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: 10373431
• 负责人: Caroline Lauren Sokol
• 金额: $ 24.41万
• 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/10373431
• 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; 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 structure; 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; base; cell age; cell motility; chronic itch; draining lymph node; genetic signature; immune function; in vivo; insight; men; migration; neuroimmunology; 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.

项目总结/摘要 皮肤感觉神经系统在过敏原的识别和过敏原的激活中起重要作用。 过敏性免疫反应蛋白酶过敏原直接激活刺激性或瘙痒诱导性感觉神经元， 神经元，导致瘙痒的感觉和P物质的局部释放，然后激活， 促进过敏性偏斜树突细胞迁移到引流淋巴结。本实验室 专注于了解这些神经免疫相互作用，特别是在确定如何刺激感觉 神经元检测过敏原，哪些免疫感受神经元的子集参与这种检测，以及感觉如何 神经元-树突细胞相互作用在皮肤中维持。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和新颖的过敏原， 新的变应性致敏与年龄呈负相关。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人最常见的症状之一， 65岁。如果过敏原诱导的免疫感受神经元的激活直接位于过敏原的上游， 致敏性，是什么解释了新的过敏性致敏性的发病率低，在非常人群与 最常见的瘙痒我们的中心假设是，衰老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 功能失调的瘙痒反应和对过敏原的神经元反应缺陷。基于我们实验室的 在先天免疫学，过敏和神经免疫学的专业知识，并采取新的方法比较 过敏原敏感的年轻成年小鼠与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，以获得对 启动和维持过敏性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）确定与年龄有关的改变感觉神经元反应的变化 （2）确定年龄相关的感觉神经元功能变化在启动过敏原中的作用。 过敏性免疫反应目的1将研究免疫细胞浸润如何改变老年人背根神经节 感觉神经元群体和这些神经元对两种小鼠中变应原诱导的激活的敏感性 还有人类目标2将集中在皮肤，过敏原暴露的网站，并解决如何老化改变 免疫感受神经元和树突状细胞之间的相互作用，以及年龄诱导的变化如何影响免疫反应。 引发过敏性免疫反应。通过研究控制瘙痒和过敏的生理过程， 免疫启动，这些研究将奠定基础的治疗策略的发展，以治疗 预防过敏性疾病。