A novel blood-CSF adaptive immune response in Alzheimer's disease

阿尔茨海默病中一种新型的血液-脑脊液适应性免疫反应

• 批准号: 10545096
• 负责人: David Gate
• 金额: $ 24.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545096
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-Protein; Antigens; Area; Autoimmune Responses; Autologous; Automobile Driving; Award; BZLF1 gene; Binding; Biological Assay; Biological Markers; Blood; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cells; Cellular biology; Cerebrospinal Fluid; Chronic; Circulation; Clonal Expansion; Clone Cells; Cloning; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Collaborations; Data; Deep Cervical Lymph Node; Disease; Extravasation; Fellowship; Fibroblasts; Genes; Germ Cells; Goals; Hematological Disease; Human; Human Herpesvirus 4; Immune; Immune response; Inflammation; Inflammatory; Intrathecal Space; Knock-out; Knowledge; Libraries; Liquid substance; Longevity; Measures; Mediating; Memory; Meningeal lymphatic system; Meninges; Mentors; Methods; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathologic; Patients; Peptide Receptor; Peptides; Peripheral; Phase; Play; Population; Process; Proteins; Public Health; Research; Research Personnel; Role; Severity of illness; Site; Specificity; Statistical Methods; Structure of choroid plexus; Subarachnoid Space; T cell clonality; T cell receptor repertoire sequencing; T-Cell Receptor; T-Lymphocyte; Testing; Training; Universities; Yeasts; adaptive immune response; age related; age related neurodegeneration; antigen-specific T cells; cell killing; cytokine; cytotoxic; effector T cell; environmental enrichment for laboratory animals; experience; experimental study; genome editing; neuroimmunology; neuroinflammation; neuron loss; new therapeutic target; next generation sequencing; novel; novel marker; rab GTP-Binding Proteins; resilience; response; screening; single-cell RNA sequencing; statistics; tau Proteins; theories; therapeutic biomarker; therapeutic target; transcription factor; transcriptomics; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-Protein; Antigens; Area; Autoimmune Responses; Autologous; Automobile Driving; Award; BZLF1 gene; Binding; Biological Assay; Biological Markers; Blood; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cells; Cellular biology; Cerebrospinal Fluid; Chronic; Circulation; Clonal Expansion; Clone Cells; Cloning; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Collaborations; Data; Deep Cervical Lymph Node; Disease; Extravasation; Fellowship; Fibroblasts; Genes; Germ Cells; Goals; Hematological Disease; Human; Human Herpesvirus 4; Immune; Immune response; Inflammation; Inflammatory; Intrathecal Space; Knock-out; Knowledge; Libraries; Liquid substance; Longevity; Measures; Mediating; Memory; Meningeal lymphatic system; Meninges; Mentors; Methods; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathologic; Patients; Peptide Receptor; Peptides; Peripheral; Phase; Play; Population; Process; Proteins; Public Health; Research; Research Personnel; Role; Severity of illness; Site; Specificity; Statistical Methods; Structure of choroid plexus; Subarachnoid Space; T cell clonality; T cell receptor repertoire sequencing; T-Cell Receptor; T-Lymphocyte; Testing; Training; Universities; Yeasts; adaptive immune response; age related; age related neurodegeneration; antigen-specific T cells; cell killing; cytokine; cytotoxic; effector T cell; environmental enrichment for laboratory animals; experience; experimental study; genome editing; neuroimmunology; neuroinflammation; neuron loss; new therapeutic target; next generation sequencing; novel; novel marker; rab GTP-Binding Proteins; resilience; response; screening; single-cell RNA sequencing; statistics; tau Proteins; theories; therapeutic biomarker; therapeutic target; transcription factor; transcriptomics

