IgE to carbohydrates causes delayed anaphylaxis

描述（由申请人提供）：过敏反应是一种严重的过敏反应，可以迅速发展和致命。在不知道触发过敏原的情况下，确定过敏反应的原因对长期风险管理至关重要。然而，确定触发是有限的，以已知的过敏反应的原因。因此，鉴定新的病原体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。该建议的总体假设是，针对碳水化合物的IgE抗体是目前似乎是特发性过敏反应的主要因素。我们最近发现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。有α -半乳糖IgE抗体的患者报告在食用牛肉、猪肉或羊肉3-6小时后发生迟发性过敏反应或荨麻疹。研究这些反应的意义不仅在于理解一种新的危及生命的食物过敏形式的明显重要性，还在于有可能定义与一种重要食物物质有关的反应的全新机制。我们的研究计划将研究α -半乳糖的IgE抗体与过敏反应的关系，并确定这些抗体是否对碳水化合物α -半乳糖具有特异性。延迟3-6小时在典型食物过敏患者中是最不寻常的，需要调查所涉及的机制。通过组胺释放和嗜碱性粒细胞激活研究，我们将确定在这些细胞中，IgE to α -gal是否可以被功能性激活。在机制研究完成后，我们将进行双盲、安慰剂对照的食物挑战，以进一步了解食用哺乳动物肉类后临床症状的延迟出现。大多数对α -半乳糖有IgE的患者在出现症状前耐受哺乳动物肉多年。有趣的是，在我们的队列中，超过90%的IgE对α -gal的患者报告在出现症状之前的几周或几个月内被大量成年或幼虫蜱（“种子蜱”）叮咬。使用树突状细胞（DC）和T细胞共培养，我们将测试一种特定的受体，即II型c型凝集素受体，对启动对蜱抗原的TH2反应至关重要的假设。我们目前的工作表明，在一组食用哺乳动物肉类后报告延迟过敏反应和过敏反应的患者中存在对碳水化合物α -半乳糖的IgE。我们认为，对α -半乳糖和其他碳水化合物的IgE是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这种碳水化合物定向IgE的特异性（特异性目标#1），阐明这种IgE在食物过敏中的功能作用（特异性目标#2），并阐明诱导TH2反应的机制，TH2反应控制着针对该片段的IgE抗体的产生（特异性目标#3）。过敏反应或休克是一种严重的过敏反应，可以迅速发展，如果不采取适当的医疗措施，可能是致命的。我们在美国东南部发现了一组患者，他们在食用牛肉、猪肉或羊肉3-6小时后出现延迟性过敏反应，似乎对红肉中的糖过敏。由于延迟，他们的症状通常被认为是“自发的”或“原因不明”，但了解延迟发生的原因以及为什么东南地区的成年患者突然对红肉过敏，可能会让我们真正了解控制过敏反应和食物过敏的因素。

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 trigger 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. 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 will investigate the relationship of IgE antibodies to alpha-gal with anaphylaxis and determine whether these antibodies are specific for the carbohydrate alpha-gal. A delay of 3-6 hours is most unusual in patients with classical food allergy and warrants investigation of the mechanism(s) involved. Using histamine release and basophil activation studies, we will determine whether IgE to alpha-gal can be functionally activated in these cells. Following the completion of the mechanistic studies, we will perform double-blind, placebo controlled food challenges to further understand the delayed appearance of clinical symptoms after eating mammalian meat. Most patients who have IgE to alpha-gal tolerated mammalian meat for many years prior to the onset of symptoms. 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. Using dendritic cell (DC) and T cell co-culture, we will test the hypothesis that a specific receptor, that of the type II C-type lectin receptor, is critical to the initiation of a TH2 response to the tick antigen. 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 establish the specificity of this carbohydrate-directed IgE (Specific Aim #1), elucidate the functional role of this IgE in food allergy (Specific Aim #2) and elucidate the mechanism for induction of TH2 responses which govern IgE antibody production to this moiety (Specific Aim #3). 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 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.