Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
J Immunol. 2010 Jan 15;184(2):796-806. doi: 10.4049/jimmunol.0901748. Epub 2009 Dec 9.
Polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis has not previously been tested in an animal model. In this study, we show that IRF5 is absolutely required for disease development in the FcgammaRIIB(-/-)Yaa and FcgammaRIIB(-/-) lupus models. In contrast to IRF5-sufficient FcgammaRIIB(-/-)Yaa mice, IRF5-deficient FcgammaRIIB(-/-)Yaa mice do not develop lupus manifestations and have a phenotype comparable to wild-type mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5 heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I IFN, IFN-alpha, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcgammaRIIB(-/-)Yaa mice lacking the type I IFN receptor subunit 1. Unlike the IRF5-deficient and IRF5-heterozygous FcgammaRIIB(-/-)Yaa mice, type I IFN receptor subunit 1-deficient FcgammaRIIB(-/-)Yaa mice maintained a substantial level of residual disease. Furthermore, in FcgammaRIIB(-/-) mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcgammaRIIB(-/-)Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I IFN production.
转录因子 IFN 调节因子 5（IRF5）的多态性在人类遗传研究中与自身免疫性疾病系统性红斑狼疮（lupus erythematosus）的发病风险增加密切相关。然而，IRF5 在狼疮发病机制中的生物学作用以前尚未在动物模型中进行测试。在这项研究中，我们表明 IRF5 在 FcγRIIB(-/-)Yaa 和 FcγRIIB(-/-)狼疮模型中是疾病发展所必需的。与 IRF5 充分的 FcγRIIB(-/-)Yaa 小鼠不同，IRF5 缺陷的 FcγRIIB(-/-)Yaa 小鼠不会出现狼疮表现，并且表型与野生型小鼠相当。引人注目的是，IRF5 的完全表达对于自身免疫的发展是必需的，因为 IRF5 杂合子疾病明显减少。IRF5 的一个作用是诱导 I 型 IFN（IFN-α）的产生，该细胞因子与狼疮发病机制有关。为了确定 IRF5 促进疾病的机制，我们评估了缺乏 I 型 IFN 受体亚基 1 的 FcγRIIB(-/-)Yaa 小鼠。与 IRF5 缺陷和 IRF5 杂合的 FcγRIIB(-/-)Yaa 小鼠不同，缺乏 I 型 IFN 受体亚基 1 的 FcγRIIB(-/-)Yaa 小鼠保持了相当水平的残留疾病。此外，在缺乏 Yaa 的 FcγRIIB(-/-)小鼠中，IRF5 缺陷也显著降低了疾病表现，表明 IRF5 缺陷在 FcγRIIB(-/-)Yaa 小鼠中的有益作用不仅归因于对与 Yaa 突变相关的增强 TLR7 信号的抑制。总的来说，我们证明了 IRF5 在小鼠模型中的狼疮发病机制中起着至关重要的作用，并且这是通过 I 型 IFN 产生以外的途径介导的。
