Regulation of Allergic Inflammation by Histamine

描述(由申请人提供)：细胞因子及其受体具有令人难以置信的能力来调节一系列不同的细胞反应，对体内平衡和保护性免疫反应的控制非常重要。越来越多地观察到细胞因子的上下文或细胞特异性影响，但由于JAK和STAT家族内细胞内信号分子的有限，调节这一影响的机制尚不清楚。最近，细胞因子受体功能的“修饰物”的概念已经出现，来自其他受体的信号可以通过细胞因子受体改变这些功能。我们令人兴奋的发现证实，组胺通过其受体H2 R发挥作用，是细胞对IL-4做出反应所必需的。这种细胞因子在过敏反应中至关重要，我们已经证明，H2R KO小鼠已经消融了IgE的产生和嗜酸性粒细胞向肺的募集。在进一步研究这种相互作用时，我们发现造血细胞和非造血细胞都具有组胺依赖性和对IL-4的独立反应性。我们假设，H_2R作为IL-4受体信号的修饰物，是从IL-4的动态平衡功能转换到促过敏反应所必需的。我们建议通过在小鼠模型和过敏患者中研究这一概念的三个具体目标来检验这一点。具体目标1将审查通过IL-4R阿尔法链(与Talal Chatila博士合作)进行反应的H_2R的功能要求。特殊目标2将使用最先进的信使核糖核酸深度测序(与Nadereh Jafari博士合作)绘制人类和小鼠细胞中组胺依赖和独立基因的独特图谱。具体目标3将检查嗜酸性食管炎发病机制中组胺相关基因模式，并在我们现有工作的基础上证明肥大细胞和组胺在这种疾病中是重要的。

DESCRIPTION (provided by applicant): Cytokines and their receptors have an incredible ability to regulate a diverse range of cellular responses, important for homeostasis and control of protective immune responses. Increasingly, context or cell-specific influences of cytokines are being observed but the mechanisms that regulate this remain unclear given the limited repertoire of intracellular signaling molecules within the Jak and Stat family. Recently, the concept of "modifiers" of cytokine receptor functions has emerged, whereby signals from other receptors can alter those through the cytokine receptor. Our exciting findings have established that histamine, acting via its receptor H2R, is necessary for cellular responses to IL-4. This cytokine is critically important in allergic responses and we have demonstrated that H2R KO mice have ablated IgE generation and eosinophil recruitment to the lungs. In studying this interaction further, we have identified that both hematopoietic and non-hematopoietic cells possess histamine-dependent and independent responsiveness to IL-4. We hypothesize that H2R functions as a modifier of signaling from the IL-4 receptor and is necessary for switching from the homeostatic functions of IL-4 to a pro- allergic response. We propose to examine this with three specific aims that investigate this concept in murine models and in allergic patients. Specific Aim 1 will examine the functional requirements for H2R on responses through the IL-4Ralpha chain (in collaboration with Dr Talal Chatila). Specific Aim 2 will map the unique profile of histamine-dependent and independent genes in human and murine cells using state-of-the-art mRNA deep sequencing (in collaboration with Dr Nadereh Jafari). Specific Aim 3 will examine histamine-associated gene patterns in the pathogenesis of eosinophilic esophagitis and build on our existing work demonstrating the mast cells and histamine are important in this disease.