Autoantibody-mediated demyelination in SFV-infected mice

描述（由申请人提供）：塞姆利基森林病毒（SFV）是一种 一种嗜神经病毒，可诱导B6小鼠瘫痪，并导致晚期 脱髓鞘病变这种脱髓鞘，发生在缺乏 在小鼠的大脑和脊髓中持续存在的病毒，是免疫介导的。 SFV感染小鼠已被用作研究其发病机制的模型。 多发性硬化症（MS）。使用这个模型，我们已经提出， 诱导白色物质损伤（脱髓鞘）的机制是介导的 由SFV感染引发的髓鞘肽抗体引起。我们 先前已经发现用SFV肽免疫B6小鼠， 与髓鞘少突胶质细胞的肽具有同源性（分子模拟 糖蛋白（MOG）诱导的交叉反应性T细胞和抗体应答， MOG肽与伴有轻微CNS炎症的迟发性神经系统疾病 和广泛的脱髓鞘病变。此外，与SFV感染的野生型不同， (WT)在小鼠中，B-细胞-/-小鼠没有表现出脱髓鞘。基于这些 我们提出的观察结果是：1）最初的炎症细胞引起 自身反应性辅助T细胞和常驻B细胞的成熟， 致病性抗体，激活小胶质细胞并诱导晚期 脱髓鞘，使用FACS和各种适当的组织学研究， 敲除（KO）小鼠。2)免疫病理性T细胞的特异性和 将研究SFV感染动物中的抗体应答。具体地说， 出现响应SFV表位的CD 4 + T细胞（和交叉反应性 与选择的模拟髓鞘肽），以及MOG和MBP蛋白， 肽，在SFV感染的动物的血液和CNS中，将被研究。 有待检验的具体假设是，这些T细胞引起 相应的抗体是脱髓鞘的效应机制。第三章 可以恢复KO小鼠中脱髓鞘的细胞类型将是 研究了在这方面有待检验的具体假设是， 只有当功能性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介导的 脱髓鞘将通过使用具有B细胞的转基因小鼠完成， 分泌SFV E2模拟的髓鞘肽抗体。具体假设是 当这些小鼠自发释放这些抗体时， 如果将药物（单独或组合）注入CNS中，将出现脱髓鞘病变。

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.