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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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.
The authors declare no competing financial interests.
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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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