Skewed MHC Class I Peptide Presentation in Psoriatic Arthritis

Given the strong association between major histocompatibility complex (MHC) class I and psoriatic arthritis (PsA), and the role of the MHC in antigen presentation potentially driving immunopathology, we performed mass spectrometry-based immunopeptidome analysis to identify MHC class I-bound peptides in PsA. MHC class I expression on circulating immune cells was determined by flow cytometric analysis. MHC class I-bound peptides were isolated via immunoaffinity purification and identified by mass spectrometry in PsA patients and healthy controls. MHC class I expression was increased on circulating immune cells in PsA. MHC class I immunopeptidome analysis revealed a high prevalence of peptides of nine-amino-acid length originating from intracellular source proteins, typical for MHC class I antigen presentation. Analysis of the MHC class I immunopeptidome showed a greater relative abundance of glutamic acid at position 2 in nonamers from PsA patients, but not controls. This finding was further corroborated by an unsupervised clustering analysis showing five different clusters in healthy individuals and six in PsA, with one featuring higher abundance of glutamic acid at position 2. The glutamic acid-containing PEQLRKLFI peptide from the heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was exclusively identified in PsA patients both via MHC class I immunopeptidome analysis and via PEPperMap epitope mapping. In PsA, MHC class I expression is increased on circulating immune cells, and the MHC class I immunopeptidome is perturbed, with disease-related skewing towards greater relative abundance of glutamic acid at position 2 in nonamers and presentation of a unique peptide motif from the putative autoantigen hnRNP A1.