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

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 infl...

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Bibliographic Details
Published in:	Nature immunology Vol. 3; no. 10; pp. 940 - 943
Main Authors:	Jones, E. Yvonne, Fugger, Lars, Lang, Heather L.E, Jacobsen, Helle, Ikemizu, Shinji, Andersson, Christina, Harlos, Karl, Madsen, Lars, Hjorth, Peter, Sondergaard, Leif, Svejgaard, Arne, Wucherpfennig, Kai, Stuart, David I, Bell, John I
Format:	Journal Article
Language:	English
Published:	United States Nature Publishing Group 01-10-2002
Subjects:	Animals Autoimmune diseases B-Lymphocytes - cytology B-Lymphocytes - immunology Cell Line Cross Reactions Crystallography, X-Ray Epstein-Barr virus Herpesvirus 4, Human - immunology HLA-DR Antigens - chemistry HLA-DR Antigens - immunology HLA-DRB1 Chains HLA-DRB5 Chains Humans Mice Mice, Transgenic Models, Molecular Multiple Sclerosis - immunology Myelin Basic Protein - chemistry Myelin Basic Protein - immunology Protein Structure, Tertiary Receptors, Antigen, T-Cell, alpha-beta - genetics Receptors, Antigen, T-Cell, alpha-beta - immunology
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Summary:	The multiple sclerosis (MS)-associated HLA major histocompatibility complex (MHC) class II alleles DRB11501, DRB50101 and DQB10602 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 DRB11501-restricted myelin basic protein (MBP) and DRB50101-restricted Epstein-Barr virus (EBV) peptide. Crystal structure determination of the DRB50101-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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1529-2908 1529-2916
DOI:	10.1038/ni835