Mechanisms of Allergen-induced Type 2 Immunity

项目摘要/摘要 这笔赠款的长期目标是研究呼吸道暴露于天然过敏原是如何导致 2型免疫和变态反应性疾病的发展。夸大的2型免疫反应被牵连进来 引起从哮喘到食物过敏的各种疾病。传统上，CD42型辅助T细胞(Th2) 产生IL-4、IL-5和IL-13的细胞被认为是引导 这些疾病的病理生理学，如呼吸道嗜酸性粒细胞增多和IgE抗体的产生。然而，它 Th2细胞是否单独能够解释疾病的临床表型谱仍未解决。为 例如，并不是所有的哮喘患者都会产生过敏原的IgE抗体，也不是所有的患者都能检测到 血清中的IgE抗体水平会发展成哮喘。T滤泡辅助性T细胞(TFH)是一种新定义的CD4亚群 不同于其他T细胞的T细胞，因为它们在协调生发中心中的选择性作用 回应。我们在上一个资助期的观察表明，产生IL-4的TFH起着关键作用 细胞在调节IgE抗体的产生，但在呼吸道炎症中不起作用，提示适应性 事实上，“2型免疫”可能至少由两条途径组成。在下一个资助期，我们将延长 这些研究和定义了过敏原暴露如何介导各种免疫学和临床表型 过敏性疾病。在目标1中，我们将研究Tfh细胞和Th2细胞在过敏性免疫反应中的作用。 由暴露在天然空气中的过敏原引起的。我们将利用鼠标模型并严格定义 这两种细胞类型的作用。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。既有小鼠遗传方法，也有 人类的前瞻性研究将被用来了解这种新细胞类型的作用。在《目标3》中，我们将 通过研究解决为什么某些环境因素会成为强烈的过敏原这一根本问题 链格孢霉，它与过敏性疾病有关。与交链孢属专家克里斯托弗博士合作 劳伦斯，我们将采用一种强大的真菌功能基因组学方法。总之，这些目标的研究将 明确2型对空气传播免疫的发展和调节的核心机制 过敏原，并将提供关于过敏性疾病各种临床表型的免疫学解释 疾病。最终，这些研究将表征关键的细胞途径(S)和参与的分子(S 过敏免疫反应，可识别开发新疗法的关键靶点 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.