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

AuthorsScholz, Erika; Mestre-Ferrer, Anna; Daura, Xavier; García-Medel, Noel ; Carrascal, Montserrat ; James, Eddie A.; Kwok, William W.; Canals, Francesc; Álvarez, Iñaki
Issue DateOct-2016
PublisherJohn Wiley & Sons
CitationArthritis and Rheumatology 68(10): 2412-2421 (2016)
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 Leu4 and basic residues at the P8 position of the binding core.
Publisher version (URL)https://doi.org/10.1002/art.39736
Identifiersdoi: 10.1002/art.39736
issn: 2326-5205
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