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

近几十年来，世界范围内过敏性疾病的发病率以惊人的速度增长，尤其是在英国，例如，哮喘的患病率是世界上最高的。在英国，六分之一的儿童患有哮喘，而对常见食物过敏原（如花生）的危及生命的过敏反应，曾经罕见，现在越来越普遍。当看似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。免疫系统对这些致敏物质产生的抗体是一种称为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，身体用这些抗体来再次防御细菌、病毒和其他“外来”入侵者。IgE抗体与细胞表面的特定“受体”蛋白结合（例如气道、皮肤或肠道中的肥大细胞以及血液中的嗜碱性细胞），当被过敏原触发时，释放出导致过敏性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，但最近开发的抗IgE药物（omalizumab）不仅非常昂贵，而且并非对所有患者都有效。我们最近在哮喘患者中发现了第五种抗体，IgD，这在很大程度上被忽视了，它可能在过敏性炎症中起着更重要的作用。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出来的。其他种类的抗体进化较晚，但IgM和IgD一直保存到今天，虽然人们对IgM的重要作用了解甚多，特别是在初次遇到外来抗原时的初级免疫反应中，但对IgD知之甚少。它在整个免疫系统的进化过程中也被保存下来，这表明了它的一个关键功能。然而，值得注意的是，虽然我们详细了解了IgM、IgA、IgG和IgE的三维结构及其与细胞受体的相互作用，但我们对IgD却一无所知。这是我们对基础免疫学理解的一个重大空白。我们已经发现，哮喘患者的呼吸道中会产生IgD抗体，而且这些抗体（通过对其基因序列的分析）显示出针对特定过敏原或抗原的证据。其他人已经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，我们还知道，某些常见于呼吸道的共生细菌（宣泄分枝杆菌和流感嗜血杆菌）表达的表面蛋白与IgD紧密结合。我们假设，这些IgD抗体的产生及其与肥大细胞和嗜碱性细胞受体的相互作用，与IgE受体不同，代表了最终导致IgE反应产生和过敏性疾病和哮喘症状的过程的早期阶段。为了了解这一过程中的IgD阶段以及共生菌的作用，我们将研究IgD抗体与过敏原、细菌蛋白以及肥大细胞和嗜碱性细胞上的受体的相互作用。我们希望通过在分子水平上描述这些机制，我们将在过敏性气道炎症和哮喘发展的早期阶段找到更有效干预的机会。IgD抗体也很可能在其他疾病中发挥作用，这里提出的工作将大大提高我们对基础免疫学领域的理解，值得注意的是，这一领域尚未被探索。

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.