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多发性硬化症（MS）进行性形式发病机制相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。考虑到没有治疗进展性MS的方法，全面了解神经退行性疾病在其发病机制中的作用应导致治疗MS的新治疗策略，从而减少残疾。本提案的目的是研究RNA结合蛋白（RBP）抗体如何导致MS神经退行性变。RBP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）的发病机制有关。然而，几乎没有关于RBP在免疫介导的疾病（如MS）中神经退行性变中所起作用的数据。许多研究已经暗示了许多病毒触发剂作为MS的原因，然而，没有单一病毒被专门证明会导致MS。一个实例是人类T淋巴细胞病毒1型（HTLV-1）相关的脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）。HAM/TSP在临床、病理和免疫学上与进行性MS相似，因此是研究其的相关模型。HAM/TSP患者被发现产生针对异质核核糖核蛋白A1（hnRNP A1）的抗体，该蛋白是在神经元中过表达的RBP。重要的是，MS患者也被发现产生hnRNP A1抗体。抗hnRNP A1抗体减少神经元放电，并引起神经元细胞系的神经变性，表明这些抗体是致病性的。此外，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，并揭示了神经变性的新途径。具体而言，脊髓截瘫基因（SPG）的RNA水平下调。SPG有助于正常的神经元功能和轴突运输。轴突运输的失调导致神经变性。SPG突变引起遗传性痉挛性下肢轻瘫，这是临床上与进行性MS和HAM/TSP难以区分的遗传性疾病。因此，SPG参与神经变性与进展性MS和HAM/TSP患者的临床表型之间存在很强的相关性，这些患者通常发生痉挛性轻瘫。这项资助的目的是研究抗hnRNP A1抗体如何引起神经变性。这将通过完成以下具体目标来实现：1.确定抗hnRNPA 1抗体作为MS诊断试验的灵敏度和特异性。检查hnRNP A1和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.使用体内神经变性模型测试抗hnRNPA 1抗体的致病性。一种可以诊断MS的血清测试还没有被发现。我们的数据表明，抗hnRNP A1抗体可用于诊断MS。抗hnRNP A1抗体也可能有助于神经变性和MS的发病机制。诊断性和致病性免疫反应的组合具有特别的相关性，并有可能对MS患者的长期护理和结局做出重要贡献。

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.