Allergenicity and allergen dominance: structural requirements for IgE-dependent recognition by B cells & effector cells

过敏性和过敏原优势：B 细胞 IgE 依赖性识别的结构要求

• 批准号: G1100090-E01/1
• 负责人: Brian Sutton
• 金额: $ 186.78万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100090-E01%2F1
• 关键词: Allergenicity; allergen; dominance; structural; requirements

The incidence of allergic disease has increased alarmingly in the UK and is now among the highest in the world. One in six children in the UK suffer from asthma, and life-threatening anaphylactic reactions to common food allergens such as peanuts, once rare, are now increasingly common; peanut allergy in children has doubled in ten years. Allergic reactions occur when apparently innocuous substances are recognised by the immune system and treated as dangerous. The antibodies produced by the immune system in response to these allergenic substances are of a type called IgE, with different properties to the more commonly produced protective (IgG) antibodies with which the body defends itself again bacterial, viral and other ?foreign? invaders. While much is known about IgE antibodies and their mechanism of action, a fundamental question in allergy remains unanswered, namely, why are only certain substances allergenic and others not? Our research has brought us to the point at which we can address this question experimentally, and we propose to do this using peanut allergy as our example. This is a particularly good example not only because of its medical importance, but also because the individual allergenic proteins within the peanut have been identified, and particular allergens have been shown to be ?dominant?, i.e. people with antibodies to these dominant allergens are clinically reactive, while those with antibodies to ?minor? peanut allergens do not react. We aim to understand these differences, and have developed methods to isolate IgE antibodies from the cells of patients with known allergic reactivity. Using a range of techniques that include determining the detailed 3D structures of the complexes formed between the IgE antibodies and the allergens, and studying whether or not the different allergens (individually and in various combinations) can trigger either the cells (called B cells) that produce the IgE antibodies or the cells (mast cells and basophils) that cause immediate hypersensitivity (anaphylactic) reactions. Our hypothesis is that the 3D structure of the allergenic protein, together with the unique structure of the IgE antibody molecule, determines whether a protein is recognized as an allergen or not. We shall also investigate whether bacterial proteins known as ?superantigens?, and a particular (and perhaps unstable) form of IgE, play a role in allergic disease. Our results will underpin immunotherapeutic methods to treat allergic disease, and lead to the development of methods to profile and predict patient?s potential for allergic reactivity.

过敏性疾病的发病率在英国惊人地增加，现在是世界上最高的。在英国，每六名儿童中就有一名患有哮喘，对花生等常见食物过敏原的危及生命的过敏反应曾经很罕见，现在越来越常见;儿童花生过敏在十年内翻了一番。当免疫系统识别出看似无害的物质并将其视为危险物质时，就会发生过敏反应。由免疫系统产生的抗体在响应这些过敏性物质是一种类型称为IgE，具有不同的属性，以更常见的产生保护性（IgG）抗体与身体防御自己再次细菌，病毒和其他？外国人？入侵者虽然对IgE抗体及其作用机制了解很多，但过敏中的一个基本问题仍然没有答案，即为什么只有某些物质是过敏性的，而其他物质不是？我们的研究使我们能够通过实验来解决这个问题，我们建议以花生过敏为例来解决这个问题。这是一个特别好的例子，不仅因为它在医学上的重要性，而且还因为花生中的个别过敏蛋白已被确定，特定的过敏原已被证明是？占优势的？也就是说，对这些主要过敏原有抗体的人在临床上是有反应的，而对？小调？花生过敏原不起反应。我们的目标是了解这些差异，并已开发出方法，从已知过敏反应性患者的细胞中分离IgE抗体。使用一系列技术，包括确定IgE抗体和过敏原之间形成的复合物的详细3D结构，并研究不同的过敏原（单独和各种组合）是否可以触发产生IgE抗体的细胞（称为B细胞）或引起速发型超敏反应（过敏性）的细胞（肥大细胞和嗜碱性粒细胞）。我们的假设是，过敏蛋白的3D结构，以及IgE抗体分子的独特结构，决定了蛋白质是否被识别为过敏原。我们还将研究是否细菌蛋白质称为？超级抗原？和一种特殊的（可能是不稳定的）IgE形式，在过敏性疾病中起作用。我们的研究结果将支持免疫方法来治疗过敏性疾病，并导致方法的发展，以档案和预测病人？过敏反应的可能性。