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: 10207808
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207808
• 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; 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; 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; 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.

阿尔茨海默病（AD）是一种无法治愈的神经退行性疾病，神经炎症在其中起着至关重要的作用。虽然先天炎症与阿尔茨海默病有关，但对适应性免疫反应的贡献知之甚少。本应用程序的初步数据表明，AD的外周免疫特征以高度分化的CD8+ T效应记忆CD45RA+ (TEMRA)细胞数量增加为特征。引人注目的是，患者脑脊液（CSF）中也存在CD8+ TEMRA细胞，T细胞受体（TCR）测序显示它们的克隆扩增，表明这些适应性免疫细胞具有抗原特异性。TCR克隆和肽筛选表明，克隆扩增的AD CSF TCR亚群对eb病毒（EBV） BZLF1抗原具有特异性。这些结果提供了克隆的第一个证据，抗原经历的T细胞巡逻脑鞘内空间受年龄相关性神经变性的影响。这项K99/R00应用将测试有害适应性免疫反应促进AD病理生物学的新理论。在Specific Aim 1中，AD血-CSF T细胞克隆型将与CSF生物标志物相关。这种方法将确定AD中的特定T细胞群以及这些细胞是否与疾病严重程度有关。在Specific Aim 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。这些检测可能会发现一种新的AD治疗靶点或生物标志物。特异性Aim 3将通过诱导神经元（in）细胞与患者CSF CD8+ T细胞共培养，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细胞是否对感染EBV和/或BZLF1分子模拟物的iN细胞产生细胞毒效应反应。候选人David Gate博士在T细胞生物学方面拥有丰富的经验，并花了十多年的时间研究AD。在该奖项的指导阶段，Gate博士旨在提高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。他们将为盖茨博士提供丰富的环境，使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，Gate博士将利用该奖学金下的培训，全面定量地评估T细胞分子成分与神经变性之间的相互作用。

项目成果

Methods to investigate intrathecal adaptive immunity in neurodegeneration.

• DOI: 10.1186/s13024-021-00423-w
• 发表时间: 2021-01-22
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Oh H;Leventhal O;Channappa D;Henderson VW;Wyss-Coray T;Lehallier B;Gate D
• 通讯作者: Gate D

Epigenetic dysregulation in Alzheimer's disease peripheral immunity.

阿尔茨海默病外周免疫的表观遗传失调。

• DOI: 10.1016/j.neuron.2024.01.013
• 发表时间: 2024
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Ramakrishnan,Abhirami;Piehl,Natalie;Simonton,Brooke;Parikh,Milan;Zhang,Ziyang;Teregulova,Victoria;vanOlst,Lynn;Gate,David
• 通讯作者: Gate,David