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A functional and structural basis for TCR cross-reactivity in multiple sclerosis

Nature Immunology volume 3, pages 940–943 (2002)Cite this article

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Abstract

The multiple sclerosis (MS)-associated HLA major histocompatibility complex (MHC) class II alleles DRB1*1501, DRB5*0101 and DQB1*0602 are in strong linkage disequilibrium, making it difficult to determine which is the principal MS risk gene. Here we show that together the DRB1 and DRB5 loci may influence susceptibility to MS. We demonstrate that a T cell receptor (TCR) from an MS patient recognized both a DRB1*1501-restricted myelin basic protein (MBP) and DRB5*0101-restricted Epstein-Barr virus (EBV) peptide. Crystal structure determination of the DRB5*0101-EBV peptide complex revealed a marked degree of structural equivalence to the DRB1*1501–MBP peptide complex at the surface presented for TCR recognition. This provides structural evidence for molecular mimicry involving HLA molecules. The structural details suggest an explanation for the preponderance of MHC class II associations in HLA-associated diseases.

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Figure 1: T cell stimulation experiments.
Figure 2: Structural comparisons.
Figure 3: The TCR recognition surface.

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  • 12 September 2002

    Affiliation for Yvonne Jones was updated with note, and PDF was appended with note. Issue PDF will contain "corrected 12 September 2002 (details online). " Affiliation was formerly Department of Clinical Immunology, Rigshospitalet, DK-2200 N, Copenhagen, Denmark

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Acknowledgements

We thank S. Davis, J. Boulter, C. Hourigan, N. Zaccai, G. C. Ebers and A. McMichael for useful discussions and the staff of ESRF beam line ID14 EH4 and the EMBL outstation at Grenoble for assistance with x-ray data collection. Supported by the MRC, the Karen Elise Jensen Foundation, the Danish MRC, the Danish MS Society, the Royal Society and Cancer Research UK (E. Y. J.).

*Note: In the AOP version of this article, the affiliation for E. Yvonne Jones was incorrect. It should be Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. These errors have been corrected in the HTML version and will appear correctly in print. The PDF version available online has been appended.

Author information

Author notes

  1. E. Yvonne Jones: (*see note below)

  2. Heather L.E. Lang and Helle Jacobsen: These authors contributed equally to this work.

Authors and Affiliations

  1. Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK

    Heather L.E. Lang & John I. Bell

  2. Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, Aarhus, DK-8200 N, Denmark

    Helle Jacobsen, Christina Andersson & Lars Fugger

  3. Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Helle Jacobsen, Christina Andersson, Lars Madsen, Arne Svejgaard & E. Yvonne Jones

  4. Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Shinji Ikemizu, Karl Harlos & David I. Stuart

  5. Institute of Molecular and Structural Biology, University of Aarhus, Aarhus C, DK-8000, Denmark

    Peter Hjorth

  6. Institute of Molecular Biology, University of Copenhagen, Copenhagen, DK-1353 K, Denmark

    Leif Sondergaard

  7. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, 02115, MA, USA

    Kai Wucherpfennig

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  1. Heather L.E. Lang
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Correspondence to E. Yvonne Jones or Lars Fugger.

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Lang, H., Jacobsen, H., Ikemizu, S. et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 3, 940–943 (2002). https://doi.org/10.1038/ni835

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