Innate and Adaptive Immune Cell Cross-Talk in Lung Allergy

哮喘是一种复杂的炎症性疾病，被认为反映了一种已确立的免疫失调状态。 肺组织中细胞因子IL-4和IL-13水平升高。与生俱来的和适应性的数量增加 IL-4/IL-13表达的细胞包括Th2细胞、嗜酸性粒细胞、嗜碱性粒细胞和肥大细胞。 受影响的肺部，以及IgE水平升高被认为是导致对空气变应原敏感的原因。尽管 诱导炎性T辅助细胞亚群的受体的微生物配体的发现，包括 Th1细胞和Th17细胞，目前已知的诱导免疫反应的分子标记很少 与过敏和哮喘有关的特有细胞类型。我们最近发现，一种常见的 与许多过敏原相关的成分能够诱导嗜酸性粒细胞和嗜碱性粒细胞涌入 小鼠的肺。此外，滴注诱导了交替激活的巨噬细胞的积累，这 越来越多地被认为是过敏免疫的关键因素。本项目将探索 蠕虫、昆虫和真菌细胞壁的这一组成部分在引发变化方面的贡献 在树突状细胞中，介导Th2细胞的分化，募集天然的IL-4/IL-13产生细胞， 诱导B细胞反应，导致IgE和lgG1，最终引起粘膜和组织反应。vbl.使用 报告Th2相关免疫关键成分忠实表达的基因修饰的小鼠，三 提出了具体目标： 1.评估甲壳素作为佐剂和曲霉真菌提取物的成分在 体内诱导树突状细胞活化。 2.评估甲壳素作为佐剂和曲霉真菌提取物的成分在 诱导Th2细胞和IL-4依赖的抗体亚型。 3.评估甲壳素在诱导限制炎症过程的反馈机制中的作用 肺部。 综述：哮喘在美国和其他发达国家的流行率仍然很高 国家。关于导致哮喘的精确环境因素的知识，可在 模型动物系统是不完整的。这项提议将利用老鼠来研究新的和相关的机制。

Asthma is a complex inflammatory disease thought to reflect a dysregulated immune state that is established by elevated levels of the cytokines IL-4 and IL-13 in lung tissues. Increased numbers of innate and adaptive IL-4/IL-13-expressing cells, including Th2 cells, eosinophils, basophils and mast cells are found in chronically affected lung, and elevated levels of IgE are believed to contribute to sensitivity to aeroallergens. Despite the discovery of microbial ligands for receptors that induce inflammatory T helper cells subsets, including Th1 cells and Th17 cells, few molecular markers are known which induce immune responses by the characteristic cell types involved in allergy and asthma. We have recently discovered that a common constituent associated with many allergens is capable of inducing influx of eosinophils and basophils into the lungs of mice. Further, instillation induced the accumulation of alternatively activated macrophages, which are increasingly being recognized as a critical element of allergic immunity. This project will explore the contributions by this constituent component of helminths, insects and fungal cell walls in provoking changes in dendritic cells that mediate differentiation of Th2 cells, recruitment of innate IL-4/IL-13-producing cells, induction of B cell responses leading to IgE and lgG1, and ultimately a mucosal and tissue response. Using mice with genes modified to report faithful expression of key components of Th2-associated immunity, three specific aims are proposed: 1. To assess the role of chitin as an adjuvant and as a component of a fungal extract of Aspergillus in inducing dendritic cell activation in vivo. 2. To assess the role of chitin as an adjuvant and as a component of a fungal extract of Aspergillus in inducing Th2 cells and IL-4-dependent antibody isotypes. 3. To assess the role of chitin in the induction of feedback mechanisms that limit the inflammatory process in the lungs. LAY SUMMARY: The prevalence of asthma remains extensive in the United States and other developed countries. Knowledge of precise environmental agents that contribute to asthma and that can be studied in model animal systems is incomplete. This proposal will use mice to study novel and relevant mechanisms.