Revisiting the Arthritogenic Peptide Theory: Quantitative Not Qualitative Changes in the Peptide Repertoire of HLA–B27 Allotypes

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 67; no. 3; pp. 702 - 713
• Main Authors: Schittenhelm, Ralf B., Sian, Terry C. C. Lim Kam, Wilmann, Pascal G., Dudek, Nadine L., Purcell, Anthony W.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2015
• Subjects: Alleles; Amino Acids - analysis; Cell Line; HLA-B27 Antigen - genetics; HLA-B27 Antigen - metabolism; Humans; Ligands; Mass spectrometry; Peptides; Peptides - metabolism; Protein Binding; Scientific imaging; Tandem Mass Spectrometry; Theory
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.38963

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–disease‐associated HLA–B27 allotypes underlie the presentation of bacterial and self‐peptides, leading to cross‐reactive T cell immunity and subsequent autoimmune attack of affected tissues. The aim of this study was to analyze and compare self‐peptides from 8 HLA–B27 allotypes, to increase existing data sets of HLA–B27 ligands, to refine and compare their consensus‐binding motifs, and to reveal similarities and differences in the peptide repertoire of the HLA–B27 subtypes. 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 were determined by highly sensitive and targeted multiple reaction monitoring mass spectrometry. Results We identified >7,500 major histocompatibility complex 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 the 9–12‐mer ligands. The peptide repertoires of these closely related alleles showed significant overlap. Allelic polymorphisms resulting in changes in the amino acid composition of the antigen‐binding cleft manifested largely as quantitative changes in the peptide cargo of these molecules. Conclusion Absolute binding preferences of HLA–B27 allotypes 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.