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The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

Genes & Immunity volume 12, pages 504–512 (2011)Cite this article

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Abstract

The objective of this study was to characterize the peptide-binding motif of the major histocompatibility complex (MHC) class II HLA-DR8 molecule included in the type 1 diabetes-associated haplotype DRB1*0801-DQA1*0401/DQB1*0402 (DR8-DQ4), and compare it with that of other diabetes-associated MHC class II alleles; DR8-bound peptides were eluted from an HLA-DR homozygous lymphoblastoid cell line. The repertoire was characterized by peptide sequencing using a LTQ ion trap mass spectrometer coupled to a multidimensional liquid chromatography system. After validation of the spectra identification, the definition of the HLA-DR8 peptide-binding motif was achieved from the analysis of 486 natural ligands, based on serial alignments of all possible HLA-DR-binding cores. The DR8 motif showed a strong similarity with the peptide-binding motifs of other MHC class II diabetes-associated alleles, HLA-DQ8 and H-2 I-Ag7. Similar to HLA-DQ8 and H-2 I-Ag7, HLA-DR8 preferentially binds peptides with an acidic residue at position P9 of the binding core, indicating that DR8 is the susceptibility component of the DR8-DQ4 haplotype. Indeed, some DR8 peptides were identical to peptides previously identified as DQ8- or I-Ag7 ligands, and several diabetes-specific peptides associated with DQ8 or I-Ag7 could theoretically bind to HLA-DR8. These data further strengthen the association of HLA-DR8 with type I diabetes.

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Acknowledgements

This work was funded by the Spanish Ministry of Education grant SAF2006-08928 to DJ. We thank JL Vicario from the Transfusion Center (Madrid) for sending us the sample from a DR8 homozygous blood donor, and the donor for accepting to donate for research purposes. PMM acknowledges funding from the Spanish MICINN/FEDER BIO2007-62954. The CSIC/UAB Proteomics Laboratory is a member of ProteoRed, funded by Genoma Spain and follows the quality criteria set up by the ProteoRed standards.

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Authors and Affiliations

  1. Department of Cell Biology, Physiology and Immunology, Immunology Unit, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain

    L Muixí, C Guitart, I Alvarez & D Jaraquemada

  2. CSIC-UAB Proteomics Facility, IIBB-CSIC, IDIBAPS, Facultat de Medicina, Barcelona, Spain

    M Gay & J Abian

  3. Bioinformatics Unit, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain

    P M Muñoz-Torres & J Cedano

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  1. L Muixí
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Correspondence to D Jaraquemada.

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Muixí, L., Gay, M., Muñoz-Torres, P. et al. The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles. Genes Immun 12, 504–512 (2011). https://doi.org/10.1038/gene.2011.26

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