Intracellular virus sensor MDA5 mutation develops autoimmune myocarditis and nephritis
Intracellular virus sensor MDA5 mutation develops autoimmune myocarditis and nephritis
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DOI：
10.1016/j.jaut.2022.102794
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发表时间：
2022-02-12
影响因子：
12.8
通讯作者：
Kato, Hiroki
中科院分区：
文献类型：
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作者：
Ohto, Taisuke;Abu Tayeh, Ahmed;Kato, Hiroki
编码病毒RNA传感器MDA 5的IFIH 1基因的突变已被报道是许多干扰素病的原因，包括Aicardi-Goutieres综合征（AGS）和单基因狼疮，然而，IFIH 1突变与各种自身免疫性症状之间的病理联系仍不清楚。在这里，我们产生了表达人MDA 5 R779 H突变体（R779 H Tg）的转基因小鼠，在AGS和单基因狼疮患者中报道。小鼠自发地发生心肌炎和肾炎，主要器官中I型IFN上调。R779 H Tg Mavs（-/-）和R779 H Tg Ifnar（-/-）未显示表型，表明直接参与MDA 5信号通路。Rag-2缺陷和骨髓细胞从野生型转移到成年小鼠并不能阻止心肌炎的发展，而心肌细胞特异性表达hMDA 5 R779 H的小鼠表现出心脏肥大和炎性细胞因子的高表达。综上所述，我们的研究阐明了I型干扰素和趋化因子从心肌细胞开始在新生儿期，是心肌炎的发展至关重要。活化的淋巴细胞和自身抗体加剧了发病机制，但对发病有利。
Mutations in IFIH1 gene encoding viral RNA sensor MDA5 have been reported responsible for many interferonopathies, including Aicardi-Goutieres syndrome (AGS) and monogenic lupus, however, the pathological link between IFIH1 mutations and various autoimmune symptoms remains unclear. Here, we generated transgenic mice expressing human MDA5 R779H mutant (R779H Tg), reported in AGS and monogenic lupus patient. Mice spontaneously developed myocarditis and nephritis with upregulation of type I IFNs in the major organs. R779H Tg Mavs(-/-) and R779H Tg Ifnar(-/-) showed no phenotypes, indicating direct MDA5-signaling pathway involvement. Rag-2 deficiency and bone marrow cells transfer from wild type to adult mice did not prevent myocarditis development, while mice with cardiomyocyte-specific expression of hMDA5 R779H showed cardiomegaly and high expression of inflammatory cytokines. Taken together, our study clarifies that type I IFNs production and chemokines from cardiomyocytes starts in neonatal period and is critical for the development of myocarditis. Activated lymphocytes and auto-antibodies exacerbate the pathogenesis but are dispensable for the onset.