An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets
An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets
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DOI：
10.1038/srep39378
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发表时间：
2016-12-21
影响因子：
4.6
通讯作者：
Flodstrom-Tullberg, Malin
中科院分区：
文献类型：
--
作者：
Domsgen, Erna;Lind, Katharina;Flodstrom-Tullberg, Malin
IFIH 1基因编码模式识别受体MDA 5。IFIH 1（rs 1990760，A946 T）的一种常见多态性增加了自身免疫性疾病的风险，包括1型糖尿病（T1 D）。柯萨奇病毒感染与T1 D有关，并在体外引起β细胞损伤。在这里，我们证明了rs 1990760多态性调节干扰素（IFN）的签名表达的人胰岛柯萨奇病毒感染。一个强的IFN信号与IFN λ 1和IFN λ 2的高表达相关，将rs 1990760与III型IFN的表达联系起来。在高反应基因型中，IRF-1的表达与III型IFN的表达相关，提示III型IFN转录的正反馈。总之，我们的研究揭示了rs 1990760对响应于用与人T1 D相关的临床相关病毒急性感染原代人实质细胞的MDA 5的典型效应子功能的影响。它还强调了rs 1990760多态性和III型IFN的表达水平之间以前未被认识到的联系。
The IFIH1 gene encodes the pattern recognition receptor MDA5. A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro. Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection. A strong IFN signature was associated with high expression of IFN lambda 1 and IFN lambda 2, linking rs1990760 to the expression of type III IFNs. In the highresponding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positivefeedback on type III IFN transcription. In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D. It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs.