Beyond Sequence: Posttranslational Remodeling of Antigens in Autoimmunity
Autoimmune responses are often attributed to failed tolerance to self‐proteins, yet protein expression alone cannot explain why certain antigens dominate disease, why autoreactivity emerges under stress, or why specific HLA alleles shape risk. This review presents a framework in which autoimmunity arises from posttranslational remodeling of antigen identity. Rather than limiting PTMs to side chain chemistry, we consider how covalent modifications, altered processing, aberrant translation, peptide recombination, and supramolecular assembly expand the repertoire of molecular forms available for immune recognition. Classical PTMs such as citrullination, deamidation, oxidation, glycosylation, phosphorylation, sulfation, and ubiquitin‐like remnants can modify proteolysis, HLA binding, and antibody recognition. Noncanonical pathways, including signal peptide processing, ERAP‐dependent trimming, defective ribosomal products, cryptic ORFs, proteasome‐catalyzed splicing, and hybrid insulin peptides, further demonstrate that the presented antigenome extends beyond annotated proteins. We also propose that aggregation functions as a supramolecular antigenic modification by altering uptake, persistence, protease accessibility, and local reaction chemistry. Examples from rheumatoid arthritis, celiac disease, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and autoimmune thyroid disease illustrate how these mechanisms converge. Finally, we discuss mass spectrometry and immunopeptidomics strategies for identifying, validating, and functionally interpreting remodeled antigens in autoimmune disease.