title: Exacerbated autoimmunity in the absence of TLR9 in MRL.Fas(lpr) mice depends on Ifnar1.
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.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Nickerson
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Cullen
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000172:deficiency* / Q000235:genetics
chemical_list: C508032:Ifnar1 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D053633:Receptor, Interferon alpha-beta