Psoriasis is a debilitating, T cell-mediated autoimmune skin disease with 2-3% of the population affected worldwide; no curative treatment is currently available. One of the best defined and the major risk-associated psoriasis susceptibility gene encodes for the human leukocyte antigen HLA-C*06:02 (HLA-Cw6). In spite of the well-established link between HLA-Cw6 and psoriasis, it is unclear which of the peptides presented by HLA-Cw6 trigger a psoriatic response. Some candidate peptides have been suggested, such as skin antigens and Streptococcus pyogenes antigens, but only a small proportion of patients test positive for T cell responses against any of the previously published trigger peptides. This implies that other peptides may form more dominant targets of autoreactive T cells in psoriasis.
We have used an immunopeptidomics workflow employing immunoaffinity purification, liquid chromatography and mass spectrometry to identify and characterise antigens displayed on HLA-Cw6. Previously, we have established the peptide motif presented by HLA-Cw6. New data generated from skin-derived HLA-Cw6+ cell lines and a novel HLA-Cw6Tg mouse model in conjunction with the imiquimod-induced mouse model of psoriasis has identified a set of novel antigens of high relevance to finding universal molecular triggers of psoriasis. Screening of this pool of peptides for antigenicity in skin-derived tissue-resident T cells of HLA-Cw6+/HLA-Cw6- psoriasis patients will establish dominant peptide triggers of psoriasis. We also show preliminary data of adapting the novel T-scan antigen discovery platform to address autoimmunity.
Defining universal HLA-Cw6-restricted epitopes in psoriasis, as is our aim, will allow to focus the therapy towards developing new tolerization strategies against self. This would achieve long-lasting remission by tackling the source of the problem instead of being limited to managing the symptoms of psoriasis as is currently the case.