Friese Manuel A, Jakobsen Karen B, Friis Lone, Etzensperger Ruth, Craner Matthew J, McMahon Róisín M, Jensen Lise T, Huygelen Véronique, Jones E Yvonne, Bell John I, Fugger Lars
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford, UK.
Nat Med. 2008 Nov;14(11):1227-35. doi: 10.1038/nm.1881. Epub 2008 Oct 26.
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.
多发性硬化症中主要的已知遗传风险因素存在于主要组织相容性复合体（MHC）区域。尽管有强有力的证据表明MHC II类等位基因和CD4(+) T细胞参与了多发性硬化症的发病机制，但MHC I类基因和CD8(+) T细胞的可能作用仍存在争议。我们构建了表达与多发性硬化症相关的MHC I类等位基因HLA-A()0301（编码人类白细胞抗原A3（HLA-A3））和HLA-A()0201（编码HLA-A2）的人源化小鼠，以及一个源自一名多发性硬化症患者的CD8(+) T细胞克隆的髓鞘特异性自身反应性T细胞受体（TCR），以研究疾病易感性机制。我们证明了HLA-A3限制性CD8(+) T细胞在诱导多发性硬化症样疾病中的作用以及CD4(+) T细胞在其进展中的作用，并且我们还确定了HLA-A(*)0201介导的保护作用的一种可能机制。据我们所知，这些数据提供了首个直接证据，表明MHC I类基因和CD8(+) T细胞参与了人类多发性硬化症的发病机制，并揭示了一个塑造多发性硬化症风险的MHC相互作用网络。
