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Arthritis Rheumatol. 2016 Oct;68(10):2412-21. doi: 10.1002/art.39736.

A Comparative Analysis of the Peptide Repertoires of HLA-DR Molecules Differentially Associated With Rheumatoid Arthritis.

Author information

1
Institut de Biotecnologia i de Biomedicina and Universitat Autònoma de Barcelona, Bellaterra, Spain.
2
Institut de Biotecnologia i de Biomedicina and Universitat Autònoma de Barcelona, Bellaterra, Spain, and Catalan Institution for Research and Advanced Studies, Barcelona, Spain.
3
InnovativeHealth Group-Parque Científico de Madrid, Madrid, Spain.
4
CSIC/UAB Proteomics Laboratory, IIBB-CSIC/Institut d'Investigacions Biomèdiques August Pi i Sunyer, Bellaterra, Spain.
5
Benaroya Research Institute at Virginia Mason, Seattle, Washington.
6
Vall d'Hebron University Hospital Research Institute Proteomics Laboratory, Barcelona, Spain.
7
Institut de Biotecnologia i de Biomedicina and Universitat Autònoma de Barcelona, Bellaterra, Spain. Inaki.Alvarez@uab.es.

Abstract

OBJECTIVE:

To evaluate similarity of the peptide repertoires bound to HLA-DR molecules that are differentially associated with rheumatoid arthritis (RA), and to define structural features of the shared peptides.

METHODS:

Peptide pools bound to HLA-DRB1*01:01, HLA-DRB1*04:01, and HLA-DRB1*10:01 (RA associated) and those bound to HLA-DRB1*15:01 (non-RA-associated) were purified and analyzed by liquid chromatography (LC) matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MS) and LC-ion-trap MS. Peptide pools from each allotype were compared in terms of size, protein origin, composition, and affinity (both theoretical and experimental with some peptides). Finally, 1 peptide sequenced from DR1, DR4, and DR10, but not from DR15, was modeled in complex with all 4 HLA-DRB1 molecules and HLA-DRB5*01:01.

RESULTS:

A total of 6,309 masses and 962 unique peptide sequences were compared. DR10 shared 29 peptides with DR1, 9 with DR4, and 1 with DR15; DR1 shared 6 peptides with DR4 and 9 with DR15; and DR4 and DR15 shared 4 peptides. The direct identification of peptide ligands indicated that DR1 and DR10 were the most similar molecules regarding the peptides that they could share. The peptides common to these molecules contained a high proportion of Leu at P4 and basic residues at P8 binding core positions.

CONCLUSION:

The degree of overlap between peptide repertoires associated with different HLA-DR molecules is low. The repertoires associated with DR1 and DR10 have the highest similarity among the molecules analyzed (∼10% overlap). Among the peptides shared between DR1 and DR10, a high proportion contained Leu(4) and basic residues at the P8 position of the binding core.

PMID:
27158783
DOI:
10.1002/art.39736
[Indexed for MEDLINE]
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