Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia.
Immunol Cell Biol. 2021 May;99(5):448-460. doi: 10.1111/imcb.12442. Epub 2021 Feb 22.
One hundred years ago, Frederick Banting, John Macleod, Charles Best and James Collip, and their collaborators, discovered insulin. This discovery paved the way to saving countless lives and ushered in the "Insulin Era." Since the discovery of insulin, we have made enormous strides in understanding its role in metabolism and diabetes. Insulin has played a dramatic role in the treatment of people with diabetes; particularly type 1 diabetes (T1D). Insulin replacement is a life-saving therapy for people with T1D and some with type 2 diabetes. T1D is an autoimmune disease caused by the T-cell-mediated destruction of the pancreatic insulin-producing beta cells that leads to a primary insulin deficiency. It has become increasingly clear that insulin, and its precursors preproinsulin (PPI) and proinsulin (PI), can play another role-not as a hormone but as an autoantigen in T1D. Here we review the role played by the products of the INS gene as autoantigens in people with T1D. From many elegant animal studies, it is clear that T-cell responses to insulin, PPI and PI are essential for T1D to develop. Here we review the evidence that autoimmune responses to insulin and PPI arise in people with T1D and discuss the recently described neoepitopes derived from the products of the insulin gene. Finally, we look forward to new approaches to deliver epitopes derived from PPI, PI and insulin that may allow immune tolerance to pancreatic beta cells to be restored in people with, or at risk of, T1D.
一百年前，弗雷德里克·班廷、约翰·麦克劳德、查尔斯·贝斯特和詹姆斯·科利尔以及他们的合作者发现了胰岛素。这一发现为拯救无数生命铺平了道路，开创了“胰岛素时代”。自胰岛素发现以来，我们在理解其在代谢和糖尿病中的作用方面取得了巨大进展。胰岛素在糖尿病患者的治疗中发挥了巨大作用；特别是 1 型糖尿病（T1D）。胰岛素替代疗法是 T1D 患者和一些 2 型糖尿病患者的救命疗法。T1D 是一种自身免疫性疾病，由 T 细胞介导的胰腺胰岛素产生β细胞破坏引起，导致原发性胰岛素缺乏。越来越明显的是，胰岛素及其前体前胰岛素原（PPI）和胰岛素原（PI）可以发挥另一种作用——不是作为激素，而是作为 T1D 的自身抗原。在这里，我们回顾了 INS 基因产物作为 T1D 患者自身抗原所起的作用。从许多优雅的动物研究中可以清楚地看出，T 细胞对胰岛素、PPI 和 PI 的反应对于 T1D 的发展是必不可少的。在这里，我们回顾了 T1D 患者中存在针对胰岛素和 PPI 的自身免疫反应的证据，并讨论了最近描述的源自胰岛素基因产物的新表位。最后，我们期待能够提供源自 PPI、PI 和胰岛素的表位，这些表位可能使 T1D 患者或有患 T1D 风险的人恢复对胰腺β细胞的免疫耐受。
