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

在英国，过敏性疾病的发病率惊人地增加，现在是世界上最高的。在英国，六分之一的儿童患有哮喘，对常见食物过敏原（如花生）产生的危及生命的过敏反应曾经很少见，但现在越来越普遍；儿童对花生过敏的人数在十年内翻了一番。当看似无害的物质被免疫系统识别并被视为危险物质时，就会发生过敏反应。免疫系统对这些致敏物质产生的抗体是一种称为IgE的抗体，它与更常见的保护性抗体（IgG）具有不同的性质，人体用IgG来再次防御细菌、病毒和其他外来物质。入侵者。虽然我们对IgE抗体及其作用机制了解很多，但过敏的一个基本问题仍未得到解答，即为什么只有某些物质会致敏，而其他物质不会？我们的研究让我们可以通过实验来解决这个问题，我们建议用花生过敏作为我们的例子。这是一个特别好的例子，不仅因为它在医学上的重要性，而且因为花生中的个体过敏原蛋白质已经被确定，并且特定的过敏原已被证明是“显性的”。，即对这些主要过敏原有抗体的人在临床上是反应性的，而对次要过敏原有抗体的人？花生过敏原不会起反应。我们的目标是了解这些差异，并开发了从已知过敏反应的患者细胞中分离IgE抗体的方法。使用一系列技术，包括确定在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（单独或以各种组合）是否可以触发产生IgE抗体的细胞（称为B细胞）或引起立即超敏反应的细胞（肥大细胞和嗜碱性细胞）。我们的假设是，致敏蛋白的三维结构，加上IgE抗体分子的独特结构，决定了一个蛋白质是否被识别为过敏原。我们还将研究被称为“超级抗原”的细菌蛋白？一种特殊的（可能不稳定的）IgE在过敏性疾病中起作用。我们的研究结果将支持免疫治疗方法来治疗过敏性疾病，并导致方法的发展，以描述和预测患者？S潜在的过敏反应。

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.