Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan; Department of Dermatology, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan.
Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan; Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan; PRESTO, Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
Immunity. 2014 Feb 20;40(2):199-212. doi: 10.1016/j.immuni.2013.12.014. Epub 2014 Feb 13.
MDA5 is an essential intracellular sensor for several viruses, including picornaviruses, and elicits antiviral interferon (IFN) responses by recognizing viral dsRNAs. MDA5 has been implicated in autoimmunity. However, the mechanisms of how MDA5 contributes to autoimmunity remain unclear. Here we provide direct evidence that dysregulation of MDA5 caused autoimmune disorders. We established a mutant mouse line bearing MDA5 mutation by ENU mutagenesis, which spontaneously developed lupus-like autoimmune symptoms without viral infection. Inflammation was dependent on an adaptor molecule, MAVS indicating the importance of MDA5-signaling. In addition, intercrossing the mutant mice with type I IFN receptor-deficient mice ameliorated clinical manifestations. This MDA5 mutant could activate signaling in the absence of its ligand but was paradoxically defective for ligand- and virus-induced signaling, suggesting that the mutation induces a conformational change in MDA5. These findings provide insight into the association between disorders of the innate immune system and autoimmunity.
MDA5 是几种病毒（包括小核糖核酸病毒）的重要细胞内传感器，通过识别病毒 dsRNA 引发抗病毒干扰素（IFN）反应。MDA5 与自身免疫有关。然而，MDA5 如何导致自身免疫的机制尚不清楚。在这里，我们提供了直接证据，表明 MDA5 的失调导致自身免疫性疾病。我们通过ENU 诱变建立了一个携带 MDA5 突变的突变小鼠系，该突变小鼠在没有病毒感染的情况下自发地发展出狼疮样自身免疫症状。炎症依赖于衔接分子 MAVS，这表明 MDA5 信号的重要性。此外，将突变小鼠与 I 型 IFN 受体缺陷型小鼠杂交可改善临床症状。这种 MDA5 突变体可以在没有配体的情况下激活信号，但对配体和病毒诱导的信号却是有缺陷的，这表明这种突变诱导了 MDA5 的构象变化。这些发现为先天免疫系统疾病与自身免疫之间的关联提供了深入的了解。
