Understanding HLA risk in immune-mediated inflammatory diseases requires antigen discovery.

Certain human leukocyte antigen (HLA) alleles occur more often in people with immune-mediated inflammatory diseases (IMIDs) than in unaffected individuals, making HLA one of the strongest inherited contributors to IMID risk. Yet how these alleles promote disease remains unclear. We argue that HLA risk has often been studied through allele-level properties or immunopeptidomic profiles without knowing which antigenic exposures matter. These approaches characterize peptide binding and presentation but rarely identify disease-relevant exposures. We propose that large-scale T cell receptor repertoire analysis provides a complementary route by identifying disease-associated clonotypes as antigenic footprints. When interpreted in their HLA context, these antigenic footprints can focus immunopeptidomic and functional studies on candidate antigens, turning HLA associations from statistical signals into testable mechanisms of disease.