Human secreted IgD: structure, interactions and mechanisms in allergic inflammation and asthma

近几十年来，全球过敏性疾病的发病率增长惊人，不比英国更严重，例如，英国的哮喘患病率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现在越来越常见，这种过敏反应危及生命。当明显无害的物质被免疫系统识别并被视为危险的外来“抗原”时，就会发生过敏反应。免疫系统对这些过敏物质产生的抗体是一种名为IgE(免疫球蛋白E)的抗体，与更常见的保护性IgG、IgM和IgA抗体具有不同的性质，身体利用这些抗体再次防御细菌、病毒和其他“外来”入侵者。免疫球蛋白E抗体与细胞表面的特定“受体”蛋白(例如，呼吸道、皮肤或肠道中的肥大细胞，以及血液中的嗜碱性细胞)结合，当过敏原触发时，释放出导致过敏疾病特征的立即超敏反应的物质。靶向IgE是一种可行的治疗策略，但最近开发的一种抗IgE药物(Omalizumab)不仅非常昂贵，而且并不是对所有患者都有效。我们最近在哮喘患者身上发现了第五种但基本上被忽视的抗体，IGD，它可能在过敏性炎症中发挥更基本的作用。在五种不同类型的人类抗体中，IgM和IGD是5亿年前随着有颌脊椎动物(如鲨鱼)免疫系统的出现而首先进化的。其他抗体类别后来进化，但IgM和IGD一直保存到今天，虽然人们对IgM发挥的重要作用知道很多，特别是在第一次遇到外来抗原时的初级免疫反应中，但对IGD知之甚少。在免疫系统的整个进化过程中，它也是保守的，这表明了一种关键的功能。然而值得注意的是，尽管我们知道详细的三维结构及其与免疫球蛋白M、免疫球蛋白A、免疫球蛋白G和免疫球蛋白E的细胞受体的相互作用，但我们没有关于免疫球蛋白D的这些信息。这是我们对基础免疫学理解的一个主要差距。我们已经发现，哮喘患者的呼吸道中产生了IGD抗体，这些抗体表明(通过对其基因序列的分析)是针对特定过敏原或抗原的。其他人在过敏患者的血液中发现了针对食物过敏原的IGD抗体。有趣的是，人们还知道某些共生细菌(华支杆菌和流感嗜血杆菌)表达的表面蛋白与IGD紧密结合，这些细菌通常存在于呼吸道。我们假设，这些IgD抗体的产生及其与肥大细胞和嗜碱性粒细胞上的受体的相互作用，不同于那些IgE受体，代表了最终导致IgE反应和过敏疾病和哮喘症状的过程的早期阶段。为了了解这一过程的IGD阶段，以及共生细菌的作用，我们将研究IGD抗体与变应原、细菌蛋白以及肥大细胞和嗜碱性粒细胞上的受体(S)的相互作用。我们希望通过在分子水平上描述这些机制，我们将找到机会在过敏性呼吸道炎症和哮喘的发展的早期阶段进行更有效的干预。IGD抗体也很可能在其他疾病中发挥作用，这里提出的工作将极大地提高我们对基础免疫学领域的理解，值得注意的是，这一领域尚未得到探索。

The incidence of allergic disease worldwide has increased alarmingly in recent decades, no more so than in the UK where, for example, the prevalence of asthma is among the highest in the world. One in six children in the UK suffers from asthma, and life-threatening anaphylactic reactions to common food allergens such as peanuts, once rare, are now increasingly common. Allergic reactions occur when apparently innocuous substances are recognised by the immune system and treated as dangerous foreign "antigens". The antibodies produced by the immune system in response to these allergenic substances are of a type called IgE (immunoglobulin E), with different properties to the more commonly produced protective IgG, IgM and IgA antibodies with which the body defends itself again bacterial, viral and other "foreign" invaders. IgE antibodies bind to specific "receptor" proteins on the surface of cells (e.g. mast cells in the airways, skin or gut, and basophils in the blood) which, when triggered by allergen, release substances that lead to immediate hypersensitivity reactions characteristic of allergic disease. Targeting IgE is a viable therapeutic strategy, but an anti-IgE agent recently developed (omalizumab) is not only very expensive but also it is not effective in all patients. We have recently discovered in asthma patients a fifth and largely overlooked type of antibody, IgD, which may play a more fundamental role in allergic inflammation.Of the five different types of human antibodies, IgM and IgD were the first to evolve with the emergence of an immune system in the jawed vertebrates (e.g. sharks) 500 million years ago. The other antibody classes evolved later, but IgM and IgD have been conserved to the present day, and while much is known about the important role that IgM plays, particularly in the primary immune response upon first encounter with a foreign antigen, very little is known about IgD. That it has also been conserved throughout the evolution of the immune system points to a critical function. Yet remarkably, while we know in detail the three dimensional structures and their interactions with cell receptors for IgM, IgA, IgG and IgE, we have none of this information for IgD. It is a major gap in our understanding of fundamental immunology.We have discovered that IgD antibodies are produced in the respiratory tract of people with asthma, and that the antibodies show evidence (from analysis of their gene sequences) of being directed against specific allergens or antigens. Others have found IgD antibodies directed against food allergens in the blood of allergic patients. Intriguingly, it is also known that surface proteins expressed by certain commensal bacteria (M. catharralis and H. influenzae), commonly found in the respiratory tract, bind tightly to IgD. We hypothesise that the production of these IgD antibodies and their interactions with receptors on mast cells and basophils, different to those receptors for IgE, represents an early stage in the process that eventually leads to the generation of an IgE response and the symptoms of allergic disease and asthma.In order to understand the IgD stage of this process, and the role of commensal bacteria, we will study the interactions of IgD antibodies with allergens, the bacterial proteins, and also the receptor(s) on mast cells and basophils. We hope that by delineating these mechanisms at the molecular level, we will identify opportunities to intervene more effectively at this early stage in the development of allergic airway inflammation and asthma. It is also very likely that IgD antibodies play a role in other diseases, and the work proposed here will substantially improve our understanding of an area of fundamental immunology which, remarkably, has yet to be explored.