Molecular Mimicry in Immune Mediated Neurologic Disease

免疫介导的神经系统疾病中的分子拟态

• 批准号: 8536552
• 负责人: Michael Levin
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536552
• 关键词: Affect; Animal Model; Animals; Antibodies; Autoimmune Diseases; Autoimmune Responses; Axonal Transport; Binding; Caring; Cell Line; Central Nervous System Diseases; Clinical; Congresses; Consensus Sequence; Data; Dementia; Demyelinating Diseases; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Down-Regulation; Early Diagnosis; Epitopes; Exposure to; Family; Gene Expression; Gene Targeting; Genes; Goals; Grant; Hereditary Disease; Hereditary Spastic Paraparesis; Heterogeneous-Nuclear Ribonucleoproteins; Human; Human T-lymphotropic virus 1; Immune; Immune response; Immunoglobulin G; Inflammatory; Lead; Life; Long-Term Care; Mediating; Mission; Modeling; Molecular Mimicry; Morbidity - disease rate; Multiple Sclerosis; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neuronal Dysfunction; Neurons; Nuclear; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Play; Primary Lateral Sclerosis; Proteins; RNA; RNA Binding; RNA-Binding Proteins; Reaction; Relapse; Research; Role; Sensitivity and Specificity; Serum; Spastic Paraparesis; Spinal Cord Diseases; Spinal Paraplegias; System; T-Lymphocyte; Testing; Translations; Tropical Spastic Paraparesis; United States; Veterans; Viral; Virus; clinical phenotype; cost; disability; immunoreactivity; in vivo Model; mortality; nervous system disorder; novel; novel therapeutics; overexpression; protein aminoacid sequence; public health relevance; spastin; therapy development

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.

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）发病机制相关的神经退行性新机制，多发性硬化症是美国退伍军人残疾的常见原因。考虑到进行性多发性硬化症尚无治疗方法，全面了解神经变性在其发病机制中的作用应该会导致治疗多发性硬化症的新治疗策略，从而减少残疾。该提案的目的是研究 RNA 结合蛋白 (RBP) 的抗体如何导致多发性硬化症的神经变性。 RBP 对神经元的正常功能至关重要，最近被认为与肌萎缩侧索硬化症和痴呆等神经退行性疾病的发病机制有关。然而，关于 RBP 在免疫介导疾病（如多发性硬化症）的神经变性中所起的作用的数据很少。许多研究表明多种病毒触发因素是多发性硬化症的病因，但目前还没有单一病毒被证明可以单独引起多发性硬化症。鉴于此，人类和动物多发性硬化症病毒模型被用来研究其发病机制。一个例子是人类 T 淋巴细胞病毒 1 型 (HTLV-1) 相关的脊髓病/热带痉挛性截瘫 (HAM/TSP)。 HAM/TSP 在临床、病理学和免疫学上与进行性 MS 相似，因此是研究它的相关模型。研究发现 HAM/TSP 患者会产生针对异质核核糖核蛋白 A1 (hnRNP A1) 的抗体，这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 抗体减少神经元放电并引起神经元细胞系神经变性，表明这些抗体具有致病性。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 功能，并揭示了神经退行性变的新途径。具体来说，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。轴突运输失调导致神经变性。 SPG 突变会导致遗传性痉挛性截瘫，这种遗传性疾病在临床上与进行性 MS 和 HAM/TSP 无法区分。因此，SPG 参与神经变性与进行性 MS 和 HAM/TSP 患者的临床表型之间存在密切关联，这些患者通常会出现痉挛性截瘫。这笔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 hnRNP A1 抗体作为 MS 诊断测试的敏感性和特异性。 2. 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变性中的作用。 3.使用神经变性体内模型测试抗hnRNP A1抗体的致病性。尚未发现可以诊断多发性硬化症的血清测试。我们的数据表明抗 hnRNP A1 抗体可用于诊断 MS。抗 hnRNP A1 抗体也可能导致神经变性和 MS 的发病机制。诊断和致病性免疫反应的结合具有特别重要的意义，并且有可能对多发性硬化症患者的长期护理和结果做出重要贡献。