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

Ralf Bernd Schittenhelm, Terry Chin Choy Lim Kam Sian, Pascal Georges Wilmann, Nadine L Dudek, Anthony W Purcell

Research output: Contribution to journalArticleResearchpeer-review

53 Citations (Scopus)

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-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.
Original languageEnglish
Pages (from-to)702 - 713
Number of pages12
JournalArthritis and Rheumatology
Volume67
Issue number3
DOIs
Publication statusPublished - 2015

Cite this

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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-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.",
author = "Schittenhelm, {Ralf Bernd} and {Lim Kam Sian}, {Terry Chin Choy} and Wilmann, {Pascal Georges} and Dudek, {Nadine L} and Purcell, {Anthony W}",
year = "2015",
doi = "10.1002/art.38963",
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journal = "Arthritis and Rheumatology",
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}

Revisiting the arthritogenic peptide theory: quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes. / Schittenhelm, Ralf Bernd; Lim Kam Sian, Terry Chin Choy; Wilmann, Pascal Georges; Dudek, Nadine L; Purcell, Anthony W.

In: Arthritis and Rheumatology, Vol. 67, No. 3, 2015, p. 702 - 713.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Revisiting the arthritogenic peptide theory: quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes

AU - Schittenhelm, Ralf Bernd

AU - Lim Kam Sian, Terry Chin Choy

AU - Wilmann, Pascal Georges

AU - Dudek, Nadine L

AU - Purcell, Anthony W

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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