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: 10054559
• 负责人: David Gate
• 金额: $ 12.23万
• 依托单位: STANFORD UNIVERSITY
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054559
• 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; Blood Circulation; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cells; Cellular biology; Cerebrospinal Fluid; Chronic; Clonal Expansion; Clone Cells; Cloning; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Data; Deep Cervical Lymph Node; Disease; Fellowship; Fibroblasts; Genes; Goals; Hematological Disease; Human; Human Herpesvirus 4; Immune; Immune response; Inflammation; Inflammatory; Intrathecal Space; Knock-out; Knowledge; Libraries; Liquid substance; Longevity; Lymphatic System; Measures; Mediating; Memory; Meningeal; 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; T cell clonality; T-Cell Receptor; T-Lymphocyte; Testing; Training; Universities; Yeasts; adaptive immune response; age related; age related neurodegeneration; antigen-specific T cells; brain circulation; 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

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.

阿尔茨海默氏病 (AD) 是一种无法治愈的神经退行性疾病，人们越来越认识到神经炎症在 AD 中发挥着关键作用，虽然先天性炎症与 AD 有关，但本申请中的初步数据表明，人们对适应性免疫反应的贡献知之甚少。 AD 的外周免疫特征是高度分化的 CD8+ T 效应记忆 CD45RA+ (TEMRA) 细胞数量增加，令人惊讶的是，患者体内也存在 CD8+ TEMRA 细胞。脑脊液 (CSF) 和 T 细胞受体 (TCR) 测序表明它们的克隆扩增，表明这些适应性免疫细胞的抗原特异性和肽筛选证明了克隆扩增的 AD CSF TCR 子集对 Epstein-Barr 病毒的特异性。 EBV）BZLF1 抗原。这些结果提供了克隆性、抗原经历过的 T 细胞在受年龄相关神经变性影响的大脑鞘内空间巡逻的第一个证据。 K99/R00 应用将测试 AD 病理学中的应激适应性免疫反应的新理论，在特定目标 1 中，AD 血液 CSF T 细胞克隆型将与 CSF 生物标志物相关。 AD 以及这些细胞是否与疾病严重程度相关。在特定目标 2 中，抗原鉴定筛选将用于检测 AD 中驱动 T 细胞克隆扩增的自身/非自身抗原。或者具体目标 3 将使用与患者 CSF CD8+ T 细胞共培养的诱导神经元 (iN) 细胞来确定 AD 中 T 细胞介导的神经元死亡和恢复机制，这些实验将评估 AD CSF CD8+ T 细胞是否具有细胞毒性。候选人 David Gate 博士在 T 细胞生物学方面拥有丰富的经验，并在 AD 领域花费了十多年的时间。 Gate 博士的目标是提升他在下一代测序分析、复杂统计方法、抗原筛选、iN 培养方法和 CRISPR 基因编辑方面的知识。 Gate 博士的导师和共同导师 Tony Wyss-Coray 博士和 Mark Davis 博士。分别在这些领域拥有全面的专业知识，他们将为盖特博士提供一个丰富的环境，让他成为神经免疫学研究领域的杰出独立研究者。作为一名独立研究者，盖特博士将利用该奖学金的培训。全面定量评估T细胞分子成分与神经退行性变之间的相互作用。