Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects as many as one in 2500 individuals. We discovered that 43% of lupus patients have dramatically increased numbers of peripheral blood B cells that express the transcription factor ARID3a. Numbers of ARID3a+ B lymphocytes were associated with increased disease activity, suggesting that ARID3a might contribute to, or be a consequence of, disease activity. The underlying reasons for increased ARID3a expression in blood cells from lupus patients, and its association with disease activity are unclear. Our data now indicate that ARID3a+ B cells produce interferon alpha, a Type I interferon previously associated with inflammatory processes and increased disease activity in SLE. It is unlikely that B lymphocytes secrete sufficient quantities of interferon to explain the high levels associated with SLE. Preliminary data indicate that plasmacytoid dendritic cells and neutrophils also show high levels of ARID3a expression in a subset of SLE blood samples, as compared to healthy controls. Intriguingly, ARID3a expression in those cells is associated with production of interferon alpha. Additional data suggest that ARID3a, and interferon alpha, are induced in healthy blood cells through toll-like receptor signals, particularly CpG. These data link ARID3a expression to normal innate immune responses. Inhibition of ARID3a in B lymphoblastoid cells also inhibits interferon alpha expression, suggesting ARID3a plays a role in regulating interferon production in those cells. We hypothesize that ARID3a expression is associated with interferon production in neutrophils and plasmacytoid dendritic cells, and that ARID3a+ neutrophils and/or dendritic cells are associated with disease pathogenesis in SLE. Furthermore, we hypothesize that ARID3a expression is induced as a consequence of innate immune signals in hematopoietic stem cell progenitor populations, and that ARID3a-expressing progenitors contribute to interferon signatures observed in SLE. The proposed studies will define associations between ARID3a expression and innate immune responses in neutrophils and plasmacytoid dendritic cells in lupus and healthy control samples. Requirements for ARID3a in interferon production will be evaluated using ARID3a knockdown experiments. Genes potentially regulated by ARID3a in innate immune signaling pathways will be identified. Finally, we will use humanized mouse models to evaluate the consequences of induced ARID3a expression in healthy hematopoietic progenitors. The results of these experiments will fill important gaps in our understanding of regulatory responses in innate immunity and abnormal responses observed in SLE that are associated with ARID3a. Ultimately, we expect these data to have broader impacts that increase our understanding of inflammatory responses associated with normal innate immunity and with autoimmune disease.
We found increased numbers of ARID3a+ blood cells in lupus patients compared to healthy controls. Our new data suggest that ARID3a is associated with Type I interferon responses previously associated with inflammatory disease in nearly half of individuals with systemic lupus erythematosus. The proposed experiments will better characterize patient and control ARID3a+ blood cells, and will determine how they are linked to autoimmune disease activity.