The adaptive-innate immune interactome across multiple tissues in Alzheimer's disease

阿尔茨海默病跨多个组织的适应性先天免疫相互作用组

• 批准号: 10662733
• 负责人: VAHRAM HAROUTUNIAN
• 金额: $ 243.82万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662733
• 关键词: Adaptive Immune System; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Antigens; Astrocytes; Automobile Driving; B-Lymphocytes; Behavioral; Biological Response Modifiers; Blood - brain barrier anatomy; Brain; CD8-Positive T-Lymphocytes; Cell Communication; Cell Surface Proteins; Cells; Central Nervous System; Cerebrospinal Fluid; Clinical; Clonal Expansion; Communication; Communities; Data; Disease; Disease Progression; Fresh Tissue; Future; Gene Expression; Generations; Genetic Transcription; Human; Image; Immune; In Situ; Innate Immune Response; Innate Immune System; Interleukins; Knock-out; Ligands; Location; Mediating; Meningeal; Meninges; Microglia; Modeling; Mus; Natural Immunity; Nerve Degeneration; Neurobiology; Pathogenesis; Pathologic; Patients; Pattern; Peripheral; Phenotype; Production; Publishing; Resolution; Resources; Role; Sampling; Source; Specificity; Specimen; Structure of choroid plexus; T-Lymphocyte; T-Lymphocyte Subsets; Taxonomy; Testing; Thinking; Tissue Banks; Tissues; Work; adaptive immune response; adaptive immunity; aging brain; brain parenchyma; brain tissue; case control; cell type; cytokine; expectation; healthy aging; insight; mouse model; multiple omics; novel; peripheral blood; programs; receptor; transcriptomic profiling; transcriptomics

PROJECT SUMMARY Recent progress has been made on understanding the role of the innate immune system in the pathogenesis of Alzheimer’s disease (AD); however, the role of adaptive immunity in the periphery and the central nervous system in AD remains largely unexplored. Therefore, a critical next step is to understand the interaction between innate and adaptive immunity, and its impact on brain aging and neurodegeneration. Previous work has shown that clonally expanded CD8+ T cells are present in the peripheral blood and the cerebrospinal fluid of patients with AD. In our ongoing work, utilizing single cell profiling of human brain immune cells, we expanded this observation and identified cell type changes of the adaptive and innate immune system in the brain parenchyma of AD derived samples. In addition, published and ongoing work from our group provides evidence in humans and mice that astrocyte and adaptive immune cell-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Further analysis of the interaction between innate and adaptive immunity in humans and mice is needed to mechanistically understand its role in AD at different stages of the disease. Studying the interaction between innate and adaptive immunity in AD in humans is challenging due to limited availability of fresh tissue specimens. Over the last 5 years, our team has established a pipeline to isolate immune cells from fresh brain tissue to generate multiscale single cell data. Building on our expertise and existing resources, here we propose to perform multi-tissue single cell multiomics and spatial transcriptomics of immune cells from AD cases and healthy controls. To gain additional mechanistic insights into the interactions between adaptive and innate immunity, we will perform parallel studies in AD mouse models. In Aim 1, we will examine the diversity, abundance and spatial location of adaptive and innate immune cells across the brain-barrier-blood axis (brain, meninges, choroid plexus, and peripheral blood) to identify differences in the composition, phenotype, and antigen specificity of adaptive immunity (T and B cells) in AD that are shared or distinct across tissues. In Aim 2, we will explore the interactome of adaptive and innate immune systems in the brain-barrier-blood axis to identify differential cell-to-cell interaction networks in AD, pointing to gain or loss of ligand-receptor relationships among immune cell subpopulations. In Aim 3, we will mechanistically delineate intercellular crosstalk between adaptive immune cells and central innate immune cells in murine models of AD. Collectively, these studies will enable us, at unprecedented resolution, to explore the adaptive and innate immune response in AD cases and provide a putative mechanistic explanation for our observations by utilizing mouse models. Importantly, our work will provide the scientific community with an urgently needed resource for adaptive and innate immunity in the central nervous system that can be utilized in future studies.

项目摘要 最近在了解先天免疫系统在发病机理中的作用方面取得了进展 阿尔茨海默氏病（AD）；但是，适应性免疫在周围和中枢神经系统中的作用 广告中的系统在很大程度上仍然是出乎意料的。因此，关键的下一步是了解互动 在先天和适应性免疫学之间及其对脑衰老和神经变性的影响。以前的工作 已经表明，外周血和脑脊液中存在克隆扩展的CD8+ T细胞 AD患者在我们正在进行的工作中，使用人脑免疫细胞的单细胞分析，我们 扩展了这种观察结果，并确定了自适应和先天免疫系统的细胞类型变化 AD衍生样品的脑实质。此外，我们小组的出版和正在进行的工作提供 人类和小鼠的证据表明星形胶质细胞和适应性免疫细胞源性白细胞介素3（IL-3）程序 小胶质细胞改善AD的病理。对先天和适应性之间的相互作用的进一步分析 需要机械地了解人类和小鼠的免疫力，以便在不同阶段的不同阶段进行机械了解其在AD中的作用 疾病。 由于有限 新鲜组织标本的可用性。在过去的5年中，我们的团队建立了一条管道来隔离 来自新鲜脑组织的免疫细胞产生多尺度的单细胞数据。以我们的专业知识为基础 现有资源，在这里我们建议执行多组织单细胞多摄像和空间转录组学 来自AD病例和健康对照的免疫细胞。为了获得更多的机械见解 自适应和先天免疫之间的相互作用，我们将在AD小鼠模型中进行平行研究。在 AIM 1，我们将检查适应性和先天免疫细胞的多样性，抽象和空间位置 跨越脑部障碍轴（大脑，脑膜，脉络丛和外周血），以识别 AD中适应性免疫组织化学（T和B细胞）组成，表型和抗原特异性的差异 在组织之间共享或不同。在AIM 2中，我们将探索适应性和先天的互动 脑屏障血管中的免疫系统，以识别AD中的差分细胞对细胞相互作用网络， 指出免疫细胞亚群中配体受体关系的增益或丧失。在AIM 3中，我们将 在自适应免疫小球和中央先天免疫球之间的机械学上划定细胞间串扰 AD鼠模型中的细胞。这些研究共同使我们能够以前所未有的决议来探索 在AD情况下​​，适应性和先天的免疫反应，为我们提供了推定的机械解释 通过使用鼠标模型进行观察。重要的是，我们的工作将为科学界提供 在中枢神经系统中，迫切需要的适应性和先天免疫的资源可用于 未来的研究。