Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Curr Opin Endocrinol Diabetes Obes. 2013 Aug;20(4):299-306. doi: 10.1097/MED.0b013e3283631417.
Description on post-translational modification of islet-autoantigens in type 1 diabetes (T1D).
T1D is an autoimmune disease characterized by progressive destruction of the insulin-producing beta-cells. It is a complex disease process that results from the loss of tolerance to beta-cell autoantigens. This loss of tolerance can be caused by modification of beta-cell autoantigens, generating 'neo-autoantigens', and inducing T-cell responses. Post-translational modifications (PTMs) within the endoplasmic reticulum of stressed beta-cells might impact on the autoantigen T-cell epitope repertoire and on T1D pathogenesis progression. This review summarizes the processes involved in beta-cell stress and PTM of beta-cell autoantigens in T1D.
PTMs of beta-cell autoantigens provide a novel hypothesis to understand how autoreactive T-cells can escape immune tolerance and cause destruction of beta-cells ('beta-cell homicide'). Additionally, aberrant proteins produced by stressed beta-cells can cause their own destruction ('beta-cell suicide'). Upon endoplasmic reticulum-stress, proteins are misfolded or modified changing the protein structure. In T1D, this may generate new beta-cell (neo)autoantigens. PTM of islet-autoantigens provides a mechanism by which pathogenic T-cells can escape thymic deletion. This amplifies the immune response when encountering a modified beta-cell neo-autoantigen bound to T1D predisposing human leucocyte antigen molecules in the periphery.
1 型糖尿病（T1D）中胰岛自身抗原的翻译后修饰。
T1D 是一种自身免疫性疾病，其特征是胰岛素产生的β细胞进行性破坏。这是一个复杂的疾病过程，是由于对β细胞自身抗原的耐受性丧失引起的。这种耐受性丧失可能是由于β细胞自身抗原的修饰，产生“新自身抗原”，并诱导 T 细胞反应。内质网中应激β细胞内的翻译后修饰（PTM）可能影响自身抗原 T 细胞表位库和 T1D 发病机制的进展。本综述总结了 T1D 中β细胞应激和β细胞自身抗原 PTM 涉及的过程。
β细胞自身抗原的 PTM 为理解自身反应性 T 细胞如何逃避免疫耐受并导致β细胞破坏（“β细胞谋杀”）提供了一个新的假说。此外，应激β细胞产生的异常蛋白可导致自身破坏（“β细胞自杀”）。在内质网应激时，蛋白质错误折叠或修饰改变了蛋白质结构。在 T1D 中，这可能会产生新的β细胞（新）自身抗原。胰岛自身抗原的 PTM 提供了一种机制，通过该机制，致病性 T 细胞可以逃避胸腺删除。当在外周遇到与 T1D 易感性人类白细胞抗原分子结合的修饰的β细胞新自身抗原时，这种机制会放大免疫反应。
