Miller S D, Vanderlugt C L, Begolka W S, Pao W, Yauch R L, Neville K L, Katz-Levy Y, Carrizosa A, Kim B S
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Nat Med. 1997 Oct;3(10):1133-6. doi: 10.1038/nm1097-1133.
Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease, which may be initiated by a virus infection. 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), 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). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.
多发性硬化症（MS）是一种由T细胞介导的自身免疫性脱髓鞘疾病，可能由病毒感染引发。泰勒氏鼠脑脊髓炎病毒（TMEV）是一种天然的小鼠病原体，属于微小核糖核酸病毒，可诱发一种慢性的、由CD4 + 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展型MS相似（参考文献3）。TMEV感染小鼠的脱髓鞘由靶向病毒的病毒特异性CD4 + T细胞介导的单核炎症反应引发，该反应在中枢神经系统中持续存在（参考文献4 - 6）。我们发现，在疾病发作3 - 4周后，T细胞对多种髓鞘自身表位的反应按顺序逐步出现，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蛋白表位（PLP139 - 151）的反应并非由于TMEV与自身表位之间的交叉反应（即分子模拟）而产生，而是由于自身反应性T细胞对因病毒特异性T细胞介导的脱髓鞘而释放的隐蔽自身抗原进行了从头启动（即表位扩展）。表位扩展是解释病毒诱导的器官特异性自身免疫疾病病因的一种重要的替代机制。
