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

Heather L.E. Lang; Helle Jacobsen; S. Ikemizu; Christina Andersson; Karl Harlos; L. Madsen; Peter Hjorth; Leif Søndergaard; Arne Svejgaard; Kai Wucherpfennig; David I. Stuart; John I. Bell; Yvonne Jones; Lars Fugger

doi:10.1038/ni835

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

Heather L.E. Lang, Helle Jacobsen, S. Ikemizu, Christina Andersson, Karl Harlos, L. Madsen, Peter Hjorth, Leif Søndergaard, Arne Svejgaard, Kai Wucherpfennig, David I. Stuart, John I. Bell, Yvonne Jones, Lars Fugger

431 Citations (Scopus)

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.

Original language	English
Journal	Nature Immunology
Volume	3
Issue number	10
Pages (from-to)	940-943
ISSN	1529-2908
DOIs	https://doi.org/10.1038/ni835
Publication status	Published - 2002

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@article{97d1098074c511dbbee902004c4f4f50,

title = "A functional and structural basis for TCR cross-resctivity in multiple sclerosis",

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.",

author = "Lang, {Heather L.E.} and Helle Jacobsen and S. Ikemizu and Christina Andersson and Karl Harlos and L. Madsen and Peter Hjorth and Leif S{\o}ndergaard and Arne Svejgaard and Kai Wucherpfennig and Stuart, {David I.} and Bell, {John I.} and Yvonne Jones and Lars Fugger",

year = "2002",

doi = "10.1038/ni835",

language = "English",

volume = "3",

pages = "940--943",

journal = "Nature Immunology",

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TY - JOUR

T1 - A functional and structural basis for TCR cross-resctivity in multiple sclerosis

AU - Lang, Heather L.E.

AU - Jacobsen, Helle

AU - Ikemizu, S.

AU - Andersson, Christina

AU - Harlos, Karl

AU - Madsen, L.

AU - Hjorth, Peter

AU - Søndergaard, Leif

AU - Svejgaard, Arne

AU - Wucherpfennig, Kai

AU - Stuart, David I.

AU - Bell, John I.

AU - Jones, Yvonne

AU - Fugger, Lars

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

U2 - 10.1038/ni835

DO - 10.1038/ni835

M3 - Journal article

SN - 1529-2908

VL - 3

SP - 940

EP - 943

JO - Nature Immunology

JF - Nature Immunology

IS - 10

ER -

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

Abstract

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