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多发性硬化症（MS）进行性发病机理有关的神经变性的新机制，这是美国退伍军人残疾的常见原因。考虑到没有治疗渐进式MS的治疗方法，对神经变性在其发病机理中的作用的全面理解应导致治疗MS的新型治疗策略，从而减少残疾。该建议的目的是检查对RNA结合蛋白（RBP）的抗体如何在MS中引起神经变性。 RBP对神经元的正常功能至关重要，最近与神经退行性疾病（如肌动肌侧面硬化症和痴呆症）的发病机理有关。但是，关于RBP在MS等免疫介导的疾病中的神经变性中的作用的数据很少。许多研究都暗示了许多病毒触发因素是MS的原因，但是，尚无单一病毒被仅显示引起MS。鉴于此，MS的人类和动物病毒模型用于研究其发病机理。一个例子是人类T-淋巴病毒类型1（HTLV-1）相关的骨髓病/热带痉挛性简调（HAM/TSP）。 HAM/TSP在临床，病理和免疫学上与进行性MS相似，因此是研究它的相关模型。发现HAM/TSP患者对异质性核核糖核蛋白A1（HNRNP A1）产生抗体，该蛋白A1（HNRNP A1）是神经元过表达的RBP。重要的是，还发现MS患者对HNRNP A1产生抗体。抗HNRNP A1抗体可降低神经元触发并在神经元细胞系中引起神经退行性，这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功能，并揭示了神经变性的新途径。具体而言，脊柱截瘫基因（SPG）的RNA水平下调。 SPG有助于正常的神经元功能和轴突运输。轴突转运的失调导致神经变性。 SPG中的突变引起遗传性痉挛性模拟，遗传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着很强的联系，这些表型通常会伴有痉挛性模拟。该赠款的目的是检查抗HNRNP A1抗体如何引起神经变性。这将通过完成以下特定目的来实现：1。确定抗HNRNP A1抗体的灵敏度和特异性作为MS的诊断测试。 2。检查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变性中的作用。 3。测试使用神经变性的体内模型的抗HNRNP A1抗体的致病性。可以诊断为MS的血清测试尚未发现。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的发病机理。诊断和致病性免疫反应的组合特别相关，并且有可能对MS患者的长期护理和结果做出重要贡献。