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

过敏性疾病的发病率在英国以惊人的速度增长，现在是世界上最高的之一。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反应危及生命的情况现在越来越常见；儿童对花生的过敏反应在十年内翻了一番。当明显无害的物质被免疫系统识别并被视为危险时，过敏反应就会发生。免疫系统对这些过敏性物质产生的抗体是一种称为IgE的抗体，与更常见的保护性(IgG)抗体具有不同的性质，身体利用这些抗体来防御细菌、病毒和其他外来物质。入侵者。虽然关于IgE抗体及其作用机制已知很多，但过敏中的一个基本问题仍然没有得到回答，即为什么只有某些物质是过敏性的，而其他物质不是？我们的研究已经把我们带到了可以通过实验解决这个问题的地步，我们建议以花生过敏为例来做这件事。这是一个特别好的例子，不仅因为它在医学上的重要性，还因为花生中的个别过敏原蛋白已经被鉴定，并且特定的过敏原已经被证明是“显性的”，即对这些主要的过敏原有抗体的人在临床上是有反应的，而对？次要的？抗体的人在临床上是有反应的。花生过敏原不起反应。我们的目标是了解这些差异，并开发出从已知过敏反应患者的细胞中分离IgE抗体的方法。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体的详细3D结构，以及研究不同的过敏原(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)或引起立即过敏(过敏)反应的细胞(肥大细胞和嗜碱性细胞)。我们的假设是，致敏蛋白的3D结构，以及IgE抗体分子的独特结构，决定了一种蛋白质是否被识别为过敏原。我们还将调查被称为超级抗原的细菌蛋白和一种特殊的(可能不稳定的)IgE形式是否在过敏性疾病中发挥作用。我们的结果将为治疗变态反应性疾病的免疫治疗方法奠定基础，并导致描述和预测患者S潜在过敏反应的方法的发展。

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.