Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery

Immunogenic cell stress and death

“…Whereas formal evidence in support of this notion is missing, it is interesting to note that bona fide autoimmunity as well as various other disorders involving some degree of autoreactivity (for example, some forms of cardiomyopathy, metabolic syndrome) 236 may not necessarily involve the loss of peripheral tolerance to purely 'self ' antigenic determinants. Rather, insults associated with disease pathogenesis (for example, oxidative stress, hyperglycemia) may promote the enzymatic or non-enzymatic alteration of endogenous proteins to generate bona fide post-translational neoantigens that are not covered by central tolerance 17 .…”

“…These observations point to ICD as a highly desirable event in the context of malignant and infectious disorders. However, accumulating evidence suggests that normal cells succumbing to specific insults may also elicit antigen-specific immune responses that contribute to disease etiology, pointing to a novel implication for ICD in (at least some) non-infectious, non-malignant disorders linked to autoreactivity 17 (Box 1).…”

Molecular Determinants Regulating the Plasticity of the MHC Class II Immunopeptidome

“…For example, in chronic metabolic conditions, such as type II diabetes, the number of MHC-II presented peptides derived from stress-related proteins, metabolic enzymes, and lipoproteins was found to be greatly enhanced ( 39 ). Among those, the increase in Apo-B epitope copy number contributed to tilting the immune response from tolerance to immunity with several autoreactive, anti-Apo-B T cells infiltrating the aorta and worsening the inflammatory process ( 39 ).The increase in Apo-B MHC-II presentation was not related to MHC-II plasma membrane upregulation because peptides were eluted from the same amounts of MHC-II molecules as quantified by ELISA ( 39 ).…”

Regulation of the BCR signalosome by the class II peptide editor, H2-M, affects the development and repertoire of innate-like B cells

“…To directly assess the effect of H2-M deficiency in murine B cells, we isolated total I-A b from H2-M À/À splenic B cells and analyzed bound peptides (Table S1). By comparison with published peptidomes from WT B6 mice (Clement et al, 2021;Nanaware et al, 2021), H2-M deficiency causes a shift in the distribution of predicted peptide-MHCII affinity to lower values (Figure 6D). As in previous studies (Alvaro-Benito et al, 2018;Nanaware et al, 2019), these affinity changes are not accompanied by alterations in the length distribution or intracellular sources of peptide cargo (Table S1).…”