Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
J Immunol. 2013 Apr 15;190(8):3889-94. doi: 10.4049/jimmunol.1203525. Epub 2013 Mar 6.
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.
TLR9 抑制 MRL.Fas(lpr) 系统性红斑狼疮小鼠模型中 TLR7 驱动的发病机制，但 TLR7 促进疾病和 TLR9 在该模型和其他狼疮模型中预防疾病的机制仍不清楚。I 型干扰素 (IFN-I) 在狼疮患者和几种疾病的小鼠模型中也与发病机制有关，但它们在 MRL.Fas(lpr) 小鼠中的作用存在争议。使用 IFN-I 受体亚单位缺失的 MRL.Fas(lpr) 小鼠 Ifnar1，我们表明 IFN-I 在该模型中对肾脏疾病有重要贡献。Ifnar1 对核小体或抗 Sm 自身抗体滴度没有影响，但调节细胞质和抗 RNA 特异性。此外，Ifnar1 缺乏可防止在该狼疮模型中观察到的 Tlr9 缺陷动物临床疾病的恶化。因此，IFN-I 信号是狼疮发病机制和抗 RNA Ab 产生的重要介质，在缺乏 TLR9 的情况下失调。
