Article abstract
Nature Medicine 14, 1227 - 1235 (2008)
Published online: 26 October 2008 | doi:10.1038/nm.1881
Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis
Manuel A Friese1,2,3, Karen B Jakobsen1, Lone Friis1, Ruth Etzensperger1, Matthew J Craner2, Róisín M McMahon1,4, Lise T Jensen5, Véronique Huygelen1, E Yvonne Jones4, John I Bell1,6 & Lars Fugger1,2,5
Abstract
The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4+ T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8+ T cells are controversial. We have generated humanized mice expressing the multiple sclerosis–associated MHC class I alleles HLA-A*0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A*0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8+ T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3–restricted CD8+ T cells in induction of multiple sclerosis–like disease and for CD4+ T cells in its progression, and we also define a possible mechanism for HLA-A*0201–mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8+ T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.
- Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DS, UK.
- Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DS, UK.
- Institut für Neuroimmunologie und Klinische MS-Forschung, Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
- Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
- Clinical Institute, Aarhus University Hospital, Skejby Sygehus, Brendstrupgaardsvej 100, 8200 N Aarhus, Denmark.
- Office of the Regius Professor of Medicine, The Richard Doll Building, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
Correspondence to: Lars Fugger1,2,5 e-mail: lars.fugger@imm.ox.ac.uk
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