Molecular Mimicry in Immune Mediated Neurologic Disease

描述(由申请人提供)： 这项研究的长期目标是阐明与进行性多发性硬化症(MS)的发病机制有关的神经退行性变的新机制，多发性硬化症是美国退伍军人残疾的常见原因。鉴于进展性多发性硬化症尚无治疗方法，全面了解神经退行性变在其发病机制中的作用将导致治疗多发性硬化症的新的治疗策略，从而减少残疾。这项建议的目的是研究RNA结合蛋白(RBPs)的抗体如何导致MS的神经变性。RBPs对神经元的正常功能至关重要，最近被认为与神经退行性疾病如肌萎缩侧索硬化症和痴呆症的发病有关。然而，有关RBPs在免疫介导性疾病(如MS)的神经退行性变中所起作用的数据很少。许多研究表明，许多病毒触发因素是MS的原因之一，然而，没有单一病毒被证明是导致MS的唯一原因。鉴于此，人们使用MS的人和动物病毒模型来研究其发病机制。一个例子是人类T淋巴细胞病毒1型(HTLV-1)相关性脊髓病/热带痉挛性瘫痪(HAM/TSP)。HAM/TSP在临床、病理和免疫学上与进行性多发性硬化相似，是研究进行性多发性硬化症的相关模型。HAM/TSP患者被发现对异质性核核糖核蛋白A1(HnRNP A1)产生抗体，hnRNP A1是一种在神经元中过度表达的RBP。重要的是，多发性硬化症患者也被发现产生hnRNP A1抗体。抗hnRNP A1抗体减少了神经元的放电，并导致神经元细胞系的神经变性，表明这些抗体是致病的。此外，对暴露于抗hnRNP A1抗体的神经元的微阵列分析改变了hnRNP A1的功能，并揭示了神经退化的新途径。具体地说，脊椎截瘫基因(SPGS)的RNA水平下调。SPGS有助于正常的神经元功能和轴突运输。轴突运输的失调会导致神经变性。SPGS基因突变会导致遗传性痉挛瘫痪，这是一种临床上无法与进行性MS和HAM/TSP相区分的遗传性疾病。因此，SPGS参与神经退行性变与进展性MS和HAM/TSP患者的临床表型之间有很强的相关性，这些患者通常会发展为痉挛性瘫痪。这项资助的目的是研究抗hnRNP A1抗体如何导致神经退化。这将通过完成以下特定目标来实现：1.确定抗hnRNP A1抗体作为MS诊断试验的敏感性和特异性2.检测hnRNP A1与靶基因之间的分子相互作用，以确定它们在神经元功能和神经退行性变中的作用。3.用体内神经变性模型检测抗hnRNP A1抗体的致病性。目前还没有发现可以诊断多发性硬化症的血清检测方法。我们的数据表明，抗hnRNP A1抗体可用于MS的诊断。抗hnRNP A1抗体也可能导致神经变性和MS的发病机制。诊断和病原性免疫反应的结合具有特别重要的意义，并有可能对MS患者的长期护理和预后做出重要贡献。

DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate novel mechanisms of neurodegeneration related to the pathogenesis of progressive forms of multiple sclerosis (MS), a common cause of disability in United States Veterans. Considering there are no treatments for progressive MS, a comprehensive understanding of the role of neurodegeneration in its pathogenesis should lead to novel therapeutic strategies to treat MS, thereby reducing disability. The purpose of this proposal is to examine how antibodies to RNA binding proteins (RBPs) cause neurodegeneration in MS. RBPs are critical to the normal function of neurons and have been recently implicated in the pathogenesis of neurodegenerative disease like amyotropic lateral sclerosis and dementia. However, there are little data on the role that RBPs play in neurodegeneration in immune-mediated diseases like MS. Many studies have implicated a number of viral triggers as a cause of MS, yet, no single virus has been exclusively shown to cause MS. Given this, human and animal viral models of MS are used to study its pathogenesis. One example is human T-lymphotropic virus type-1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is similar clinically, pathologically, and immunologically to progressive MS and thus is a relevant model to study it. HAM/TSP patients were found to make antibodies to heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), an RBP overexpressed in neurons. Importantly, MS patients were also found to make antibodies to hnRNP A1. Anti-hnRNP A1 antibodies reduced neuronal firing and caused neurodegeneration in neuronal cell lines, suggesting that these antibodies are pathogenic. Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies altered hnRNP A1 function and revealed novel pathways of neurodegeneration. Specifically, there was downregulation of RNA levels of the spinal paraplegia genes (SPGs). SPGs contribute to normal neuronal function and axonal transport. Dysregulation of axonal transport results in neurodegeneration. Mutations in SPGs cause hereditary spastic paraparesis, genetic disorders clinically indistinguishable from progressive MS and HAM/TSP. Thus, there is a strong association between involvement of SPGs in neurodegeneration and the clinical phenotype of progressive MS and HAM/TSP patients, who commonly develop spastic paraparesis. The objective of this grant is to examine how anti-hnRNP A1 antibodies cause neurodegeneration. This will be accomplished by completing the following specific aims: 1. Determine the sensitivity and specificity of anti-hnRNP A1 antibodies as a diagnostic test for MS. 2. Examine molecular interactions between hnRNP A1 and target genes to determine their role in neuronal function and neurodegeneration. 3. Test for the pathogenicity of anti-hnRNP A1 antibodies using in vivo models of neurodegeneration. A serum test that can diagnose MS has yet to be discovered. Our data indicate that anti-hnRNP A1 antibodies can be used to diagnose MS. Anti-hnRNP A1 antibodies might also contribute to neurodegeneration and the pathogenesis of MS. The combination of both a diagnostic and pathogenic immune reaction is of particular relevance and has the potential to make important contributions to the long- term care and outcomes of people with MS.