Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis
Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis
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DOI：
10.1038/nm.1881
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发表时间：
2008-11-01
期刊：
影响因子：
82.9
通讯作者：
Fugger, Lars
中科院分区：
文献类型：
--
作者：
Friese, Manuel A.;Jakobsen, Karen B.;Fugger, Lars
已知的多发性硬化症的主要遗传危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细胞参与多发性硬化症的发病机制，但MHC I类基因和CD8(+) T细胞可能起的作用仍存在争议。我们培育了表达多发性硬化症相关MHC I类等位基因HLA-A*0301（编码人白细胞抗原a3 (HLA-A3)）和HLA-A*0201（编码HLA-A2）的人源化小鼠，以及来自多发性硬化症患者的CD8(+) T细胞克隆的髓磷脂特异性自身反应性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样疾病中的作用，以及CD4(+) T细胞在其进展中的作用，我们还定义了HLA-A*0201介导的保护的可能机制。据我们所知，这些数据提供了第一个直接证据，证明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MHC相互作用形成多发性硬化症风险的网络。
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.