Project Summary/Abstract Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation is increasingly recognized to play a critical function. While innate inflammation has been implicated in AD, little is known about the contribution of the adaptive immune response. Preliminary data featured in this application demonstrate a peripheral immune signature of AD characterized by increased numbers of highly-differentiated CD8+ T effector memory CD45RA+ (TEMRA) cells. Strikingly, CD8+ TEMRA cells were also present in patient cerebrospinal fluid (CSF) and T cell receptor (TCR) sequencing indicated their clonal expansion, suggesting antigen specificity of these adaptive immune cells. TCR cloning and peptide screens demonstrated specificity of a subset of clonally expanded AD CSF TCRs to the Epstein-Barr virus (EBV) BZLF1 antigen. These results provide the first evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration. This K99/R00 application will test the novel theory of a detrimental adaptive immune response contributing to AD pathobiology. In Specific Aim 1, AD blood-CSF T cell clonotypes will be related to CSF biomarkers. This approach will determine specific T cell populations in AD and whether these cells relate to disease severity. In Specific Aim 2, antigen identification screens will be used to detect the self/non-self antigen(s) driving T cell clonal expansion in AD. These assays could uncover a novel therapeutic target or biomarker for AD. Specific Aim 3 will determine mechanisms of T cell-mediated neuronal death and resiliency in AD using induced neuronal (iN) cells co-cultured with patient CSF CD8+ T cells. These experiments will assess whether AD CSF CD8+ T cells mount cytotoxic effector responses to iN cells infected with EBV and/or to a molecular mimic of BZLF1. The candidate, Dr. David Gate, has extensive experience in T cell biology and has spent more than a decade studying AD. During the mentoring phase of this award, Dr. Gate aims to advance his knowledge in next-generation sequencing analysis, sophisticated statistical methods, antigen screening, iN culturing methods and CRISPR gene editing. Dr. Gate's mentor and co-mentor, Dr. Tony Wyss-Coray and Dr. Mark Davis, respectively, have comprehensive expertise in these areas. They will provide an enriching environment for Dr. Gate to develop as a prominent independent investigator in neuroimmunology research. As an independent investigator, Dr. Gate will leverage the training under this fellowship to comprehensively and quantitatively evaluate the interactions between T cell molecular components and neurodegeneration.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种无法治愈的神经退行性疾病，其中神经炎症越来越多 承认发挥关键功能。尽管在广告中实施了先天注射，但对 适应性免疫反应的贡献。本应用程序中列出的初步数据证明了 AD的外周免疫特征，其特征是高分差异CD8+ T效应器数量增加 记忆CD45RA+（TEMRA）细胞。令人惊讶的是，CD8+ TEMRA细胞也存在于患者脑脊液中 （CSF）和T细胞受体（TCR）测序表明它们的克隆膨胀，表明抗原特异性 这些适应性免疫核管。 TCR克隆和胡椒屏幕显示了克隆的子集的特异性 将AD CSF TCR扩展到Epstein-Barr病毒（EBV）BZLF1抗原。这些结果提供了第一个证据 克隆，抗原经验的T细胞巡逻大脑的鞘内空间，受年龄相关的影响 神经变性。该K99/R00应用将测试有害自适应免疫的新颖理论 导致AD病理生物学的反应。在特定的目标1中，AD Blood-CSF T细胞clonotypes将与 CSF生物标志物。这种方法将确定AD中的特定T细胞群，以及这些细胞是否相关 疾病的严重程度。在特定的目标2中，抗原识别屏幕将用于检测自我/非自我 AD中驱动T细胞克隆膨胀的抗原。这些测定可能会发现新颖的治疗靶标或 广告的生物标志物。具体目标3将确定T细胞介导的神经元死亡和弹性的机制 在AD中，使用与患者CSF CD8+ T细胞共培养的诱导神经元（IN）细胞。这些实验将评估 AD CSF CD8+ T细胞是否安装了对感染EBV和/或对A的细胞中的细胞毒性效应子的反应 BZLF1的分子模仿。候选人David Gate博士在T细胞生物学方面拥有丰富的经验，并具有 花十多年的学习广告。在该奖项的心理阶段，Gate博士旨在推动他的 下一代测序分析，复杂的统计方法，抗原筛选，中的知识 培养方法和CRISPR基因编辑。 Gate博士的心理和院长Tony Wyss-Coray博士和博士 马克·戴维斯（Mark Davis）分别在这些领域拥有全面的专业知识。他们将提供丰富的 Gate博士发展为神经免疫研究的著名独立研究者的环境。作为 Gate博士是一个独立的调查员，将利用该奖学金下的培训进行全面和 定量评估T细胞分子成分与神经变性之间的相互作用。