN signatures. Furthermore, both ARID3a and IFNa production were elicited in healthy control B cells upon stimulation with the TLR 9 agonist, CpG. Importantly, secretion of IFNa from ARID3a+ healthy B lymphocytes stimulated increased IFNa production in plasmacytoid dendritic cells. These data identify ARID3a+ B cells as a novel type of effector B cell, and link ARID3a expression in B lymphocytes to IFN-associated inflammatory responses in SLE.
Although hematopoietic progenitor/stem cells (HPSCs) are used for transplantation, characterization of the multiple subsets within this population in man has lagged behind similar studies in mice. We found that expression of the DNA-binding protein, ARID3a, in mouse stem cells was important for normal development of hematopoietic lineages; however, progenitors expressing ARID3a in man have not been defined. We previously showed increased numbers of ARID3a+ B cells in nearly half of systemic lupus erythematosus (SLE) patients, and that total numbers of ARID3a+ B cells were associated with increased disease severity. Because expression of ARID3a in those SLE patients occurred throughout all B cell subsets, we hypothesized that ARID3a expression in patient HSPCs might also be increased relative to expression in healthy controls. Our data now show that ARID3a expression is not limited to any defined subset of HPSCs in either healthy controls or SLE patients. Numbers of ARID3a+ HSPCs in SLE patients were increased over numbers of ARID3a+ cells in healthy controls. While all SLE-derived HPSCs exhibited poor colony formation in vitro compared to controls, SLE HPSCs with high numbers of ARID3a+ cells yielded increased numbers of cells expressing the early progenitor marker, CD34. SLE HPSCs with high numbers of ARID3a+ cells also more readily generated autoantibody producing cells than HPSCs with lower levels of ARID3a in a humanized mouse model. These data reveal new functions for ARID3a in early hematopoiesis and suggest that knowledge regarding ARID3a levels in HPSCs could be informative for applications requiring transplantation of those cells.
ARID3a/Bright is a DNA-binding protein that was originally discovered for its ability to increase immunoglobulin transcription in antigen-activated B cells. It interacts with DNA as a dimer through its ARID, or A/T-rich interacting domain. In association with other proteins, ARID3a increased transcription of the immunoglobulin heavy chain and led to improved chromatin accessibility of the heavy chain enhancer. Constitutive expression of ARID3a in B lineage cells resulted in autoantibody production, suggesting its regulation is important. Abnormal ARID3a expression has also been associated with increased proliferative capacity and malignancy. Roles for ARID3a in addition to interactions with the immunoglobulin locus were suggested by transgenic and knockout mouse models. Over-expression of ARID3a resulted in skewing of mature B cell subsets and altered gene expression patterns of follicular B cells, whereas loss of function resulted in loss of B1 lineage B cells and defects in hematopoiesis. More recent studies showed that loss of ARID3a in adult somatic cells promoted developmental plasticity, alterations in gene expression patterns, and lineage fate decisions. Together, these data suggest new regulatory roles for ARID3a. The genes influenced by ARID3a are likely to play pivotal roles in lineage decisions, highlighting the importance of this understudied transcription factor. Keywords: Bright, ARID3a, hematopoietic regulation, B cell development, gene regulationBright (B cell regulator of immunoglobulin heavy chain transcription) is a 70 kDa DNA-binding protein first characterized in the mouse as a component of a protein complex associated with increased transcription of the immunoglobulin heavy chain (IgH) locus in activated B lymphocytes (1-3). Bright, also known as DRIL1, E2FBP1, or ARID3a (the designation for the human ortholog, hereafter referred to as Bright), is a member of the A + T rich interaction domain (ARID) protein family, many of which have been shown recently to have epigenetic regulatory functions [reviewed in ]. These proteins bind to A + T rich DNA sequences and are typically members of larger chromatin modulatory complexes. Bright, and other ARID3 family members, require dimerization for DNA-binding activity and contain an extended DNA-binding domain that confers increased DNA sequence specificity to these proteins compared to other ARID family members (7-9). Although Bright was the first member of this family identified in mammalian cells, its functions have only begun to be elucidated. Previously, Bright expression in adult, mouse, and human cells was thought to be largely restricted to B lymphocyte lineage cells. However, more recently, we and others have shown that Bright plays important regulatory functions in early hematopoiesis. Although Bright expression is restricted in adults, it is more widely expressed in the embryo/fetus and plays important regulatory roles in embryonic stem cell differentiation (10). These data also highlight novel roles for Bright in gene repression. This artic...
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