Miller S D, Olson J K, Croxford J L
Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
J Autoimmun. 2001 May;16(3):219-27. doi: 10.1006/jaut.2000.0489.
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 exmine 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 Th1 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.
用野生型Theiler鼠脑脊髓炎病毒（TMEV）的BeAn株感染SJL小鼠，会导致CD4(+)T细胞介导的中枢神经系统脱髓鞘，其特征是在疾病的慢性阶段通过表位扩展产生抗髓鞘表位自身免疫反应。为了检验病毒编码的模拟表位引发中枢神经系统自身免疫的可行性，我们最近开发了一种病毒诱导的脱髓鞘疾病分子模拟模型，其中对TMEV的一个非致病性变异株进行工程改造，使其编码一个包含免疫显性髓鞘蛋白脂蛋白PLP139 - 151表位的30肽。脑内感染编码天然PLP139 - 151决定簇或该表位各种肽模拟物的TMEV的SJL小鼠，会发展出由活化的PLP139 - 151特异性Th1细胞介导的早发性脱髓鞘疾病。这种早发性脱髓鞘疾病的自身免疫性质体现在以下事实上：诱导对PLP139 - 151肽的耐受性可预防临床疾病及相关的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。最显著的是，编码一种源自流感嗜血杆菌的分子模拟肽的TMEV（该模拟肽仅在13个核心氨基酸中的6个上具有同源性）导致了中枢神经系统疾病。这些研究提供了确凿证据，表明病毒诱导的髓鞘特异性自身反应性T细胞可通过分子模拟诱导产生，并提供了一个有用的模型来研究编码与人类疾病相关模拟肽的病毒的致病能力。
