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Immunoglobulin Y: an IgG-like antibody with an IgE-like structure?

免疫球蛋白 Y：具有 IgE 样结构的 IgG 样抗体？

基本信息

批准号：
BB/D011418/1
负责人：
Brian Sutton
金额：
$ 37.31万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FD011418%2F1
关键词：
Immunoglobulin IgG like antibody IgE

项目摘要

The human immune system provides protection against foreign invading organisms including parasites, bacteria and viruses, through a variety of different cells, such as the white blood cells, and proteins, such as the antibodies. In man, as in other mammals, there are specialized types of antibodies: a type known as IgG deal principally with viruses and bacteria, while another, called IgE, is produced in defence against parasites. However, in regions of the world where parasitic infections no longer present a challenge, these IgE antibodies are instead produced in response to substances that we call allergens. People with a tendency to produce high levels of IgE are especially susceptible to allergies, such as hayfever, asthma and food allergies. We have been studying IgE antibodies in order to understand how they cause allergy, and have discovered that there is a particular part of the antibody molecule, present in IgE but not in IgG, which gives it special properties. In particular, it causes the IgE molecules to stick extremely tightly to cells and activate them when parasites invade the body. Although this is very effective against parasites, it unfortunately has the same effects, which include a sudden inflammation reaction, when allergens such as grass pollen, bee venom or particular foods, for example peanuts, enter the body. The effects of these sudden allergic reactions are well-known, and can even be fatal. One aim of our work in this field is to develop improved drugs to treat these conditions. There is however much that we have yet to learn about the human immune system, such as the 'polarization' into the IgG and IgE type responses, and why only certain molecules that we know as allergens provoke the IgE response. One way of approaching this is from an evolutionary standpoint. Birds do not have IgG or IgE, but instead have a single type of antibody called IgY. In fact, an IgY-like antibody was present in the last common ancestor of birds and mammals, 300 million years ago, and was the evolutionary predecessor of IgG and IgE. IgY combines in a single molecule the properties of both IgG and IgE, yet birds do respond differently to viruses and parasites in their immune response, despite having only one type of antibody. We propose to study IgY from chickens, since they have the best-studied non-mammalian immune system. The publication last year of the complete DNA sequence of the chicken genome has greatly enhanced these studies. In particular, we propose to isolate the molecules to which IgY binds on the surfaces of cells, and we are the first, to our knowledge, to have identified such a 'receptor' for IgY. We shall study how IgY binds to cells, and aim to discover how it combines the roles of both IgG and IgE, thus helping us to understand, and perhaps then prevent, the unwanted IgE allergic response in man. One of the outcomes of this research is therefore an improved understanding of the human immune system and its evolution, with future benefits for human medicine. However, improved understanding of the chicken immune system is not without its own benefits. Poultry meat is an important source of human disease, and the control of bacterial disease in chickens is largely based on an indiscriminate use of antibiotics; this over-use of antibiotics has severely reduced their usefulness in controlling human bacterial infections, as the emergence of strains of antibiotic-resistant 'super-bugs' has shown. A better understanding of the chicken immune system may lead to better ways of controlling bacterial infection in these commercially important animals. Chickens and other avian species can also harbour viruses that can in turn threaten man, such as the recent outbreak of avian 'flu, and improved knowledge of immunity in birds may help us to understand how this transmission process occurs.

人体免疫系统通过各种不同的细胞（如白细胞）和蛋白质（如抗体）提供保护，抵御外来入侵生物，包括寄生虫、细菌和病毒。人和其他哺乳动物一样，人体内也有专门类型的抗体：一种被称为IgG的抗体主要对付病毒和细菌，而另一种被称为IgE的抗体是用来防御寄生虫的。然而，在寄生虫感染不再构成威胁的地区，这些IgE抗体是对我们称为过敏原的物质作出反应而产生的。倾向于产生高水平IgE的人特别容易过敏，如花粉热、哮喘和食物过敏。我们一直在研究IgE抗体，以了解它们是如何引起过敏的，并发现抗体分子中有一个特殊的部分，存在于IgE中，而不存在于IgG中，这赋予了它特殊的性质。特别是，它使IgE分子紧紧地附着在细胞上，并在寄生虫入侵人体时激活它们。虽然这对寄生虫非常有效，但不幸的是，它也有同样的效果，当草花粉、蜂毒或特定食物（如花生）等过敏原进入人体时，它会引起突然的炎症反应。这些突发过敏反应的影响是众所周知的，甚至可能是致命的。我们在这一领域的工作目标之一是开发改进的药物来治疗这些疾病。然而，我们对人类免疫系统还有很多需要了解的，比如IgG和IgE型反应的“极化”，以及为什么只有某些我们已知的过敏原分子会引发IgE反应。解决这个问题的一种方法是从进化的角度出发。鸟类没有IgG或IgE，而是有一种叫做IgY的抗体。事实上，在3亿年前，鸟类和哺乳动物的最后一个共同祖先中就存在一种类似igy的抗体，它是IgG和IgE的进化前身。IgY在单个分子中结合了IgG和IgE的特性，尽管鸟类只有一种抗体，但它们对病毒和寄生虫的免疫反应是不同的。我们建议从鸡身上研究卵黄蛋白，因为鸡的免疫系统在非哺乳动物中被研究得最多。去年公布的鸡基因组完整DNA序列极大地促进了这些研究。特别是，我们建议分离IgY在细胞表面结合的分子，据我们所知，我们是第一个发现IgY的这种“受体”。我们将研究IgY如何与细胞结合，并旨在发现它如何结合IgG和IgE的作用，从而帮助我们理解，也许然后预防人类不想要的IgE过敏反应。因此，这项研究的结果之一是提高了对人类免疫系统及其进化的理解，对人类医学有未来的好处。然而，提高对鸡免疫系统的了解并非没有好处。禽肉是人类疾病的一个重要来源，对鸡的细菌性疾病的控制在很大程度上是基于滥用抗生素；抗生素的这种过度使用严重降低了它们在控制人类细菌感染方面的作用，抗生素耐药“超级细菌”菌株的出现已经表明了这一点。更好地了解鸡的免疫系统可能会找到更好的方法来控制这些具有重要商业价值的动物的细菌感染。鸡和其他鸟类也可能携带病毒，进而威胁人类，例如最近爆发的禽流感，提高对鸟类免疫力的认识可能有助于我们了解这种传播过程是如何发生的。