PROTEOMICS 2015* Revisiting the arthritogenic peptide theory: Quantitative - not qualitative - changes in the peptide repertoire of HLA-B27 allotypes (#223)
The association of Human Leukocyte Antigen (HLA) B27 with spondyloarthropathy is one of the strongest documented for any autoimmune disease. A common hypothesis for this association is the arthritogenic peptide theory. It dictates that differences in the peptide binding preferences of disease-associated and non-associated HLA-B27 allotypes underpin the presentation of bacterial and self-peptides leading to cross-reactive T cell immunity and subsequent autoimmune attack of affected tissues.
Using high-resolution mass spectrometry in combination with SWATH-MS and MRM, we have analyzed and comprehensively quantified the peptide repertoires derived from the 8 most common HLA B27 allotypes, HLA-B*27:02 to HLA-B*27:09. Differences in the peptide binding pockets of these molecules manifest largely as quantitative, but not qualitative changes in the peptide cargo. Thus, absolute binding preferences do not explain disease-association and the arthritogenic peptide theory needs to be reassessed in terms of quantitative changes in self-peptide presentation, T cell selection and altered conformation of bound peptides.
