Understanding alpha-gal red meat allergy

项目摘要 过敏反应是一种严重的过敏反应，可迅速进展和致命。的情况下 触发过敏原未知，确定过敏反应的病因是长期风险的关键 管理我们最近的工作已经确定了一种新的IgE抗体反应的哺乳动物寡糖 表位，半乳糖-α-1，3-半乳糖（α-gal），与两种不同形式的过敏反应相关： i）在首次暴露于静脉内西妥昔单抗期间的速发型过敏反应，和ii）延迟发作 在摄取哺乳动物食品后3-6小时的过敏反应（例如，牛肉和猪肉）。总体目标 这一建议是，确定α-gal IgE反应的原因和机制，以及 确定负责延迟食物反应的抗原，将提供对因素的深入了解， 控制过敏反应和过敏性反应。我们的新型α-半乳糖过敏小鼠模型将允许 我们测试了中心假设，蜱叮咬诱导嗜碱性粒细胞依赖性，α-gal特异性免疫反应 由于非常规的T细胞抗原呈递，导致对红肉的延迟过敏反应。的 研究这些反应的重要性不仅来自于理解 一种新的危及生命的食物过敏形式，但也因为有可能定义一种全新的 与重要食品物质相关的反应机制。我们的研究计划集中在 阐明免疫细胞在鼠模型中的作用，确定蜱叮咬在引发IgE中的作用， 了解吃牛肉、猪肉或羊肉后3-6小时血液中出现的抗原。 我们目前的工作表明，对碳水化合物α-半乳糖的IgE存在于一组患者中， 他们报告在食用哺乳动物肉后出现迟发性过敏反应和过敏反应。我们认为，IgE对α- 半乳糖代表了食物过敏的一种新原因。本提案中概述的具体目标旨在 确定蜱叮咬在启动α-gal IgE反应（特异性目的1）中的作用，研究其机制 IgE产生（特异性目标2），并阐明延迟反应的机制（特异性目标3）。总体而言， 这些研究具有独特的地位，可以深入了解最近认识到的过敏反应， 美国东南部超过3，500名患者，以及识别过敏反应期间存在的分子 并建立一个体外寄生蜱叮咬引发IgE反应的模型。

PROJECT SUMMARY Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (α-gal), that has been associated with two distinct forms of anaphylaxis: i) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and ii) delayed onset anaphylaxis 3-6 hours after ingestion of mammalian food products (e.g., beef and pork). The overarching goal for this proposal is that defining both the cause and the mechanism of α-gal IgE response, as well as identifying the antigen responsible for the delayed food reactions, will provide insight into the factors that govern allergic responses and control anaphylaxis. Our novel α-gal-allergic mouse model will allow us to test the central hypothesis that tick bites induce a basophil-dependent, α-gal specific immune response that, due to unconventional T cell antigen presentation, results in delayed allergic reactions to red meat. The significance of investigating these reactions comes not only from the obvious importance of understanding a novel life-threatening form of food allergy, but also because of the possibility of defining a totally new mechanism for reactions related to an important food substance. Our plan of research focuses on the elucidating the role of immune cells in the murine model, defining the role of tick bites in initiating the IgE and understanding the antigen that appears in the bloodstream 3-6 hours after eating beef, pork or lamb. Our current work has shown that IgE to the carbohydrate alpha-gal is present in a cohort of patients who report delayed anaphylaxis and allergic reactions after eating mammalian meat. We believe that IgE to α- gal represents a novel cause of food allergy. The specific aims outlined in this proposal are designed to establish the role of tick bites in initiating the α-gal IgE response (Specific Aim 1), investigate the mechanism for IgE production (Specific Aim 2) and elucidate the mechanism for delayed reactions (Specific Aim 3). Overall, these studies are uniquely positioned to provide insight into a recently recognized allergic response that affects >3,500 patients in the southeastern U.S. as well as identify the molecules present during an allergic reaction and establish a model for ecto-parasitic tick bites initiating an IgE response.