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Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development.
Microorganisms ( IF 4.5 ) Pub Date : 2020-07-03 , DOI: 10.3390/microorganisms8070993
Samuel I Blum 1 , Hubert M Tse 1
Affiliation  

Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by immune-mediated destruction of insulin-producing β-cells. The concordance rate for T1D in monozygotic twins is ≈30–50%, indicating that environmental factors also play a role in T1D development. Previous studies have demonstrated that enterovirus infections such as coxsackievirus type B (CVB) are associated with triggering T1D. Prior to autoantibody development in T1D, viral RNA and antibodies against CVB can be detected within the blood, stool, and pancreata. An innate pathogen recognition receptor, melanoma differentiation-associated protein 5 (MDA5), which is encoded by the IFIH1 gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms in IFIH1 alter the structure and function of MDA5 that may lead to exacerbated antiviral responses contributing to increased T1D-susceptibility. Binding of viral dsRNA via MDA5 induces synthesis of antiviral proteins such as interferon-alpha and -beta (IFN-α/β). Viral infection and subsequent IFN-α/β synthesis can lead to ER stress within insulin-producing β-cells causing neo-epitope generation, activation of β-cell-specific autoreactive T cells, and β-cell destruction. Therefore, an interplay between genetics, enteroviral infections, and antiviral responses may be critical for T1D development.

中文翻译:

先天性病毒传感器MDA5与柯萨奇病毒在1型糖尿病发展中的相互作用。

1型糖尿病(T1D)是一种多基因自身免疫性疾病,其特征在于免疫介导的产生胰岛素的β细胞破坏。T1D在单卵双胞胎中的一致性率为≈30–50%,这表明环境因素也在T1D的发展中起作用。先前的研究表明,肠道病毒感染(例如柯萨奇B型病毒(CVB))与T1D触发有关。在T1D中开发自身抗体之前,可以在血液,粪便和胰腺中检测到病毒RNA和针对CVB的抗体。由IFIH1基因编码的先天病原体识别受体黑素瘤分化相关蛋白5(MDA5)与T1D发作有关。尚不清楚IFIH1中的单核苷酸多态性改变MDA5的结构和功能,可能导致抗病毒反应加剧,从而增加T1D敏感性。病毒dsRNA通过MDA5的结合诱导了抗病毒蛋白的合成,例如干扰素-α和-β(IFN-α/β)。病毒感染和随后的IFN-α/β合成可导致产生胰岛素的β细胞内产生内质网应激,从而导致新表位的产生,β细胞特异性自身反应性T细胞的活化以及β细胞的破坏。因此,遗传学,肠病毒感染和抗病毒反应之间的相互作用可能对T1D的发展至关重要。
更新日期:2020-07-03
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