Delayed Anaphylaxis to Mammalian Meat caused by IgE Ab to alpha-gal

描述(申请人提供)：过敏反应是一种严重的过敏反应，可迅速发展和致命。在触发过敏原未知的情况下，确定过敏反应的病因学对长期风险管理至关重要。我们最近的工作发现了一种新的对哺乳动物低聚糖表位半乳糖-α-1，3-半乳糖(α-GAL)的IgE抗体(Ab)反应，该抗体与两种不同形式的过敏反应有关：i)首次静脉注射西妥昔单抗时发生即刻过敏反应；ii)摄入哺乳动物食品(如牛肉和猪肉)后3-6小时出现延迟性过敏反应。这一建议的主要假设是，确定IgE抗体对α-Gal反应的原因和机制，以及确定导致延迟食物反应的抗原，将有助于深入了解控制过敏反应和控制过敏反应的因素。研究这些反应的意义不仅来自于了解一种新的威胁生命的食物过敏形式的明显重要性，还因为有可能定义与一种重要食品物质相关的反应的全新机制。我们的研究计划侧重于针对α-GAL的IgE抗体的流行病学，即在食用牛肉、猪肉或羊肉后3-5小时出现在血液中的抗原，以及扁虱叮咬在启动IgE反应中的作用。我们目前的工作表明，碳水化合物α-半乳糖的IgE存在于一组报告延迟过敏反应和食用哺乳动物肉类后的过敏反应的患者中。我们认为，α-GAL的IgE代表了一种导致食物过敏的新原因。本提案中概述的具体目标旨在调查这种碳水化合物导向的IgE的流行病学(特异性目标#1)，阐明延迟反应的机制(特异性目标#1)，确定IgE反应的原因(特异性目标#2)，并调查针对糖类的特异性IgE产生的机制(特异性目标#2)。总体而言，这些研究具有独特的地位，可以提供对最近发现的过敏反应的洞察，以及确定过敏反应期间存在的分子，并可能建立外部寄生虫叮咬启动IgE反应的模型。

DESCRIPTION (provided by applicant): 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 (Ab) response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-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 hypothesis for this proposal is that defining both the cause and the mechanism of the IgE Ab response to alpha-gal 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. 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 epidemiology of IgE Ab to alpha-gal, the antigen that appears in the bloodstream 3-5 hours after eating beef, pork or lamb, and the role of tick bites in initiating the IgE response. 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 alpha-gal represents a novel cause of food allergy. The specific aims outlined in this proposal are designed to investigate the epidemiology of this carbohydrate-directed IgE (Specific Aim #1), elucidate the mechanism for delayed reactions (Specific Aim #1), establish the cause of the IgE response (Specific Aim #2), and investigate the mechanism of specific IgE production against a glycan (Specific Aim #2). Overall, these studies are uniquely positioned to provide insight into a recently recognized allergic response as well as identify the molecules present during an allergic reaction and possibly establish a model for ecto-parasitic tick bites initiating an IgE response.