Irf1 regulates the homeostasis of pathogenic age-associated B cells (ABC) and antibody secreting cells (ASC) subsets in autoimmunity and inflammaging 2731

Abstract Description Interferon regulatory factor 1 (IRF1) is a transcriptional regulator of inflammation. Given the role of inflammation in autoimmunity, we hypothesized that IRF1 would influence the progression of systemic lupus erythematosus (SLE). Consistent with this, human SLE B cells expressed higher IRF1 levels and showed increased chromatin accessibility at IRF1-binding sites. To study the role of IRF1 in SLE, we analyzed lupus-prone B6.Yaa.Fcgr2b-/- (YFc) mice lacking Irf1 globally (YFc.Irf1) and only in B cells (B-YFc.Irf1). YFc.Irf1 mice had reduced ASCs and ABCs, smaller spleens, decreased serum autoantibodies, reduced glomerular IgG deposition and attenuated kidney damage. Interestingly, similar results were seen in B-YFc.Irf1 mice. Mechanistically, Irf1 tuned the response of B cells to TLR7/8 ligands. This phenotype was not limited to the YFc model. Lupus-prone B6.MRL-Faslpr/J (Lpr) mice lacking Irf1 globally (Lpr.Irf1) and in B cells (B-Lpr.Irf1) also had reduced IgG ASCs and decreased serum autoantibodies. To test whether Irf1 drives or accelerates inflammation in B cells, we analyzed aged B6 mice lacking Irf1 in all cells (B6.Irf1) and B cells (B-Irf1). Both models had decreased ASCs and ABCs and aged B6.Irf1 mice had decreased age-associated kidney pathology. These findings reveal that Irf1 modulates pathogenic B cell subsets in autoimmunity and inflammaging, suggesting IRF1 as a potential B cell target for SLE treatment. Funding Sources Supported by grants from NIH (R01 AI110508 & R01AI153365) Topic Categories Basic Autoimmunity (BA)