Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Diabetes. 2019 May;68(5):879-886. doi: 10.2337/dbi18-0066.
Type 1 diabetes (T1D) is an autoimmune disease that is caused, in part, by T cell-mediated destruction of insulin-producing β-cells. High risk for disease, in those with genetic susceptibility, is predicted by the presence of two or more autoantibodies against insulin, the 65-kDa form of glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2 (IA-2), and zinc transporter 8 (ZnT8). Despite this knowledge, we still do not know what leads to the breakdown of tolerance to these autoantigens, and we have an incomplete understanding of T1D etiology and pathophysiology. Several new autoantibodies have recently been discovered using innovative technologies, but neither their potential utility in monitoring disease development and treatment nor their role in the pathophysiology and etiology of T1D has been explored. Moreover, neoantigen generation (through posttranslational modification, the formation of hybrid peptides containing two distinct regions of an antigen or antigens, alternative open reading frame usage, and translation of RNA splicing variants) has been reported, and autoreactive T cells that target these neoantigens have been identified. Collectively, these new studies provide a conceptual framework to understand the breakdown of self-tolerance, if such modifications occur in a tissue- or disease-specific context. A recent workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together investigators who are using new methods and technologies to identify autoantigens and characterize immune responses toward these proteins. Researchers with diverse expertise shared ideas and identified resources to accelerate antigen discovery and the detection of autoimmune responses in T1D. The application of this knowledge will direct strategies for the identification of improved biomarkers for disease progression and treatment response monitoring and, ultimately, will form the foundation for novel antigen-specific therapeutics. This Perspective highlights the key issues that were addressed at the workshop and identifies areas for future investigation.
1 型糖尿病（T1D）是一种自身免疫性疾病，部分由 T 细胞介导的胰岛素产生β细胞破坏引起。在具有遗传易感性的人群中，疾病的高风险由针对胰岛素、谷氨酸脱羧酶 65kDa 形式（GAD65）、胰岛瘤相关蛋白 2（IA-2）和锌转运蛋白 8（ZnT8）的两种或更多种自身抗体的存在来预测。尽管有这些知识，但我们仍不知道是什么导致了对这些自身抗原的耐受性丧失，我们对 T1D 的病因和发病机制也了解得并不完整。最近使用创新技术发现了几种新的自身抗体，但它们在监测疾病发展和治疗方面的潜在用途及其在 T1D 的病理生理学和病因学中的作用尚未得到探索。此外，已经报道了新抗原的产生（通过翻译后修饰、包含抗原或抗原的两个不同区域的杂交肽的形成、替代开放阅读框的使用以及 RNA 剪接变体的翻译），并且已经鉴定了针对这些新抗原的自身反应性 T 细胞。总之，这些新的研究为理解自身耐受性的破坏提供了一个概念框架，如果这些修饰发生在组织或疾病特异性背景下。最近由美国国立糖尿病、消化和肾脏疾病研究所（National Institute of Diabetes and Digestive and Kidney Diseases）主办的一个研讨会汇集了使用新方法和技术来鉴定自身抗原并描述针对这些蛋白质的免疫反应的研究人员。具有不同专业知识的研究人员分享了想法，并确定了资源，以加速抗原发现和 T1D 自身免疫反应的检测。对这些知识的应用将指导用于识别改善的疾病进展和治疗反应监测的生物标志物的策略，最终将为新型抗原特异性治疗奠定基础。本观点突出了研讨会讨论的关键问题，并确定了未来研究的领域。
