Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading
Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading
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DOI：
10.1038/nm1097-1133
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发表时间：
1997-10-01
期刊：
影响因子：
82.9
通讯作者：
Kim, BS
中科院分区：
文献类型：
--
作者：
Miller, SD;Vanderlugt, CL;Kim, BS
多发性硬化症（MS）是一种T细胞介导的自身免疫性脱髓鞘疾病（1），可能由病毒感染引发（2）。Theiler鼠脑脊髓炎病毒（TMEV）是一种天然小鼠病原体，是一种小核糖核酸病毒，可诱导慢性CD 4（+）T细胞介导的脱髓鞘疾病，其临床病程和组织病理学与慢性进行性MS相似（参考文献3）。TMEV感染小鼠中的脱髓鞘是由病毒特异性CD 4（+）T细胞介导的单核炎症反应引发的，该细胞靶向病毒，长期存在于CNS中（参考文献4-6）。我们发现，在疾病发作后3-4周开始，T细胞对多个髓鞘自身表位的反应以有序的进展出现，并可能在慢性疾病中发挥病理作用。动力学和功能研究表明，T细胞对免疫显性髓鞘蛋白脂质蛋白表位的应答（PLP 139 -151）没有出现，因为TMEV和自身表位之间的交叉反应性（即分子模拟）（7，8），但由于自身反应性T细胞对病毒特异性T细胞介导的脱髓鞘继发释放的隔离自身抗原的从头引发（即表位扩散）（9，10）。表位扩散是解释病毒引起的器官特异性自身免疫性疾病的重要机制。
Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease(1), which may be initiated by a virus infection(2). Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4(+) T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4(+) T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry)(7,8), but because of de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (that is, epitope spreading)(9,10). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.