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 近年来，对先天免疫系统在该病发病机制中的作用的研究取得了新的进展 阿尔茨海默病（AD）;然而，适应性免疫在外周和中枢神经系统中的作用 AD系统在很大程度上尚未探索。因此，关键的下一步是了解 先天免疫和适应性免疫之间的关系，以及它对大脑衰老和神经退行性变的影响。以前的工作 已经表明克隆扩增的CD 8 + T细胞存在于外周血和脑脊液中 AD患者。在我们正在进行的工作中，利用人脑免疫细胞的单细胞分析，我们 扩大了这一观察，并确定了适应性和先天免疫系统的细胞类型的变化， AD衍生样品的脑实质。此外，我们小组已发表和正在进行的工作提供了 在人类和小鼠中的证据表明，星形胶质细胞和适应性免疫细胞来源的白细胞介素-3（IL-3）程序 小胶质细胞，以改善AD的病理。进一步分析先天与适应之间的相互作用 需要在人类和小鼠中进行免疫，以机械地理解其在AD的不同阶段的作用。 疾病 研究人类AD中先天免疫和适应性免疫之间的相互作用是具有挑战性的， 新鲜组织标本的可用性。在过去的5年里，我们的团队已经建立了一个管道， 从新鲜脑组织中提取免疫细胞，以生成多尺度单细胞数据。基于我们的专业知识和 利用现有资源，我们建议进行多组织单细胞多组学和空间转录组学 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， 在适应性免疫和先天免疫之间的相互作用方面，我们将在AD小鼠模型中进行平行研究。在 目的1，我们将研究适应性和先天性免疫细胞的多样性，丰度和空间位置 穿过脑屏障-血轴（脑、脑膜、脉络丛和外周血）， AD中获得性免疫（T和B细胞）的组成、表型和抗原特异性的差异 在不同组织中共享或不同。在目标2中，我们将探索适应性和先天性的相互作用组， 免疫系统在脑屏障-血液轴中识别AD中的差异细胞间相互作用网络， 这表明免疫细胞亚群之间配体-受体关系的获得或丧失。在目标3中，我们 机械地描绘适应性免疫细胞和中枢先天免疫细胞之间的细胞间串扰 AD小鼠模型中的细胞。总的来说，这些研究将使我们能够以前所未有的分辨率探索 获得性和先天性免疫反应，并提供了一个假定的机制解释，我们 利用小鼠模型进行观察。重要的是，我们的工作将为科学界提供一个 迫切需要的资源，为适应性和先天性免疫的中枢神经系统，可用于 未来的研究。