Age-Related Alterations in Neuro-Immune Recognition of Allergens

项目摘要/摘要 皮肤感觉神经系统在过敏原的识别和激活中起着至关重要的作用。 过敏性免疫反应。蛋白水解酶过敏原直接激活瘙痒或瘙痒感觉神经 神经元，导致瘙痒的感觉和局部P物质的释放，然后激活和 促进过敏性偏斜树突状细胞向引流淋巴结的迁移。我们的实验室是 重点是了解这些神经免疫相互作用，特别是在识别瘙痒感觉如何 神经元检测过敏原，瘙痒感觉神经元的哪些亚群参与了这一检测，以及感觉如何 神经元-树突状细胞的相互作用在皮肤中保持不变。为了更好地了解神经免疫 控制过敏免疫反应启动的机制，我们建议研究衰老是如何导致 这些机制中的缺陷。尽管我们继续接触新的和新的过敏原，但 新的过敏性反应与年龄呈负相关。与此同时，老年人的瘙痒反应是 功能障碍，慢性压力引起的瘙痒是老年人最常见的症状之一 65岁。如果过敏原诱导的瘙痒感觉神经元的激活直接位于过敏的上游 致敏，是什么解释了为什么新型过敏性致敏在患有 瘙痒患病率最高？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 对过敏原的功能性瘙痒反应和神经元反应缺陷。在我们实验室的基础上 在先天免疫学、过敏症和神经免疫学方面的专业知识，并采用新的方法比较 过敏原敏感的青壮年小鼠与过敏原不敏感的老年小鼠，我们将使用单细胞和 单一的核转录学、细胞免疫学和神经生物学，以获得对 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 两个特定目标的假说：(1)确定与年龄相关的改变感觉神经元反应的变化 以及(2)确定与年龄相关的感觉神经元功能变化在启动 过敏性免疫反应。目标1将研究免疫细胞渗入老年背根神经节的变化 两种小鼠感觉神经元群及其对变应原诱导激活的敏感性 和人类。Aim 2将专注于皮肤，过敏原暴露的部位，并解决衰老如何改变 瘙痒感觉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 启动过敏性免疫反应。通过研究控制瘙痒和过敏的生理过程 免疫启动，这些研究将为制定治疗策略奠定基础 并预防过敏性疾病。

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.