Dendritic cell produced IL-33 in Th2 responses

描述（由申请人提供）：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了解表明，Th 2细胞在炎症反应中起主要作用。然而，诱导T细胞向Th 2表型分化的因子仍然是这些疾病中重要的未解决的问题之一。IgE在哮喘和过敏性疾病的发病机制中有确定的作用，但抗原特异性IgG也大量存在于这些个体的血清中。我们以前已经发现了一个新的IgG激活受体，Fc？RIII，在小鼠模型中调节Th 2依赖性炎症。我们的发现，以前的致敏，导致抗原特异性IgG，可以改变抗原呈递细胞的反应，可能为治疗干预提供了一个新的范例。以前，人们认为，抗原呈递细胞在初级和次级反应中对TLR激动剂等刺激的反应相似。然而，我们的研究结果现在表明，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产生的差异基因谱，其中包括IL-33细胞因子的产生的上调。我们的总体假设是，抗原特异性IgG交联的Fc？R部分地通过DC产生IL-33来增加Th 2免疫应答。我们提出了以下具体目标：目标#1：确定IL-33在体外和体内由免疫复合物信号传导的骨髓来源的DC产生的增强的Th 2应答中的作用。在这个目标中，我们建议调查的假设，IL-33的生产BMDCs，直接或间接，诱导增强Th 2反应。目的#2：确定IL-33是否由先天免疫细胞通过Fc产生？体内R信号传导。在这个目标中，我们建议调查的假设，Fc？内源性TLR 4激活的呼吸道DC上的R信号传导诱导IL-33产生，这反过来又增强Th 2介导的炎症。我们的研究将对我们理解DC功能的IgG调节以及它如何影响Th 2介导的疾病产生重大影响。此外，我们将获得有价值的洞察机制调节DC介导的T细胞分化，并有可能确定新的目标，在临床治疗。在我们的实验室中，我们拥有成功分析体内Th 2介导的气道炎症的专业知识，以及完成本提案目标所需的所有必要资源和工具。此外，我们已经取得了一个创新性的发现，DC激活和基因调控的次级反应可能会受到抗原特异性IgG的存在。

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.