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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. [Display omitted] • Oxidative post-translational modifications (PTMs) are observed in T2D subjects • PTMs were mapped to the MHC class II antigen processing and presentation machinery • PTMs affected epitope-specific antigen processing and MHC class II presentation • Increased presentation of an APO-B peptide associated with clinical complications of T2D Hyperglycemia and hyperlipidemia during diabetes and metabolic syndrome induce protein oxidative post-translational modifications (PTMs) that affect the MHC class II processing and presentation machinery. Clement et al. reveal that these PTMs are linked to epitope-specific changes in the MHC class II peptidome, with increased presentation of an apolipoprotein B100 peptide, contributing to diabetes-related complications. [ABSTRACT FROM AUTHOR]