Using immunopeptidomics and spatial genomics to determine the autoantigen, presenting cells and responding CD8 T cells in ankylosing spondylitis

Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting patients globally with limited and often costly treatment options. Diagnostic delay and higher disease activity are also correlated with poor mental health, especially in young, female and lower-income patients. The strong association of the MHC-class I gene HLA-B27 with AS has led to the arthritogenic peptide hypothesis of disease, where self-peptide presented by HLA-B27 is recognised as foreign by CD8 T cells, thus leading to autoimmunity. My proposal leverages the latest advancements in immunopeptidomics to identify peptides presented by HLA-B27 in AS joint tissue, and establishes which of those peptides are immunogenic in patients. Spatial and droplet-based single-cell sequencing are then used to co-locate and phenotype both cells presenting immunogenic peptides, and their cognate pathogenic T cells. This research could lead to a completely new category of targeted (potentially tolerogenic) therapies and diagnostic tools being developed for AS that require knowledge of AS autoantigen. By also focusing on cells directly participating in the autoimmune response I may further identify druggable targets that would be highly selective for those cells and minimise potential side effects.