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Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Genes & Immunity volume 12, pages 415–427 (2011)Cite this article

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Abstract

Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 trans-molecules composed of α and β chains from DQ2 and DQ8 express unique β-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis- and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to ‘epitope stealing’, thereby inducing a regulatory, rather than a pathogenic immune response.

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Acknowledgements

We thank Demetrios Kyrkas and Martijn Rabelink for technical support. These studies were funded in part by the European Union 3rd Regional Development Framework for Greece (Program ARCHIMEDES) to GKP, the Dutch Diabetes Research Foundation, The Netherlands Organization for Health Research and Development (ZonMW) and the Juvenile Diabetes Research Foundation to BOR. The Silicon Graphics Fuel instrument and the accompanying software were obtained via the Epirus Regional Development Programme to Epirus Institute of Technology and of the 3rd Community Support Framework of the EU.

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  1. P Eerligh and M van Lummel: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    P Eerligh, M van Lummel, G Duinkerken, B P C Koeleman & B O Roep

  2. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

    A Zaldumbide

  3. Department of Organic Farming, Technological Educational Institute of Ionian Islands, Argostoli, Greece

    A K Moustakas

  4. Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta, Greece

    G Bondinas & G K Papadopoulos

  5. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    B P C Koeleman

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  1. P Eerligh
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Correspondence to B O Roep.

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Eerligh, P., van Lummel, M., Zaldumbide, A. et al. Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes. Genes Immun 12, 415–427 (2011). https://doi.org/10.1038/gene.2011.24

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