Exacerbated Autoimmunity in the Absence of TLR9 in MRLFaslpr Mice Depends on Ifnar11

TLR9 suppresses TLR7-driven pathogenesis in the MRL. Fas lpr murine model of systemic lupus erythematosus, but the mechanisms by which TLR7 promotes and TLR9 prevents disease in this and other lupus models remain unclear. Type I interferons have also been implicated in the pathogenesis of lupus both in patients and in several murine models of disease, but their role in MRL. Fas lpr mice is controversial. Using MRL. Fas lpr mice genetically deficient in a subunit of the receptor for type I interferon, Ifnar1 , we show that type I interferons contribute significantly to renal disease in this model. Ifnar1 had no effect on anti-nucleosome or anti-Sm autoantibody titers, but instead regulated anti-cytoplasmic and anti-RNA specificities. Moreover, Ifnar1 deficiency prevented the exacerbation of clinical disease observed in Tlr9 -deficient animals in this lupus model. Thus, type I interferon signaling is an important mediator of lupus pathogenesis and anti-RNA antibody production that is dysregulated in the absence of Tlr9 .