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.

项目总结 最近在了解先天性免疫系统在发病机制中的作用方面取得了进展。 阿尔茨海默病(AD)；然而，获得性免疫在外周和中枢神经中的作用 AD中的系统在很大程度上仍未被探索。因此，关键的下一步是了解交互 先天免疫和获得性免疫之间的关系，以及它对大脑老化和神经退化的影响。以前的工作 已表明外周血和脑脊液中存在克隆性扩增的CD8+T细胞 阿尔茨海默病患者中。在我们正在进行的工作中，利用人脑免疫细胞的单细胞图谱，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变化 阿尔茨海默病标本的脑实质。此外，我们小组发表的和正在进行的工作提供了 人类和小鼠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)程序的证据 小胶质细胞可改善AD的病理改变。再论先天与后天的相互作用 需要人类和小鼠的免疫来机械地了解它在AD不同阶段的作用。 疾病。 在人类AD中研究先天免疫和获得性免疫之间的相互作用是具有挑战性的，因为 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条管道来分离 来自新鲜脑组织的免疫细胞，以生成多尺度单细胞数据。以我们的专业知识和 现有资源，这里我们建议执行多组织单细胞多组学和空间转录组学 阿尔茨海默病患者和健康对照的免疫细胞。为了更深入地了解 对于适应性免疫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……里面 目标1，我们将研究获得性免疫细胞和先天免疫细胞的多样性、丰度和空间位置。 通过脑-屏障-血轴(脑、脑膜、脉络丛和外周血液)识别 AD患者获得性免疫(T细胞和B细胞)的组成、表型和抗原特异性的差异 在组织中共享或不同的组织。在目标2中，我们将探索适应性和先天的相互作用 脑-屏障-血轴的免疫系统识别阿尔茨海默病不同的细胞间相互作用网络， 指出免疫细胞亚群之间的配体-受体关系的获得或丢失。在《目标3》中，我们将 获得性免疫细胞与中枢天然免疫之间细胞间串扰的机制研究 阿尔茨海默病小鼠模型的细胞。总的来说，这些研究将使我们能够以前所未有的决心探索 AD患者的适应性和先天免疫反应，并为我们的 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 中枢神经系统中迫切需要的适应性和先天免疫资源，可用于 未来的研究。