Blum Samuel I, Tse Hubert M
Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Microorganisms. 2020 Jul 3;8(7):993. doi: 10.3390/microorganisms8070993.
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 gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms in 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.
1型糖尿病（T1D）是一种多基因自身免疫性疾病，其特征是免疫介导的胰岛素生成β细胞破坏。单卵双胞胎中T1D的一致性率约为30%-50%，这表明环境因素在T1D的发生发展中也起作用。先前的研究表明，肠道病毒感染，如B型柯萨奇病毒（CVB），与引发T1D有关。在T1D自身抗体产生之前，可在血液、粪便和胰腺中检测到病毒RNA和抗CVB抗体。一种由该基因编码的天然病原体识别受体，黑色素瘤分化相关蛋白5（MDA5），已与T1D发病相关。目前尚不清楚该基因中的单核苷酸多态性如何改变MDA5的结构和功能，这可能导致抗病毒反应加剧，从而增加T1D易感性。通过MDA5结合病毒双链RNA可诱导抗病毒蛋白如α和β干扰素（IFN-α/β）的合成。病毒感染及随后的IFN-α/β合成可导致胰岛素生成β细胞内的内质网应激，从而导致新表位产生、β细胞特异性自身反应性T细胞活化及β细胞破坏。因此，遗传因素、肠道病毒感染和抗病毒反应之间的相互作用可能对T1D的发生发展至关重要。
