Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA
Diabetes Research Center, Department of Medicine, Baylor College of Medicine, Houston, TX.
Diabetes. 2018 Jun;67(6):1035-1042. doi: 10.2337/dbi17-0030.
Prior to the onset of type 1 diabetes, there is progressive loss of immune self-tolerance, evidenced by the accumulation of islet autoantibodies and emergence of autoreactive T cells. Continued autoimmune activity leads to the destruction of pancreatic β-cells and loss of insulin secretion. Studies of samples from patients with type 1 diabetes and of murine disease models have generated important insights about genetic and environmental factors that contribute to susceptibility and immune pathways that are important for pathogenesis. However, important unanswered questions remain regarding the events that surround the initial loss of tolerance and subsequent failure of regulatory mechanisms to arrest autoimmunity and preserve functional β-cells. In this Perspective, we discuss various processes that lead to the generation of neoepitopes in pancreatic β-cells, their recognition by autoreactive T cells and antibodies, and potential roles for such responses in the pathology of disease. Emerging evidence supports the relevance of neoepitopes generated through processes that are mechanistically linked with β-cell stress. Together, these observations support a paradigm in which neoepitope generation leads to the activation of pathogenic immune cells that initiate a feed-forward loop that can amplify the antigenic repertoire toward pancreatic β-cell proteins.
在 1 型糖尿病发病之前，存在免疫自身耐受的进行性丧失，这表现在胰岛自身抗体的积累和自身反应性 T 细胞的出现。持续的自身免疫活性导致胰腺β细胞的破坏和胰岛素分泌的丧失。对 1 型糖尿病患者样本和鼠类疾病模型的研究为导致易感性的遗传和环境因素以及对发病机制重要的免疫途径提供了重要的见解。然而，关于围绕初始耐受丧失和随后调节机制失效以阻止自身免疫和保留功能性β细胞的事件，仍存在重要的未解决问题。在本观点中，我们讨论了导致胰腺β细胞中产生新抗原的各种过程，以及它们被自身反应性 T 细胞和抗体识别的情况，以及这些反应在疾病发病机制中的潜在作用。新出现的证据支持通过与β细胞应激在机制上相关的过程产生新表位的相关性。这些观察结果共同支持了这样一种范例，即新表位的产生导致致病性免疫细胞的激活，从而引发一个正反馈回路，可以放大针对胰腺β细胞蛋白的抗原库。
