Antigen-processing rewiring expose cryptic self promoting organ-specific autoimmunity

Autoimmune disease is traditionally attributed to failure of immune tolerance toward normally presented self-antigens. Although strong HLA associations implicate antigen presentation in disease risk, whether altered antigen processing contributes directly to autoimmunity remains unclear. To address this question, we analysed experimentally verified human T-cell autoantigens across twenty autoimmune diseases and classified them according to their natural presentation on HLA-DR in healthy individuals as either tolerant (detectably presented on MHC) or cryptic (not detectably presented). These classes exhibited distinct molecular and clinical associations: cryptic autoantigens were enriched in membrane proteins with tissue-specific functions and were predominantly linked to organ-specific autoimmune diseases, whereas tolerant autoantigens were largely extracellular, enriched in immune-related functions, and associated with systemic autoimmunity. Analysis of immunopeptidomics datasets from rheumatoid arthritis and multiple sclerosis further revealed disease-associated shifts in peptide flanking residues and increased relative solvent accessibility compared with healthy donors, consistent with altered proteolytic processing. Cryptic proteins were markedly overrepresented among multiple sclerosis-derived ligands. Together, these findings define two mechanistically distinct routes to autoimmune activation: one driven by altered antigen processing that exposes previously unseen self-proteins, and another driven by breakdown of tolerance toward normally presented self-antigens. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/693959v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@9249f5org.highwire.dtl.DTLVardef@35a55borg.highwire.dtl.DTLVardef@1fb0beforg.highwire.dtl.DTLVardef@cc97b3_HPS_FORMAT_FIGEXP M_FIG C_FIG