The β-cell plays a crucial role in the pathogenesis of type 1 diabetes, in part through the posttranslational modification of self-proteins by biochemical processes such as deamidation. These neoantigens are potential triggers for breaking immune tolerance. We report the detection by LC-MS/MS of 16 novel Gln and 27 novel Asn deamidations in 14 disease-related proteins within inflammatory cytokine-stressed human islets of Langerhans. T-cell clones responsive against one Gln and three Asn deamidated peptides could be isolated from peripheral blood of individuals with type 1 diabetes. Ex vivo HLA class II tetramer staining detected higher T-cell frequencies in individuals with the disease compared to control individuals. Furthermore, there was a positive correlation between the frequencies of T cells specific for deamidated peptides, insulin antibody levels at diagnosis, and duration of disease. These results highlight that stressed human islets are prone to enzymatic and biochemical deamidation and suggest that both Gln and Asn deamidated peptides can promote the activation and expansion of autoreactive CD4+ T cells. These findings add to the growing evidence that post-translational modifications undermine tolerance and may open the road for the development of new diagnostic and therapeutic applications for individuals living with type 1 diabetes.

中文翻译：

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1 型糖尿病患者的 CD4+ T 细胞对胰岛中形成的一类新型脱酰胺肽有反应

β细胞在 1 型糖尿病的发病机制中发挥着至关重要的作用，部分是通过脱酰胺等生化过程对自身蛋白进行翻译后修饰。这些新抗原是破坏免疫耐受的潜在触发因素。我们报告了通过 LC-MS/MS 在炎症细胞因子应激的人类朗格汉斯胰岛中的 14 种疾病相关蛋白中检测到 16 个新型 Gln 和 27 个新型 Asn 脱酰胺。可以从 1 型糖尿病患者的外周血中分离出对一种 Gln 和三种 Asn 脱酰胺肽有反应的 T 细胞克隆。与对照个体相比，离体 HLA II 类四聚体染色检测到患有该疾病的个体具有更高的 T 细胞频率。此外，脱酰胺肽特异性 T 细胞的频率、诊断时的胰岛素抗体水平和疾病持续时间之间存在正相关。这些结果强调，受压力的人类胰岛容易发生酶促和生化脱酰胺，并表明 Gln 和 Asn 脱酰胺肽都可以促进自身反应性 CD4+ T 细胞的激活和扩增。这些发现进一步证明翻译后修饰会破坏耐受性，并可能为 1 型糖尿病患者开发新的诊断和治疗应用开辟道路。