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.
journal_name
Nat Medjournal_title
Nature medicineauthors
Friese MA,Jakobsen KB,Friis L,Etzensperger R,Craner MJ,McMahon RM,Jensen LT,Huygelen V,Jones EY,Bell JI,Fugger Ldoi
10.1038/nm.1881subject
Has Abstractpub_date
2008-11-01 00:00:00pages
1227-35issue
11eissn
1078-8956issn
1546-170Xpii
nm.1881journal_volume
14pub_type
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