IFN regulatory factor 5 is required for disease development in the FcgammaRIIB-/-Yaa and FcgammaRIIB-/- mouse models of systemic lupus erythematosus.
IFN regulatory factor 5 is required for disease development in the FcgammaRIIB-/-Yaa and FcgammaRIIB-/- mouse models of systemic lupus erythematosus.
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DOI：
10.4049/jimmunol.0901748
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Rifkin IR
中科院分区：
文献类型：
--
作者：
Richez C;Yasuda K;Bonegio RG;Watkins AA;Aprahamian T;Busto P;Richards RJ;Liu CL;Cheung R;Utz PJ;Marshak-Rothstein A;Rifkin IR
在人类遗传学研究中，转录因子干扰素调节因子5(IRF5)的多态与自身免疫性疾病系统性红斑狼疮的风险增加密切相关。然而，IRF5在狼疮发病机制中的生物学作用之前还没有在动物模型中进行过测试。在这项研究中，我们证明了在FCγRIIB−/−YAA和FCγRIIB−/−狼疮模型中，IRF5对于疾病的发展是绝对必要的。与IRF5充足的FcγRIIB−/−YAa小鼠不同，IRF5缺乏的FcγRIIB−/−YAa小鼠不会出现狼疮症状，并且具有与野生型小鼠相似的表型。值得注意的是，IRF5的充分表达是自身免疫发展所必需的，因为IRF5杂合子大大减少了疾病的发生。IRF5的作用之一是诱导I型干扰素-α的产生，这是一种与狼疮发病有关的细胞因子。为了阐明IRF5促进疾病的机制，我们评估了缺乏I型干扰素受体IFNAR1的FcγRIIB−/−YAA小鼠。与IRF5缺陷和IRF5杂合子FcγRIIB−/−YAA小鼠不同，IFNAR1缺陷的FcγRIIB−/−YAA小鼠保持了相当高的残留病水平。此外，在缺乏YAA的FcγRIIB−/−小鼠中，IRF5缺乏也显著减少了疾病表现，这表明IRF5缺乏对FcγRIIB−/−YaA小鼠的有益影响不仅仅是由于抑制了与YAA突变相关的增强的TLR7信号。总之，我们证明了IRF5在狼疮小鼠模型的发病机制中发挥了重要作用，并且这是通过产生I型干扰素以外的途径来调节的。
Polymorphisms in the transcription factor interferon 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 FcγRIIB−/−Yaa and FcγRIIB−/− lupus models. In contrast to IRF5-sufficient FcγRIIB−/−Yaa mice, IRF5-deficient FcγRIIB−/−Yaa mice do not develop lupus manifestations and have a phenotype comparable to wildtype 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 interferon IFN-α, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcγRIIB−/−Yaa mice lacking the type I interferon receptor IFNAR1. Unlike the IRF5-deficient and IRF5-heterozygous FcγRIIB−/−Yaa mice, IFNAR1-deficient FcγRIIB−/−Yaa mice maintained a substantial level of residual disease. Furthermore, in FcγRIIB−/− mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations indicating that the beneficial effects of IRF5 deficiency in FcγRIIB−/−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 interferon production.
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影响因子：
13.6
作者：
Bonegio, RGB;Fuhro, R;Lieberthal, W
通讯作者：
Lieberthal, W
影响因子：
32.4
作者：
Berland, Robert;Fernandez, Luis;Imanishi-Kari, Thereza
通讯作者：
Imanishi-Kari, Thereza
Toll样受体9控制鼠狼疮中的抗DNA自身抗体产生。
DOI：
10.1084/jem.20050338
发表时间：
2005-07-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Christensen SR;Kashgarian M;Alexopoulou L;Flavell RA;Akira S;Shlomchik MJ
通讯作者：
Shlomchik MJ
影响因子：
30.5
作者：
Fenner, JE;Starr, R;Hertzog, PJ
通讯作者：
Hertzog, PJ
影响因子：
4.8
作者：
Hu, Guodong;Barnes, Betsy J.
通讯作者：
Barnes, Betsy J.