Sunday, October 1, 2023
10/1/2023
Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems and for which current treatments are toxic and impair immune responses to pathogens, so new treatment regimens are needed. Identification of new therapeutic targets is complicated by a lack of understanding of the mechanisms that cause SLE. ARID3a is a DNA-binding protein that can alter gene expression both at the transcription level, and by contributing to epigenetic landscapes. We found that ARID3a protein is expressed in low density neutrophils (LDNs) of SLE patients, but not in LDNs from healthy controls, and ARID3a expression was associated with production of the inflammatory cytokine, interferon alpha (IFNa) in the same cells. Surprisingly, increased numbers of ARID3a+ LDNs are more significantly associated with increased disease activity indices (SLEDAI scores; R2=0.65) in SLE patients than were numbers of IFNa-producing LDNs. These data suggest that ARID3a-expressing LDNs contribute to disease activity in SLE through other mechanisms than IFNa production. Our previous data suggested that ARID3a protein expression was associated with differential gene expression patterns in LDNs. We hypothesize that ARID3a-associated gene dysregulation contributes to SLE disease pathogenesis. Therefore, our first aim is to define binding sites for ARID3a near differentially expressed genes and accessible epigenetic domains in SLE. The second specific aim will directly test known functions of LDNs to define which of those functions require ARID3a expression and which may be inhibited with ARID3a-specific inhibitors. Finally, we found that ARID3a expression in LDNs is not regulated at the level of transcription, perhaps explaining why ARID3a has not been previously identified through elegant RNA-seq studies as potential driver of pathogenesis in SLE LDNs. Our third aim will determine how ARID3a protein expression is induced in LDNs. Our published and preliminary data support the idea that ARID3a contributes to, or is a consequence of, disease activity in SLE and that inhibition of ARID3a decreases autoimmune symptoms. These experiments will fill important gaps in our understanding of how ARID3a is associated with SLE and will define functions and genetic pathways that may serve as new therapeutic targets for this devastating disease.
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