Delayed anaphylaxis to beef and pork: mechanisms and causes of a new food allergy

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，确定过敏反应的原因对于长期风险管理至关重要。然而，确定病因学仅限于已知的过敏反应原因。因此，识别新的致病因素将通过降低疾病风险和促进新的、特定的治疗方法向前迈出重要的一步。这一建议的首要假设是，碳水化合物的IgE抗体是目前看来是特发性过敏反应的主要因素。我们最近鉴定并描述了一种碳水化合物，α-半乳糖，作为一种新的食物过敏原。阿尔法-半乳糖IgE抗体阳性的患者报告称，在食用牛肉、猪肉或羊肉3-6小时后出现迟发性过敏反应或荨麻疹。通过了解控制这一反应的因素并导致延迟，拟议的研究将提供对控制过敏反应的因素的洞察，并推动食物过敏领域的发展。在典型的食物过敏患者中，延迟3-6小时是最不寻常的，需要调查相关机制(S)。利用体外组胺释放和嗜碱性粒细胞激活研究，我们将确定IgE到α-Gal是否能够产生这些细胞的激活。大多数患有IgE到α-GAL的患者多年来一直耐受哺乳动物肉。有趣的是，在我们的队列中，超过90%的患有IgE到α-GAL的患者报告说，在出现症状之前的几周或几个月里，被大量的成虫或幼虫叮咬。因此，这些叮咬可能是对α-半乳糖和潜在其他碳水化合物的IgE抗体产生的激发事件。 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-半乳糖和其他碳水化合物的IgE代表了食物过敏的一种新原因。这项提案中概述的具体目标旨在更准确地定义与IgE到α-GAL相关的临床病史，阐明这种IgE在食物过敏中的功能作用，并调查症状延迟的原因(具体目标1)。具体目的2通过建立对α-半乳糖的IgE抗体反应的流行病学，发展对非α-半乳糖抗原的IgE抗体的分析，以及使用动物模型来研究非α-半乳糖抗原的IgE抗体反应，重点阐述了硬蜱在启动对α-半乳糖的IgE产生中的作用。过敏性反应或休克是一种严重的过敏反应，进展迅速，如果不采取适当的医疗措施，可能会致命。我们在美国东南部发现了一组患者，他们在被扁虱或恙虫叮咬后，在食用牛肉、猪肉或羊肉3-6小时后出现迟发性过敏反应，并似乎对红肉中的糖过敏。由于这种延迟，他们的症状通常会被认为是“自发的”或“不明原因的”，但了解延迟发生的原因，以及为什么东南部的成年患者突然对红肉过敏，可能会为控制过敏和食物过敏的因素提供真正的洞察。

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 cause of anaphylaxis is pivotal to long-term risk management. Determining the etiology is limited, however, to known causes of anaphylaxis. Therefore, identification of novel causative agents will provide an important step forward by reducing risk of disease and facilitating new, specific treatment approaches. The overarching hypothesis for this proposal is that IgE antibodies to carbohydrates are a major factor in anaphylaxis that currently appears to be idiopathic. We have recently identified and described a carbohydrate, alpha-gal, as a novel food allergen. Patients who have IgE antibodies to alpha-gal report delayed anaphylaxis or urticaria occurring 3-6 hours after eating beef, pork or lamb. By understanding the factors that control this reaction and contribute to the delay, the proposed research will provide insight into the factors that control anaphylaxis and advance the field of food allergy. A delay of 3-6 hours is most unusual in patients with classical food allergy and warrants investigation of the mechanism(s) involved. Using ex-vivo histamine release and basophil activation studies, we will determine whether IgE to alpha-gal can produce activation of these cells. Most patients who have IgE to alpha-gal tolerated mammalian meat for many years. Interestingly, greater than 90% of patients in our cohort who have IgE to alpha-gal report being bitten by large numbers of adult or larval ticks ('seed ticks') in the weeks or months prior to developing symptoms. Hence, these bites may serve as the inciting event in the development of IgE antibodies to alpha-gal and potentially other carbohydrates. 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 and other carbohydrates represents a novel cause of food allergy. The specific aims outlined in this proposal are designed to more accurately define the clinical histories associated with IgE to alpha-gal, elucidate the functional role of this IgE in food allergy and investigate the cause of the delay in symptoms (Specific Aim 1). Specific Aim 2 focuses on the role of ticks in initiating the production of IgE to alpha-gal through establishing the epidemiology of the IgE antibody response to alpha-gal, developing assays for IgE antibodies to tick antigens other than alpha-gal and using animal models to study the IgE antibody response to ticks. Anaphylaxis, or shock, is a severe allergic reaction that can progress quickly and may be fatal if appropriate medical action is not taken. We have identified a group of patients in the Southeastern U.S. who, after being bitten by ticks or chiggers, develop delayed anaphylaxis 3-6 hours after eating beef, pork or lamb and appear to be allergic to a sugar on red meat. Because of the delay, their symptoms would normally be regarded as 'spontaneous' or 'of unknown cause' but understanding why the delay occurs and why adult patients in the Southeast are suddenly becoming allergic to red meat may provide real insight into the factors that control anaphylaxis and food allergy.