A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor
A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor
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DOI：
10.1038/15525
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发表时间：
1999-11-01
期刊：
影响因子：
30.8
通讯作者：
Fugger, L
中科院分区：
文献类型：
--
作者：
Madsen, LS;Andersson, EC;Fugger, L
多发性硬化症（MS）是一种复杂的慢性神经系统疾病，疑为自身免疫性发病1,2。虽然有证据表明MS的发展是由环境影响和基因共同决定的，但这些因素在很大程度上是不确定的3,4，除了主要的组织相容性（MHC）基因。连锁分析和关联研究表明，MS易感性与人类组织相容性白细胞抗原（HLA） II类区域的基因有关，但与胰岛素依赖型糖尿病等疾病相比，这些基因对MS疾病发展的贡献要小得多。由于MHC II类区域存在强烈的连锁不平衡，因此无法确定是哪个基因导致了这种遗传易感性。在转基因小鼠中，我们表达了三种参与t细胞识别由HLA-DR2分子呈递的MS相关自身抗原的人类成分：DRA* 0101/DRB1* 1501 (HLA-DR2)，一种在欧洲血统个体中发现的MHC II类MS候选易感基因；来自ms患者衍生的t细胞克隆的t细胞受体（TCR），特异性针对HLA-DR2结合的免疫显性髓鞘碱性蛋白（MBP） 84-102肽13,14；和人类CD4辅助受体MBP 84-102肽的氨基酸序列在人和小鼠的MBP中是相同的。在给予MBP肽、佐剂和百日咳毒素后，转基因小鼠出现局灶性中枢神经系统炎症和脱髓鞘，导致与ms相似的临床表现和病程，4%的小鼠出现自发性疾病。当DR2和TCR双转基因小鼠与Rag2（重组激活基因2）缺陷小鼠回交两次时，自发性疾病的发生率增加，这表明针对HLA-DR2结合的MBP肽的特异性T细胞对于疾病的发展是充分和必要的。我们的研究提供了证据，证明HLA-DR2可以通过向T细胞呈递MBP自肽介导类似MS的诱导和自发疾病。
Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis 1, 2. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined 3, 4, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development is less compared with their contribution to disorders such as insulin-dependent diabetes mellitus 5, 6, 7, 8, 9, 10, 11. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene (s) is responsible for the genetic predisposition 12. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA* 0101/DRB1* 1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 84–102 peptide 13, 14; and the human CD4 coreceptor. The amino acid sequence of the MBP 84–102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells.