ARID3a functions in autoimmune B cells

About This Grant

Abstract Systemic lupus erythematosus (SLE) is a heterogeneous disease affecting multiple organ systems. Current treatments result in toxicity and impaired immune responses to pathogens. Identification of new therapeutic targets is complicated by a lack of understanding of the underlying mechanisms that result in SLE and in other autoimmune diseases. We found that ARID3a (A+T-rich interaction domain protein 3a) over-expression in transgenic mouse B lymphocytes was sufficient to cause autoantibody production and immune complex formation in kidney glomeruli. Further, numbers of ARID3a+ B cells are increased in SLE patients compared to healthy controls and those numbers are highly associated with increased disease activity in patients as determined by disease activity indices (SLEDAI scores). Although ARID3a is a DNA-binding protein involved in gene regulation, mechanisms by which ARID3a contributes to gene dysregulation in autoimmunity are unknown. Naïve B cells represent a tolerance check-point and we observed that a subset of naïve B cells from SLE patients express ARID3a, while ARID3a was absent from healthy control naïve B cells. We recently used single cell RNA-seq to identify genes differentially expressed in naïve ARID3a+ versus ARID3a- B cells from SLE patients, identifying new markers to enable additional functional studies of those cells. We also found that complex stimuli developed by others to generate “activated” naïve B cells and pathogenic double--negative B cell subsets similar to those increased in SLE patients, also induced ARID3a expression in the “activated” naïve B cell subset. Therefore, we hypothesize that ARID3a is a mediator of dysregulated gene expression in SLE naïve B cells that contributes to tolerance breaches. The proposed aims will 1) define genes and epigenetic regions that bind ARID3a and may be directly regulated by ARID3a expression; 2) determine how ARID3a contributes to functions associated with breaches in B cell tolerance; and 3) determine if inhibition of ARID3a-regulated pathways in autoimmune mouse models ameliorates disease symptoms and functional attributes. The proposed studies will fill gaps in our knowledge of how ARID3a functions in naïve B cells and will define genes and intragenic regions regulated by ARID3a that may contribute to autoimmune characteristics in SLE. These experiments will provide new mechanistic insights into ARID3a functions and may direct future design of novel therapeutics.