Evidence of altered antigen processing in autoimmune disease revealed by comparative immunopeptidomics

BackgroundT cell-mediated autoimmunity arises when autoreactive T cells recognise self-peptides presented on MHC class II molecules and get activated. Although HLA associations strongly link antigen presentation to autoimmune risk, it remains unclear whether altered antigen processing itself contributes to disease. MethodsWe compiled a curated catalogue of experimentally verified human T-cell autoantigens and classified their source proteins based on their natural presentation on HLA-DR in healthy individuals. If the protein has peptides presented it is classified as tolerant, and if there are no peptides presented it is classified as cryptic. Protein features, subcellular localizations, and biological functions were compared between groups. To evaluate disease-specific presentation, we analyzed immunopeptidomics datasets from patients with rheumatoid arthritis and multiple sclerosis and compared their peptide repertoires, flanking residues, and structural properties with those from healthy donors. FindingsThe cryptic and tolerant autoantigen classes revealed distinct molecular and disease-related characteristics, including differences in subcellular localization, biological function, and association with organ-specific or systemic autoimmunity. Cryptic autoantigens are enriched in the membrane, have functions related to the targeted tissue, and are primarily associated with organ-specific diseases. Tolerant autoantigens are found extracellularly, have functions connected with the immune system and are enriched in systemic autoimmunities. In rheumatoid arthritis and multiple sclerosis, MHC-presented peptides displayed altered terminal amino-acid preferences in the peptide flanking regions, and higher relative surface accessibility compared with their healthy donors MHC-presented peptide counterparts, consistent with modified proteolytic processing. Cryptic proteins were substantially overrepresented among MS-derived ligands, suggesting increased antigen-processing dysregulation in organ-specific autoimmunity. InterpretationWe propose that there exist two different autoimmune activation mechanisms. In the first mechanism cryptic proteins are revealed due to aberrant antigen processing resulting in autoimmune responses. In the second mechanism, peripheral tolerance breaks down, driving autoimmune responses toward normally presented self-proteins. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/693959v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1b037d0org.highwire.dtl.DTLVardef@206bd1org.highwire.dtl.DTLVardef@868a4eorg.highwire.dtl.DTLVardef@e245ba_HPS_FORMAT_FIGEXP M_FIG C_FIG