Can single nucleotide variations in human endogenous retroviral sequences affect peptide presentation by HLA-B27: implications for viral mimicry and ankylosing spondylitis? 3534

Abstract Description The etiology of ankylosing spondylitis (AS), an autoimmune condition with a significant association with the HLA-B27 genotype, remains incompletely understood. We investigated a novel mechanism involving single nucleotide variations (SNVs) within human endogenous retroviral (HERV) gene sequences in the HLA-B27 genomic region and their potential impact on AS pathogenesis. Specifically, we explored how an SNV (rs13202464) alters the binding affinity of the HLA-B27 molecule to self and microbial peptides. Our study hypothesizes that this SNV-induced missense mutation (methionine to threonine) may lead to differential T cell selection during immune development, where HSV peptides that mimic self-proteins are insufficiently tolerated. We compared predicted peptide binding to HLA-B27 using predictive modeling utilizing the Immune Epitope Database suite, demonstrating decrease in binding affinity for peptides in HLA-B27-positive individuals carrying the variant by a ten-fold increase in the predicted ANN IC50 values. This potentially could initiate AS pathogenesis, through either altered thymic selection or triggering molecular mimicry through sequence similarity between HSV- and HERV-derived peptides. Our findings underscore the need for further investigation into the interplay between HERV sequences, viral mimicry, and immune tolerance to identify novel therapeutic strategies targeting AS at its genetic and immunological roots. Funding Sources Supported by a MSTP grant from the NIH T32GM152349 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program; F30 Predoctoral Fellowship from the NCI 5F30CA278653-02 Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)