title: Revisiting the arthritogenic peptide theory: quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Monash University, Clayton, Victoria, Australia.
authors.forename: Ralf B
authors.initials: RB
authors.lastname: Schittenhelm
authors.forename: Terry C C Lim Kam
authors.initials: TC
authors.lastname: Sian
authors.forename: Pascal G
authors.initials: PG
authors.lastname: Wilmann
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
mesh_terms: D000483:Alleles; D000596:Amino Acids / Q000032:analysis; D002460:Cell Line; D015796:HLA-B27 Antigen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D053719:Tandem Mass Spectrometry
chemical_list: D000596:Amino Acids; D015796:HLA-B27 Antigen; D010455:Peptides