Age-Related Alterations in Neuro-Immune Recognition of Allergens

过敏原神经免疫识别中与年龄相关的变化

• 批准号: 10559576
• 负责人: Caroline Lauren Sokol
• 金额: $ 20.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559576
• 关键词: Acute; Address; Affect; Afferent Neurons; Age; Age Years; Aging; Allergens; Allergic; Allergic Disease; Anatomy; Antibody Formation; Antigens; Behavioral; CD8B1 gene; Cell Communication; Cell Migration Inhibition function; Cells; Cellular Immunology; Chronic; Cutaneous; Data; Defect; Dendritic Cells; Dendritic cell activation; Detection; Development; Elderly; Exhibits; Exposure to; Flow Cytometry; Foundations; Gene Expression Profiling; Genetic Transcription; Goals; High Prevalence; Homeostasis; Human; Hydration status; Hypersensitivity; IgE; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; Immunology; Impairment; In Vitro; Incidence; Individual; Infiltration; Inflammation; Laboratories; Lead; Link; Location; Mechanical Stimulation; Mus; Nervous System; Neurobiology; Neuroimmune; Neuroimmunomodulation; Neurons; Neuropeptides; Neurotransmitters; Nuclear; Peptide Hydrolases; Peripheral; Persons; Physiological Processes; Play; Population; Production; Pruritus; Research; Role; Sensory; Site; Skin; Spinal Ganglia; Substance P; Symptoms; TRPV1 gene; Testing; Th1 Cells; Th2 Cells; Time; United States; adaptive immune response; age effect; age related; aged; airborne allergen; cell age; cell motility; chronic itch; draining lymph node; genetic signature; immune cell infiltrate; immune function; in vivo; insight; men; migration; neuroimmunology; neuronal cell body; normal aging; novel; novel strategies; novel therapeutic intervention; novel therapeutics; predictive modeling; pressure; prevent; programs; pruriceptive neurons; response; therapeutic development; tool; transcriptomics; young adult

Project Summary/Abstract The cutaneous sensory nervous system plays an essential role in the recognition of allergens and activation of the allergic immune response. Protease allergens directly activate pruriceptive, or itch-inducing, sensory neurons, leading to the sensation of itch and the local release of Substance P, which then activates and promotes the migration of allergic-skewing dendritic cells into the draining lymph node. Our laboratory is focused on understanding these neuro-immune interactions, specifically in identifying how pruriceptive sensory neurons detect allergens, what subsets of pruriceptive neurons are involved in this detection, and how sensory neuron-dendritic cell interactions are maintained in the skin. In order to better understand the neuro-immune mechanisms controlling the initiation of the allergic immune response, we propose to study how aging leads to defects in these mechanisms. Despite our continued exposure to new and novel allergens, the development of new allergic sensitizations is inversely correlated with age. At the same time, the itch response in the elderly is dysfunctional, with chronic pressure-induced itch being one of the most frequent symptoms in individuals over 65 years of age. If allergen-induced activation of pruriceptive neurons is directly upstream of allergic sensitization, what explains the low incidence of novel allergic sensitization in the very population with the highest prevalence of itch? Our central hypothesis is that aging leads to altered neuro-immune interactions within the dorsal root ganglia (the anatomical location of sensory neuron cell bodies) and the skin, resulting in dysfunctional itch responses and defective neuronal responses to allergens. Building upon our laboratory’s expertise in innate immunology, allergy and neuro-immunology, and taking the novel approach of comparing allergen sensitive young adult mice with allergen insensitive aged mice, we will use the tools of single cell and single nuclear transcriptomics, cellular immunology, and neurobiology to gain a fundamental understanding of the neuro-immune interactions required to initiate and maintain allergic immunity. We will test our central hypothesis in two specific aims: (1) identify the age-related changes that alter the sensory neuronal response to allergens, and (2) determine the role of age-related changes in sensory neuron function in the initiation of allergic immune responses. Aim 1 will examine how immune cell infiltration into aged dorsal root ganglia alters sensory neuronal populations and the sensitivity of those neurons to allergen-induced activation in both mice and humans. Aim 2 will focus on the skin, the site of allergen exposure, and address how aging alters the interactions between pruriceptive neurons and dendritic cells, and how age-induced alterations then impact the initiation of the allergic immune response. By studying the physiologic processes that control itch and allergic immune initiation, these studies will lay the groundwork for the development of therapeutic strategies to treat and prevent allergic diseases.

项目概要/摘要 皮肤感觉神经系统在识别过敏原和激活过敏原方面发挥着重要作用。 过敏性免疫反应。蛋白酶过敏原直接激活瘙痒或诱发瘙痒的感觉 神经元，导致瘙痒感和 P 物质局部释放，然后激活并 促进过敏偏向树突状细胞迁移到引流淋巴结。我们的实验室是 专注于理解这些神经免疫相互作用，特别是确定瘙痒感觉如何 神经元检测过敏原，哪些瘙痒神经元子集参与此检测，以及感觉如何 皮肤中维持神经元-树突状细胞的相互作用。为了更好地了解神经免疫 控制过敏性免疫反应启动的机制，我们建议研究衰老如何导致 这些机制的缺陷。尽管我们不断接触新的过敏原，但 新的过敏反应与年龄呈负相关。同时，老年人的瘙痒反应是 功能失调，慢性压力引起的瘙痒是个体最常见的症状之一 65岁。如果过敏原诱导的瘙痒神经元激活是过敏的直接上游 致敏，这解释了在患有该病的人群中新型过敏致敏的发生率低的原因 瘙痒症发病率最高？我们的中心假设是衰老会导致神经免疫相互作用的改变 在背根神经节（感觉神经元细胞体的解剖位置）和皮肤内，导致 瘙痒反应功能失调和对过敏原的神经元反应有缺陷。建立在我们实验室的基础上 先天免疫学、过敏和神经免疫学方面的专业知识，并采用新的比较方法 过敏原敏感的年轻成年小鼠和过敏原不敏感的老年小鼠，我们将使用单细胞和 单核转录组学、细胞免疫学和神经生物学，以获得基本的了解 启动和维持过敏免疫所需的神经免疫相互作用。我们将测试我们的中央 假设有两个具体目标：（1）确定改变感觉神经元反应的与年龄相关的变化 过敏原，以及（2）确定感觉神经元功能中与年龄相关的变化在引发过敏反应中的作用 过敏性免疫反应。目标 1 将检查免疫细胞浸润到老化的背根神经节中如何改变 两只小鼠的感觉神经元群体以及这些神经元对过敏原诱导的激活的敏感性 和人类。目标 2 将重点关注皮肤（过敏原暴露部位），并解决衰老如何改变皮肤的问题。 瘙痒神经元和树突状细胞之间的相互作用，以及年龄引起的改变如何影响 过敏性免疫反应的启动。通过研究控制瘙痒和过敏的生理过程 免疫启动，这些研究将为开发治疗策略奠定基础 并预防过敏性疾病。