Mechanisms of Allergen-induced Type 2 Immunity

项目概要/摘要 该基金的长期目标是研究气道暴露于天然过敏原如何导致 2型免疫和过敏性疾病的发展。夸大的2型免疫反应与 从哮喘到食物过敏的各种疾病。传统上，CD4 + 2型辅助性T细胞（Th2） 产生白细胞介素（IL）-4，IL-5和IL-13的细胞被认为是指导细胞凋亡的主要参与者。 这些疾病的病理生理学，如气道嗜酸性粒细胞增多和IgE抗体产生。但 Th2细胞是否可以单独解释疾病的临床表型谱仍然没有解决。为 例如，并非所有哮喘患者都会产生过敏原的IgE抗体， 血清IgE抗体水平发展为哮喘。滤泡辅助性T细胞（Tfh）是一种新定义的CD4 + T细胞亚群。 T细胞与其他T细胞的区别在于它们在协调生殖中心中的选择性作用 应答我们在上一个资助期间的观察表明，产生IL-4的Tfh在细胞内的表达中起着关键作用。 细胞在调节IgE抗体的产生，但不是在气道炎症，这表明适应性 "2型免疫"实际上可能由至少两种途径组成。在下一个融资期内，我们将 这些研究和定义过敏原暴露如何介导各种免疫和临床表型， 过敏性疾病在目的1中，我们将研究Tfh细胞和Th2细胞在过敏性免疫应答中的作用 由暴露于空气中的天然过敏原引起。我们将利用小鼠模型，并严格定义 这两种细胞的作用。在目标2中，我们将研究过敏性免疫反应的调节机制 通过关注新发现的T滤泡调节（Tfr）细胞。小鼠遗传学方法和 人类的前瞻性研究将用于了解这种新细胞类型的作用。在目标3中，我们 解决为什么某些环境因素作为强有力的过敏原的基本问题，通过研究 链格孢属，与过敏性疾病有关。与链格孢属专家克里斯托弗博士合作， 劳伦斯，我们将采取一个强大的真菌功能基因组方法。总之，这些目标的研究将 定义2型免疫的发展和调节的核心机制， 并将提供关于过敏性疾病的各种临床表型的免疫学解释。 疾病最终，这些研究将表征参与细胞凋亡的关键细胞途径和分子。 过敏性免疫反应，允许鉴定用于开发新的治疗药物的关键靶标 治疗或预防哮喘和过敏性疾病的策略。

PROJECT SUMMARY/ABSTRACT The long-term objective of this grant is to investigate how airway exposure to natural allergens leads to development of type 2 immunity and allergic diseases. Exaggerated type 2 immune responses are implicated in a wide variety of disorders ranging from asthma to food allergy. Traditionally, CD4+ type 2 helper T (Th2) cells that produce interleukin (IL)-4, IL-5, and IL-13 have been considered major players in directing the pathophysiology of these diseases, such as airway eosinophilia and IgE antibody production. However, it remains unresolved whether Th2 cells alone can explain the spectrum of clinical phenotypes of disease. For example, not all patients with asthma develop IgE antibodies to allergens, and not all patients with detectable serum IgE antibody levels develop asthma. T follicular helper (Tfh) cells are a newly defined subset of CD4+ T cells that are distinguished from other T cells by their selective role in orchestrating germinal center responses. Our observations during the last funding period demonstrate a pivotal role for IL-4-producing Tfh cells in the regulation of IgE antibody production, but not in airway inflammation, suggesting that adaptive “type 2 immunity” may in fact consist of at least two pathways. In the next funding period, we will extend these studies and define how allergen exposure mediates various immunologic and clinical phenotypes of allergic diseases. In Aim 1, we will examine the roles of Tfh cells and Th2 cells in allergic immune responses induced by exposure to natural airborne allergens. We will leverage mouse models and critically define the roles of these two cell types. In Aim 2, we will examine regulatory mechanisms in allergic immune responses by focusing on newly identified T follicular regulatory (Tfr) cells. Both a mouse genetic approach and a prospective study in humans will be used to understand the roles of this new cell type. In Aim 3, we will address the fundamental question of why certain environmental factors serve as potent allergens by studying Alternaria, which is implicated in allergic diseases. In collaboration with an Alternaria expert, Dr. Christopher Lawrence, we will take a robust fungal functional genomic approach. Together, the studies in these aims will define the central mechanisms underlying the development and regulation of type 2 immunity to airborne allergens and will provide an immunologic explanation regarding various clinical phenotypes of allergic diseases. Ultimately, these studies will characterize key cellular pathway(s) and molecule(s) involved in allergic immune responses, allowing identification of critical targets for development of novel therapeutic strategies to treat or to prevent asthma and allergic diseases.