Multiple pathways to induction of virus-induced autoimmune demyelination: Lessons from Theiler's virus infection
Multiple pathways to induction of virus-induced autoimmune demyelination: Lessons from Theiler's virus infection
复制标题
DOI：
10.1006/jaut.2000.0489
复制
发表时间：
2001-05-01
影响因子：
12.8
通讯作者：
Croxford, JL
中科院分区：
文献类型：
--
作者：
Miller, SD;Olson, JK;Croxford, JL
用泰勒氏小鼠脑脊髓炎病毒(TMEV)野生型Bean株感染SJL小鼠，可导致CD4(+)T细胞介导的中枢神经系统脱髓鞘，其特征是在疾病慢性期通过表位扩散产生抗髓鞘表位的自身免疫反应。为了研究病毒编码的模拟表位启动中枢神经系统自身免疫的可行性，我们最近发展了一种病毒诱导的脱髓鞘疾病的分子模拟模型，在该模型中，TMEV的非致病性变异株被设计成编码一个30多肽的多肽，其中包含免疫优势的髓鞘蛋白脂蛋白PLP139-151表位。SJL，脑内感染编码PLP139-151表位的天然决定簇或各种肽模拟物的TMEV的小鼠发生由活化的PLP139-151特异性THL细胞介导的早期脱髓鞘疾病。这种早发性脱髓鞘疾病的自身免疫本质表现为对PLP139-151肽的耐受诱导可以防止临床疾病和相关的PLP139-151特异性T细胞反应，而不影响T细胞对病毒表位的反应性。最重要的是，编码来自流感嗜血杆菌的分子模拟肽的TMEV，在13个核心氨基酸中只有6个同源，导致了中枢神经系统疾病。这些研究提供了确凿的证据，证明病毒诱导的髓鞘特异性自身反应性T细胞可以通过分子模仿诱导，并为研究编码人类疾病相关拟态肽的病毒的致病能力提供了有用的模型。(C)2001年学术出版社。
Infection of SJL mice with wild-type BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) leads to CD4(+) T cell-mediated CNS demyelination characterized by the development of anti-myelin epitope autoimmune responses via epitope spreading during the chronic stage of disease. To examine the feasibility of virus-encoded mimic epitopes to initiate CNS autoimmunity, we recently developed a molecular mimicry model of virus-induced demyelinating disease wherein a non-pathogenic variant strain of TMEV was engineered to encode a 30-mer peptide encompassing the immunodominant myelin proteolipid protein, PLP139-151, epitope. SJL,mice infected intracerebrally with TMEV encoding either the native PLP139-151 determinant or various peptide mimics of the epitope develop an early onset demyelinating disease mediated by activated PLP139-151-specific Thl cells. The autoimmune nature of this early-onset demyelinating disease is shown by the fact that induction of tolerance to the PLP139-151 peptide prevents clinical disease and associated PLP139-151-specific T cell responses without affecting T cell reactivity to virus epitopes. Most significantly, TMEV encoding a molecular mimic peptide derived from the Haemophilus influenzae bacteria, homologous at only six out of thirteen of the core amino acids, led to CNS disease. These studies provide conclusive evidence that virus-induced myelin-specific autoreactive T cells can be induced by molecular mimicry and provide a useful model to study the disease inducing ability of viruses encoding human-disease-related mimicry peptides. (C) 2001 Academic Press.