Role for acidity and GPR65 in food allergy

描述(申请人提供)：食物过敏反应包括多种疾病，从急性口服抗原诱导的IgE介导的过敏反应到慢性组织特异性炎症，如嗜酸性食管炎(EoE)。这些反应的一个共同特征是暴露在酸性微环境中，因为全身过敏反应可能与酸中毒有关，嗜酸性食管炎与生理性或病理性反流引起的酸暴露有关。我们最近发现了一条新的途径，参与了质子感应G蛋白偶联受体GPR65介导的过敏性炎症细胞功能。具体地说，我们确定GPR65是嗜酸性粒细胞上的一个非冗余的酸感受器，导致嗜酸性粒细胞在酸性pH中的存活率增加。食道经常暴露在酸中，这可能导致嗜酸性粒细胞反应增强，包括存活(和蓄积)。此外，我们的初步数据表明，肥大细胞上表达GPR65，这是大多数口服抗原诱导过敏反应模型所必需的。我们现在假设，酸性微环境和/或GPR65参与了过敏原诱导的反应，包括实验性EoE和食物过敏。此外，我们假设酸度增强了这些模型所涉及的细胞的功能，包括嗜酸性粒细胞和肥大细胞。我们希望这项研究将揭开涉及IgE介导的炎症的新的分子机制，并将有助于更好地了解这种疾病。最后，通过确定一条新的途径，这项研究可能会为疾病的新靶点提供机会。食物过敏反应包括各种疾病，从危及生命的过敏反应到慢性嗜酸性食管炎。这些反应的一个共同特征是暴露在酸性微环境中。这笔赠款将测试酸性微环境在食物过敏中的作用。我们还将关注酸度对肥大细胞和嗜酸性粒细胞的影响，这两种细胞在这些疾病中至关重要。

DESCRIPTION (provided by applicant): Food allergic responses include diverse diseases ranging from acute oral antigen-induced IgE-mediated anaphylaxis to chronic tissue-specific inflammation such as eosinophilic esophagitis (EoE). A common characteristic of these responses is exposure to acidic microenvironments as systemic anaphylaxis may be associated with acidosis and eosinophilic esophageal inflammation is associated with acid exposure from physiological or pathological reflux. We have recently identified a new pathway involved in allergic inflammatory cell function mediated by the proton-sensing G-protein coupled receptor GPR65. Specifically, we identified GPR65 as a nonredundant acid sensor on eosinophils, leading to increased survival of eosinophils in acidic pH. The esophagus is regularly exposed to acid and this may contribute to enhanced eosinophil responses, including survival (and accumulation). Further, our preliminary data suggest expression of GPR65 on mast cells, which are essential for most models of oral antigen-induced anaphylaxis. We now hypothesize that acidic microenvironment and/or GPR65 are involved in allergen-induced responses including experimental EoE and food allergy. Furthermore, we hypothesize that acidity enhances the function of cells involved in these models, including eosinophils and mast cells. We are hopeful that this study will unravel novel molecular mechanisms involved in IgE-mediated inflammation and will help provide a better understanding of the disease. Finally, by identifying a new pathway, this study may present opportunities for new targets in the disease. Food allergic responses include diverse diseases ranging from life-threatening anaphylaxis to chronic eosinophilic esophagitis. A common characteristic of these responses is exposure to acidic microenvironments. This grant will test the role of acidic microenvironment in food allergy. We will also focus on the effect of acidity on mast cells and eosinophils, cells critically important in these diseases.