Autoantibody-mediated demyelination in SFV-infected mice

描述(申请人提供)：塞姆利基森林病毒(SFV)是一种 一种嗜神经病毒，可导致B6小鼠瘫痪并导致迟发 脱髓鞘损伤。这种脱髓鞘，发生在缺乏 在小鼠的大脑和脊髓中持续存在的病毒是由免疫介导的。 以小鼠SFV感染为模型，研究猪瘟的发病机制。 多发性硬化(MS)。利用这个模型，我们提出了效应器 白质损伤(脱髓鞘)的诱导机制是介导的 由猪瘟病毒感染触发的抗髓磷脂多肽抗体(S)。我们 此前已发现用SFV多肽免疫B6小鼠 与髓鞘少突胶质细胞的一种多肽有同源性(分子模拟) 糖蛋白(MOG)诱导T细胞和抗体的交叉反应 MOG多肽与一种迟发性中枢神经系统轻度炎症 和广泛的脱髓鞘损伤。此外，与感染SFV的野生型不同 (WT)小鼠、B细胞-/-小鼠无脱髓鞘现象。基于这些 据观察，我们提出1)最初的炎性细胞 自身反应性辅助T细胞和分泌的常驻B细胞的成熟 致病抗体，激活小胶质细胞并诱导迟发 脱髓鞘，用流式细胞仪和组织学研究各种合适的 基因敲除(KO)小鼠。2)免疫致病T细胞的特异性和 将研究感染SFV的动物的抗体反应。具体来说， 对SFV表位(和交叉反应)有反应的CD4+T细胞的出现 具有选定的模拟髓磷脂多肽)，以及MOG和MBP蛋白和 将对感染SFV的动物血液和中枢神经系统中的多肽进行研究。 需要检验的特定假设是，这些T细胞能够产生 相应的抗体是脱髓鞘的效应机制。3) 可以恢复KO小鼠脱髓鞘的细胞类型将是 调查过了。在这一目标中要检验的具体假设是 只有当功能正常的B细胞存在时，脱髓鞘活性才会恢复。 4)抗体在诱导自身免疫中的终极作用 脱髓鞘将通过使用带有B细胞的转基因小鼠来完成 分泌抗SFV E2的抗体，髓磷脂多肽。具体假设有待确定 测试表明，当这些小鼠自发释放这些抗体时 (单独或合并)进入中枢神经系统，就会出现脱髓鞘病变。

DESCRIPTION (provided by applicant): Semliki Forest virus (SFV) is a neurotropic virus that induces paralysis in B6 mice and leads to late demyelinating lesions. This demyelination, which occurs in the absence of persisting virus in the brains and spinal cords of mice, is immune-mediated. SFV-infection of mice has been used as a model to study the pathogenesis of multiple sclerosis (MS). Using this model, we have suggested that the effector mechanism in the induction of white matter injury (demyelination) is mediated by antibodies to myelin peptides(s) that are triggered by SFV-infection. We have previously found that immunization of B6 mice with a peptide of SFV that has homology (molecular mimicry) with a peptide of myelin oligodendrocyte glycoprotein (MOG) induced cross-reactive T cell and antibody responses to a MOG peptide and a late-onset neurological disease with minimal CNS inflammation and extensive demyelinating lesions. Moreover, unlike SFV-infected wild-type (WT) mice, B-cell-/- mice did not exhibit demyelination. Based on these observations we have proposed that 1) The initial inflammatory cells give rise to autoreactive helper T cells and maturation of resident B cells that secrete pathogenic antibodies, that activate the microglia and induce late demyelination, using FACS and histological studies of various appropriate knock-out (KO) mice. 2) The specificity of the immunopathogenic T cell and antibody response in SFV-infected animals will be investigated. Specifically, the appearance of CD4+ T cells responding to SFV epitopes (and cross reactive with selected mimicked myelin peptides), and to MOG and MBP proteins and peptides, in the blood and CNS of SFV-infected animals, will be studied. Specific hypothesis to be tested is that these T cells give rise to corresponding antibodies which are the effector mechanism in demyelination. 3) The cell type that can restore demyelination in the KO mice will be investigated. The specific hypothesis to be tested in this aim is that demyelinating activity will be restored only if functional B cells are present. 4) The ultimate role of antibody in the induction of autoimmune mediated demyelination will be completed by using transgenic mice with B cells that secrete antibody to SFV E2-mimicked, myelin peptides. Specific hypothesis to be tested is that when these mice spontaneously release these antibodies (separately or combined) into the CNS, demyelinating lesions will appear.