Miller S D, Gerety S J, Kennedy M K, Peterson J D, Trotter J L, Tuohy V K, Waltenbaugh C, Dal Canto M C, Lipton H L
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611.
J Neuroimmunol. 1990 Jan;26(1):9-23. doi: 10.1016/0165-5728(90)90115-4.
Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains produces a chronic demyelinating disease in which mononuclear cell-rich infiltrates in the central nervous system (CNS) are prominent. Current evidence strongly supports an immune-mediated basis for myelin breakdown, with an effector role proposed for TMEV-specific, major histocompatibility complex (MHC) class II-restricted delayed-type hypersensitivity (DTH) responses in which lymphokine-activated macrophages mediate bystander demyelination. The present study examined the possibility that concomitant or later-appearing neuroantigen-specific autoimmune T cell responses, such as those demonstrated in chronic-relapsing experimental allergic encephalomyelitis (R-EAE), may contribute to the demyelinating process following TMEV infection. T cell responses against intact, purified major myelin proteins (myelin basic protein (MBP) and proteolipid protein (PLP], and against altered myelin constituents were readily demonstrable in SJL/J mice with R-EAE, but were not detectable in SJL/J mice with TMEV-induced demyelinating disease. TMEV-infected mice also did not display T cell responses against the peptide fragments of MBP(91-104) and PLP(139-151) recently shown to be encephalitogenic in SJL/J mice. In addition, induction of neuroantigen-specific tolerance to a heterogeneous mixture of CNS antigens, via the i.v. injection of syngeneic SJL/J splenocytes covalently coupled with mouse spinal cord homogenate, resulted in significant suppression of clinical and histologic signs of R-EAE and the accompanying MBP- and PLP-specific DTH responses. In contrast, neuroantigen-specific tolerance failed to alter the development of clinical and histologic signs of TMEV-induced demyelinating disease or the accompanying virus-specific DTH and humoral immune responses. These findings demonstrate that TMEV-induced demyelinating disease can occur in the apparent absence of neuroantigen-specific autoimmune responses. The relationship of the present results to the immunopathology of multiple sclerosis is discussed.
将泰勒氏小鼠脑脊髓炎病毒（TMEV）脑内接种到易感小鼠品系中会引发一种慢性脱髓鞘疾病，其中中枢神经系统（CNS）中富含单核细胞的浸润很明显。目前的证据有力地支持了髓鞘破坏的免疫介导基础，有人提出TMEV特异性、主要组织相容性复合体（MHC）II类限制性迟发型超敏反应（DTH）起效应作用，其中淋巴因子激活的巨噬细胞介导旁观者脱髓鞘。本研究探讨了伴随出现或后来出现的神经抗原特异性自身免疫性T细胞反应（如在慢性复发性实验性变应性脑脊髓炎（R-EAE）中所显示的那些反应）可能在TMEV感染后的脱髓鞘过程中起作用的可能性。在患有R-EAE的SJL/J小鼠中很容易检测到针对完整、纯化的主要髓鞘蛋白（髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP））以及针对改变的髓鞘成分的T细胞反应，但在患有TMEV诱导的脱髓鞘疾病的SJL/J小鼠中未检测到。感染TMEV的小鼠也未表现出针对最近显示在SJL/J小鼠中具有致脑炎作用的MBP(91-104)和PLP(139-151)肽片段的T细胞反应。此外，通过静脉注射与小鼠脊髓匀浆共价偶联的同基因SJL/J脾细胞，诱导对CNS抗原异质混合物的神经抗原特异性耐受，可显著抑制R-EAE的临床和组织学体征以及伴随的MBP和PLP特异性DTH反应。相比之下，神经抗原特异性耐受未能改变TMEV诱导的脱髓鞘疾病的临床和组织学体征的发展或伴随的病毒特异性DTH和体液免疫反应。这些发现表明，TMEV诱导的脱髓鞘疾病可以在明显没有神经抗原特异性自身免疫反应的情况下发生。讨论了本研究结果与多发性硬化症免疫病理学的关系。
