Graham Kate L, Sutherland Robyn M, Mannering Stuart I, Zhao Yuxing, Chee Jonathan, Krishnamurthy Balasubramanian, Thomas Helen E, Lew Andrew M, Kay Thomas W H
St. Vincent´s Institute of Medical Research, Fitzroy, Victoria, Australia.
Rev Diabet Stud. 2012 Winter;9(4):148-68. doi: 10.1900/RDS.2012.9.148. Epub 2012 Dec 28.
Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4⁺ T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8⁺ T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms.
我们对1型糖尿病发病机制的理解在疾病的各个阶段都有了新进展。本综述概述了免疫系统用于介导胰腺β细胞破坏的致病机制。针对β细胞的自身免疫反应似乎始于胰腺淋巴结，在那里，逃避了胸腺阴性选择的T细胞首次接触由树突状细胞呈递的β细胞抗原。胰岛素原是早期糖尿病中的一种重要抗原。T细胞通过循环迁移至胰岛，并最初在胰岛周围形成胰岛炎。胰岛炎中的T细胞对胰岛抗原具有特异性，而非旁观者细胞。致病性CD4⁺ T细胞可能识别胰岛内局部产生的胰岛素原肽段。CD8⁺ T细胞在胰岛中分化为效应T细胞，然后主要通过穿孔素-颗粒酶途径杀死β细胞。细胞因子在体内似乎并非重要的细胞毒性分子。现在已知胰岛内免疫反应的成熟会导致糖尿病，这突出了胰岛既是疾病的驱动因素又是疾病的靶点。我们对这些致病过程的大部分认识来自非肥胖糖尿病（NOD）小鼠模型，尽管有些过程在人类疾病中也有体现。然而，需要开展更多工作，将来自NOD小鼠的数据转化为我们对人类糖尿病发病机制的理解。新技术，尤其是MHC四聚体和现代成像技术，将增进我们对致病机制的理解。
