Exacerbated autoimmunity in the absence of TLR9 in MRL. Faslpr mice depends on Ifnar1

KM Nickerson, JL Cullen, M Kashgarian… - The Journal of …, 2013 - journals.aai.org
KM Nickerson, JL Cullen, M Kashgarian, MJ Shlomchik
The Journal of Immunology, 2013journals.aai.org
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 IFNs (IFN-I) 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 IFN-I, Ifnar1, we show that IFN-I …
Abstract
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 IFNs (IFN-I) 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 IFN-I, Ifnar1, we show that IFN-I contribute significantly to renal disease in this model. Ifnar1 had no effect on anti-nucleosome or anti-Sm autoantibody titers, but instead regulated anticytoplasmic and anti-RNA specificities. Moreover, Ifnar1 deficiency prevented the exacerbation of clinical disease observed in Tlr9-deficient animals in this lupus model. Thus, IFN-I signaling is an important mediator of lupus pathogenesis and anti-RNA Ab production that is dysregulated in the absence of Tlr9.
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