Revisiting the arthritogenic peptide theory: quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes

Objective: The association of HLA-B27 with spondyloarthropathy is one of the strongest documented for any autoimmune disease. A common hypothesis for this association is the arthritogenic peptide concept. This 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. Methods: Qualitative differences in the peptides bound to the 8 most frequent HLA-B27 subtypes were determined by tandem mass spectrometry and quantitative changes in allelic binding specificities determined by highly sensitive and targeted multiple reaction monitoring mass spectrometry. Results: Here we identify over 7500 MHC class I peptides derived from the 8 most common HLA-B27 allotypes, HLA-B*27:02 to HLA-B*27:09. We describe individual binding motifs for these alleles for 9-12 mer ligands. The peptide repertoires of these closely related alleles show significant overlap. Allelic polymorphism resulting in changes in the amino acid composition of the antigen binding cleft manifests largely as quantitative changes in the peptide cargo of these molecules. Conclusion: Absolute binding preferences do not explain disease association. 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. This article is protected by copyright. All rights reserved.