Role for acidity and GPR65 in food allergy

描述（由申请方提供）：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，如嗜酸性粒细胞性食管炎（EoE）。这些反应的一个共同特征是暴露于酸性微环境，因为全身过敏反应可能与酸中毒相关，嗜酸性食管炎症与生理或病理反流引起的酸暴露相关。我们最近发现了一个新的途径参与过敏性炎症细胞功能介导的质子敏感G蛋白偶联受体GPR 65。具体来说，我们确定GPR 65作为一个非冗余的酸性传感器嗜酸性粒细胞，导致增加的生存嗜酸性粒细胞在酸性pH值。食管经常暴露于酸，这可能有助于增强嗜酸性粒细胞的反应，包括生存（和积累）。此外，我们的初步数据表明GPR 65在肥大细胞上的表达，这对于大多数口服抗原诱导的过敏反应模型是必需的。我们现在假设酸性微环境和/或GPR 65参与过敏原诱导的反应，包括实验性EoE和食物过敏。此外，我们假设酸性增强了参与这些模型的细胞的功能，包括嗜酸性粒细胞和肥大细胞。我们希望这项研究将揭示IgE介导的炎症的新分子机制，并有助于更好地了解这种疾病。最后，通过确定一个新的途径，这项研究可能为疾病的新靶点提供机会。食物过敏反应包括多种疾病，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于酸性微环境。这项资助将测试酸性微环境在食物过敏中的作用。我们还将重点关注酸性对肥大细胞和嗜酸性粒细胞的影响，这些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.