Copenhagen Diabetes Research Center (DIRECT), Herlev University Hospital, Herlev Ringvej 75, 2730, Herlev, Denmark,
Diabetologia. 2013 Nov;56(11):2347-54. doi: 10.1007/s00125-013-3045-3. Epub 2013 Sep 19.
Type 1 diabetes is considered an autoimmune disease characterised by specific T cell-mediated destruction of the insulin-producing beta cells. Yet, except for insulin, no beta cell-specific antigens have been discovered. This may imply that the autoantigens in type 1 diabetes exist in modified forms capable of specifically triggering beta cell destruction. In other immune-mediated diseases, autoantigens targeted by the immune system have undergone post-translational modification (PTM), thereby creating tissue-specific neo-epitopes. In a similar manner, PTM of beta cell proteins might create beta cell-specific neo-epitopes. We suggest that the current paradigm of type 1 diabetes as a classical autoimmune disease should be reconsidered since the immune response may not be directed against native beta cell proteins. A modified model for the pathogenetic events taking place in islets leading to the T cell attack against beta cells is presented. In this model, PTM plays a prominent role in triggering beta cell destruction. We discuss literature of relevance and perform genetic and human islet gene expression analyses. Both direct and circumstantial support for the involvement of PTM in type 1 diabetes exists in the published literature. Furthermore, we report that cytokines change the expression levels of several genes encoding proteins involved in PTM processes in human islets, and that there are type 1 diabetes-associated polymorphisms in a number of these. In conclusion, data from the literature and presented experimental data support the notion that PTM of beta cell proteins may be involved in triggering beta cell destruction in type 1 diabetes. If the beta cell antigens recognised by the immune system foremost come from modified proteins rather than native ones, the concept of type 1 diabetes as a classical autoimmune disease is open for debate.
1 型糖尿病被认为是一种自身免疫性疾病，其特征是特定的 T 细胞介导的胰岛素产生细胞β的破坏。然而，除了胰岛素，没有发现β细胞特异性抗原。这可能意味着 1 型糖尿病中的自身抗原以能够特异性触发β细胞破坏的修饰形式存在。在其他免疫介导的疾病中，免疫系统靶向的自身抗原已经经历了翻译后修饰（PTM），从而产生组织特异性新表位。以类似的方式，β细胞蛋白的 PTM 可能会产生β细胞特异性新表位。我们建议重新考虑当前将 1 型糖尿病视为经典自身免疫性疾病的范例，因为免疫反应可能不是针对天然β细胞蛋白的。提出了一个关于发生在胰岛中的致病事件的改良模型，这些事件导致 T 细胞攻击β细胞。在该模型中，PTM 在外周血单核细胞（PBMC）和胰岛β细胞中发挥重要作用。我们讨论了相关文献，并进行了遗传和人胰岛基因表达分析。在已发表的文献中，既有直接证据也有间接证据支持 PTM 在 1 型糖尿病中的作用。此外，我们报告细胞因子改变了人胰岛中参与 PTM 过程的几种基因的表达水平，并且这些基因中有许多与 1 型糖尿病相关的多态性。总之，文献中的数据和提出的实验数据支持这样一种观点，即β细胞蛋白的 PTM 可能参与触发 1 型糖尿病中的β细胞破坏。如果免疫系统识别的β细胞抗原主要来自修饰蛋白而不是天然蛋白，那么 1 型糖尿病作为经典自身免疫性疾病的概念就值得商榷。
