Autoimmune associated HLAs and T cell autoantigens exhibit common patterns across several autoimmune diseases

Approximately 80 autoimmune diseases have been identified, with only a few proteins targeted by the immune system in each disease. The rest of the human proteome remains unaffected, indicating that the selection of these specific proteins is not random. Most autoimmune diseases show strong genetic associations with HLA alleles, suggesting a critical role for antigen presentation in autoimmunity. In this study, we analyzed validated T cell epitopes and their associated HLAs from 21 autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus, using experimental data from the IEDB. We compared autoantigens to proteins not implicated in autoimmunity, investigated HLA binding motifs, and contrasted autoimmunogenic T cell epitopes with non-autoimmune T cell epitopes. Autoantigens, compared to other non-autoimmunogenic proteins, exhibited higher mRNA expression, greater abundance in disease-specific tissues, and were frequently found in exposed subcellular locations such as membranes and extracellular spaces. Disease-associated HLAs showed distinct binding motifs compared to other HLAs, but the autoimmunogenic epitopes themselves did not differ markedly from other T cell epitopes. Autoantigens were enriched on MHC class II presented peptides, and the self-peptides differed from those seen in non-autoimmune contexts. Our findings suggest that the interplay between specific HLA class II alleles and specific antigen features play a pivotal role in initiating autoimmune responses, while subsequent T cell activation likely follows typical immune mechanisms.