IFIH1 risk variant primes the immune system to promote lupus nephritis 4370

Abstract Description Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and has been linked to a dysregulated type I interferon (IFN I) program. One genetic variant linked to dysregulated IFN I and multiple autoimmune diseases, including SLE, is in the anti-viral cytosolic RNA sensor IFIH1 (rs1990760) and results in an amino acid change (IFIH1A946T; IFIH1R). We hypothesized that IFIH1R would induce a heightened inflammatory environment priming the immune system to promote pathogenesis in an induced murine model of LN. Following injection of sheep nephrotoxic serum (NTS), we found Ifih1R mice exhibited increased kidney disease. Splenic Ifih1R follicular B cells were increased concomitantly with a decrease in the marginal zone B cell frequency compared to non-risk Ifih1 (Ifih1NR) mice. Further, activated CD8+ T cell frequency was elevated in Ifih1R mice. We also evaluated the immune response locally in the kidneys. Ifih1R mice exhibited increased mouse IgG deposition in the glomeruli. Interestingly, we found increased CD4+ T cell recruitment into the glomeruli in Ifih1R compared to Ifih1NR kidneys. Thus, our data suggest that IFIH1R primes the immune system, thereby leading to a more robust response to the NTS which subsequently results in increased susceptibility to developing kidney disease. These data reveal crucial mechanisms connecting Ifih1R to SLE and LN. Funding Sources Supported by NIH COBRE P20GM139763, NIH S10OD028479-01, Center for Adult Stem Cell Research Grant, and the Oklahoma Medical Research Foundation. Topic Categories Basic Autoimmunity (BA)