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

人类分泌的 IgD:过敏性炎症和哮喘的结构、相互作用和机制

基本信息

  • 批准号:
    MR/V010557/1
  • 负责人:
  • 金额:
    $ 107.53万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2021
  • 资助国家:
    英国
  • 起止时间:
    2021 至 无数据
  • 项目状态:
    未结题

项目摘要

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.
近几十年来,世界范围内过敏性疾病的发病率惊人地增加,例如,英国的哮喘患病率是世界上最高的。在英国,六分之一的儿童患有哮喘,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。当免疫系统识别出看似无害的物质并将其视为危险的外来“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称为IgE(免疫球蛋白E)的抗体,与更常见的保护性IgG,IgM和伊加抗体具有不同的特性,身体再次防御细菌,病毒和其他“外来”入侵者。IgE抗体与细胞表面的特异性“受体”蛋白结合(例如气道、皮肤或肠道中的肥大细胞和血液中的嗜碱性粒细胞),当被过敏原触发时,释放导致过敏性疾病特征性的速发型超敏反应的物质。靶向IgE是一种可行的治疗策略,但最近开发的抗IgE药物(奥马珠单抗)不仅非常昂贵,而且并非对所有患者都有效。最近,我们在哮喘患者身上发现了第五种抗体,即IgD,这种抗体在过敏性炎症中可能起着更重要的作用。在五种不同的人类抗体中,IgM和IgD是第一种随着5亿年前有颌脊椎动物(如鲨鱼)免疫系统的出现而进化出来的抗体。其他的抗体种类进化较晚,但IgM和IgD一直保存到今天,虽然对IgM所起的重要作用了解很多,特别是在第一次遇到外来抗原时的初次免疫应答中,但对IgD知之甚少。它在整个免疫系统的进化过程中也是保守的,这表明它具有关键的功能。然而,值得注意的是,虽然我们详细了解了IgM、伊加、IgG和IgE的三维结构及其与细胞受体的相互作用,但我们没有IgD的这些信息。这是我们对基础免疫学理解的一个重大空白,我们发现哮喘患者的呼吸道中产生IgD抗体,并且这些抗体显示出针对特定过敏原或抗原的证据(从其基因序列分析)。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,还已知由某些细菌表达的表面蛋白(M. catharralis和H.流感病毒)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粒细胞上的受体(不同于IgE的那些受体)的相互作用代表了最终导致IgE应答产生和过敏性疾病和哮喘症状的过程的早期阶段。为了理解该过程的IgD阶段以及肠道细菌的作用,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粒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,我们将确定在过敏性气道炎症和哮喘发展的早期阶段进行更有效干预的机会。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。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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James McDonnell其他文献

James McDonnell的其他文献

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{{ truncateString('James McDonnell', 18)}}的其他基金

Elucidating the mechanisms of accelerated dissociation and allosteric processes in the antibody immunoglobulin E
阐明抗体免疫球蛋白 E 加速解离和变构过程的机制
  • 批准号:
    BB/P000436/1
  • 财政年份:
    2017
  • 资助金额:
    $ 107.53万
  • 项目类别:
    Research Grant

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