Dendritic cell produced IL-33 in Th2 responses

描述(申请人提供)：哮喘和过敏影响全球约6亿人，是基础科学造福临床医学的重要挑战。我们目前对这些疾病的理解表明，Th2细胞在炎症反应中发挥着重要作用。然而，诱导T细胞分化为Th2表型的因素仍然是这些疾病中尚未解决的重要问题之一。免疫球蛋白E在哮喘和过敏性疾病的发病机制中已有确定的作用，但在这些人的血清中也存在大量的抗原特异性免疫球蛋白G。我们以前发现了一种新的免疫球蛋白激活受体Fc？RIII，在小鼠模型中调节Th2依赖的炎症。我们的发现是，以前的致敏作用可以改变抗原提呈细胞的反应，这可能为治疗干预提供了一个新的范式。以前，人们认为初级和次级反应中的抗原提呈细胞对TLR激动剂等刺激的反应相似。然而，我们的发现现在证明，当抗原摄取是由免疫复合物介导的，而不是简单的可溶性抗原摄取，TLR刺激的DC产生不同的基因谱，包括上调IL-33细胞因子的产生。我们的总体假设是，抗原特异性的Fc？R的Ig G交联会增加Th2免疫反应，部分是通过DC产生IL-33。我们提出以下具体目标：目的1：确定IL-33在免疫复合体信号的骨髓来源的DC体外和体内产生的Th2增强反应中的作用。在这一目标中，我们建议研究一种假设，即BMDCs产生IL-33直接或间接诱导Th2应答增强。目的#2：确定体内天然免疫细胞是否通过Fc？R信号产生IL-33。为此，我们提出了一种假设，即内源性TLR4激活的呼吸树突状细胞上的Fc？R信号诱导IL-33的产生，进而增强Th2介导的炎症。我们的研究将对我们理解免疫球蛋白对DC功能的调节以及它如何影响Th2介导的疾病产生重大影响。此外，我们将获得有价值的洞察调控DC介导的T细胞分化的机制，并有可能在临床上识别新的治疗靶点。在我们的实验室中，我们拥有成功分析体内Th2介导的呼吸道炎症的专业知识，以及完成该提案目标所需的所有必要资源和工具。此外，我们还取得了一项创新性的发现，即DC的激活和二次反应中的基因调控可能会受到抗原特异性抗体的存在的影响。 公共卫生相关性：哮喘和过敏影响全球约6亿人，是基础科学造福临床医学的重要挑战。儿童是哮喘患者的主要群体，而且还在不断增加。我们的研究探讨了高免疫反应导致哮喘和过敏的机制。

DESCRIPTION (provided by applicant): Asthma and allergy affect an estimated 600 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Our current understanding of these diseases demonstrates that Th2 cells play a major role in the inflammatory responses. However, the factors that induce T cells to differentiate towards a Th2 phenotype remain one of the important unresolved problems in these diseases. There is an established role of IgE in the pathogenesis of asthma and allergic disorders, but antigen-specific IgG is also present in large quantities in the serum of these individuals. We have previously found a novel role for the IgG activating receptor, Fc?RIII, in the regulation of Th2-dependent inflammation in a mouse model. Our findings that previous sensitization, which leads to antigen-specific IgG, could change the response of antigen-presenting cells may provide a new paradigm for therapeutic interventions. Previously, it was believed that antigen-presenting cells in both primary and secondary responses responded similarly stimuli such as TLR agonist. However, our findings now demonstrate that when antigen uptake is mediated by immune complexes instead of simple soluble antigen uptake, the TLR stimulated-DCs produce a differential gene profile that includes the up-regulation of IL-33 cytokine production. Our overall hypothesis is that antigen-specific IgG crosslinking of Fc?R increases Th2-immune responses, in part, through the production of IL-33 by DC. We propose the following specific aims: Aim #1: Determine the role of IL-33 in the augmented Th2 responses produced by immune-complex signaled bone marrow derived DC in vitro and in vivo. In this Aim, we propose to investigate the hypothesis that IL-33 production by BMDCs, directly or indirectly, induces augmented Th2 responses. Aim #2: Determine whether IL-33 is produced by innate immune cells through Fc?R signaling in vivo. In this Aim, we propose to investigate the hypothesis that Fc?R signaling on endogenous TLR4 activated respiratory DCs induces IL-33 production, which in turn augments Th2-mediated inflammation. Our studies will have a significant impact on our understanding of IgG modulation of DC function and how it affects Th2-mediated diseases. Further, we will gain valuable insight into the mechanisms regulating DC-mediated T cell differentiation and have the potential to identify novel targets for therapy in the clinic. In our laboratory, we have the expertise to successfully analyze Th2- mediated airway inflammation in vivo, and all the necessary resources and tools to complete the aims of this proposal. Further, we have made an innovative discovery that DC activation and gene regulation in secondary responses may be influenced by the presence of antigen specific IgG. PUBLIC HEALTH RELEVANCE: Asthma and allergy affect an estimated 600 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Children are a major and growing population of asthma sufferers. Our studies investigate the mechanisms by which hyper-immune response lead to asthma and allergies.