Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.
Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
Immunity. 2021 Apr 13;54(4):721-736.e10. doi: 10.1016/j.immuni.2021.02.019. Epub 2021 Mar 15.
Hyperglycemia and hyperlipidemia are often observed in individuals with type II diabetes (T2D) and related mouse models. One dysmetabolic biochemical consequence is the non-enzymatic reaction between sugars, lipids, and proteins, favoring protein glycation, glycoxidation, and lipoxidation. Here, we identified oxidative alterations in key components of the major histocompatibility complex (MHC) class II molecule antigen processing and presentation machinery in vivo under conditions of hyperglycemia-induced metabolic stress. These modifications were linked to epitope-specific changes in endosomal processing efficiency, MHC class II-peptide binding, and DM editing activity. Moreover, we observed some quantitative and qualitative changes in the MHC class II immunopeptidome of Ob/Ob mice on a high-fat diet compared with controls, including changes in the presentation of an apolipoprotein B100 peptide associated previously with T2D and metabolic syndrome-related clinical complications. These findings highlight a link between glycation reactions and altered MHC class II antigen presentation that may contribute to T2D complications.
高血糖和高血脂在 II 型糖尿病（T2D）患者和相关的小鼠模型中经常观察到。一种代谢失调的生化后果是糖、脂和蛋白质之间的非酶反应，有利于蛋白质糖化、糖基化和脂基化。在这里，我们在高血糖诱导的代谢应激条件下，体内鉴定了主要组织相容性复合体（MHC）II 类分子抗原加工和呈递机制关键成分的氧化改变。这些修饰与内体加工效率、MHC II 类肽结合和 DM 编辑活性的表位特异性变化有关。此外，我们观察到高脂饮食的 Ob/Ob 小鼠 MHC II 免疫肽组与对照组相比发生了一些定量和定性的变化，包括与 T2D 和代谢综合征相关临床并发症相关的载脂蛋白 B100 肽的呈现发生了变化。这些发现强调了糖化反应与改变的 MHC II 类抗原呈递之间的联系，这可能导致 T2D 并发症。
