Autoantibody-mediated demyelination in SFV-infected mice

SFV 感染小鼠自身抗体介导的脱髓鞘

• 批准号: 6709349
• 负责人: FOROOZAN MOKHTARIAN
• 金额: $ 21.34万
• 依托单位: MAIMONIDES MEDICAL CENTER (BROOKLYN)
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709349
• 关键词: B lymphocyte; Semliki Forest virus; antigen antibody reaction; autoantibody; autoimmune disorder; disease /disorder model; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; flow cytometry; genetically modified animals; helper T lymphocyte; histopathology; immunofluorescence technique; inflammation; laboratory mouse; microglia; multiple sclerosis; myelin basic proteins; myelin glycoprotein; neurotropic virus; oligodendroglia; paralysis; polymerase chain reaction; tissue /cell culture; viral myelinopathy

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.

描述（由申请人提供）：Semliki Forest病毒（SFV）是 诱导B6小鼠麻痹并导致迟到的神经性病毒 脱髓鞘病变。这种脱髓鞘在没有的情况下发生 小鼠的大脑和脊髓中持续的病毒是免疫介导的。 小鼠的SFV感染已被用作研究的模型来研究 多发性硬化症（MS）。使用此模型，我们建议效应器 诱导白质损伤（脱髓鞘）的机制是介导的 通过SFV感染触发的髓磷脂肽的抗体。我们 以前已经发现，用SFV肽对B6小鼠的免疫接种 具有与髓磷脂少突胶质细胞肽的同源性（分子模仿） 糖蛋白（MOG）诱导交叉反应T细胞和对A的抗体反应 MOG肽和一种最小CNS炎症的晚期神经系统疾病 和广泛的脱髓鞘病变。此外，与SFV感染的野生型不同 （WT）小鼠，B细胞 - / - 小鼠没有表现出脱髓鞘。基于这些 观察结果我们提出，1）初始炎症细胞产生 自动反应性辅助T细胞和分泌的居民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）免疫发育性T细胞和 将研究SFV感染动物的抗体反应。具体来说， CD4+ T细胞对SFV表位的出现（和交叉反应性 与选定的模仿髓磷脂肽），以及MOG和MBP蛋白以及 将研究在SFV感染动物的血液和中枢神经系统中的肽。 要测试的具体假设是这些T细胞产生 相应的抗体是脱髓鞘中的效应机制。 3） 可以恢复KO小鼠中脱髓鞘的细胞类型将是 调查。在此目标中要检验的具体假设是 仅当存在功能性B细胞时，才能恢复脱髓活性。 4）抗体在自身免疫介导的诱导中的最终作用 通过将转基因小鼠与B细胞一起使用，将完成脱髓鞘 分泌对SFV e2的抗体抗体，髓磷脂肽。特定的假设为 测试的是，当这些小鼠自发释放这些抗体时 （分别或组合）进入中枢神经系统，将出现脱髓鞘病变。

项目成果

Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis.

• DOI: 10.1016/j.brainres.2008.07.124
• 发表时间: 2008-10-21
• 期刊: BRAIN RESEARCH
• 影响因子: 2.9
• 作者: Hassen, Getaw Worku;Feliberti, Jason;Kesner, Leo;Stracher, Alfred;Mokhtarian, Foroozan
• 通讯作者: Mokhtarian, Foroozan

Microinfusion into the rat brain of antibodies against Semliki Forest Virus produces changes in behavioral response to apomorphine.

将抗塞姆利基森林病毒抗体微量输注到大鼠大脑中会导致对阿扑吗啡的行为反应发生变化。

• DOI: 10.1016/j.jneuroim.2006.12.004
• 发表时间: 2007
• 期刊: Journal of neuroimmunology
• 影响因子: 3.3
• 作者: Knopf,PaulM;Harling-Berg,ChristineJ;Lee,DarrinJ;Hallett,JosephJ;Stopa,EdwardG;Mokhtarian,Foroozan
• 通讯作者: Mokhtarian,Foroozan