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Article
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.
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