Nature Immunology
3, 940 - 943 (2002)
Published online: 3 September 2002; Corrected online: 12 September 2002 | doi:10.1038/ni835
A functional and structural basis for TCR cross-reactivity in multiple sclerosisHeather L.E. Lang1, 8, Helle Jacobsen2, 3, 8, Shinji Ikemizu4, Christina Andersson2, 3, Karl Harlos4, Lars Madsen3, Peter Hjorth5, Leif Sondergaard6, Arne Svejgaard3, Kai Wucherpfennig7, David I. Stuart4, John I. Bell1, E. Yvonne Jones3
& Lars Fugger21
Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. 2
Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, DK-8200 N Aarhus, Denmark. 3
Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. (*see note below)
4
Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. 5
Institute of Molecular and Structural Biology, University of Aarhus, DK-8000, Aarhus C, Denmark. 6
Institute of Molecular Biology, University of Copenhagen, DK-1353 K, Copenhagen, Denmark. 7
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. 8
These authors contributed equally to this work.
Correspondence should be addressed to E. Yvonne Jones yvonne@strubi.ox.ac.uk or Lars Fugger fugger@inet.uni2.dkThe 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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