Regulation of Allergic Inflammation by Histamine

描述（由申请人提供）：细胞因子及其受体具有不可思议的调节多种细胞反应的能力，对体内平衡和保护性免疫反应的控制很重要。越来越多的人观察到细胞因子的环境或细胞特异性影响，但由于Jak和Stat家族的细胞内信号分子有限，调节这种影响的机制仍不清楚。近年来，出现了细胞因子受体功能“修饰因子”的概念，即来自其他受体的信号可以通过细胞因子受体改变这些信号。我们令人兴奋的发现已经确定，组胺通过其受体H2R起作用，是细胞对IL-4的反应所必需的。这种细胞因子在过敏反应中至关重要，我们已经证明H2R KO小鼠的IgE生成和肺嗜酸性粒细胞募集减少。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对IL-4具有组胺依赖性和独立的反应性。我们假设H2R作为IL-4受体信号的修饰剂，并且是IL-4从稳态功能转换为促过敏反应所必需的。我们建议用三个特定的目的来研究这一概念在小鼠模型和过敏患者中。Specific Aim 1将通过il - 4r - α链研究H2R的功能要求（与Talal Chatila博士合作）。Specific Aim 2将利用最先进的mRNA深度测序技术（与Nadereh Jafari博士合作）绘制人类和小鼠细胞中依赖组胺和独立基因的独特图谱。特异性目的3将研究嗜酸性粒细胞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该疾病中很重要。

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.