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

人类免疫系统通过各种不同的细胞（如白色血细胞）和蛋白质（如抗体）提供对外来入侵生物体（包括寄生虫、细菌和病毒）的保护。人类和其他哺乳动物一样，也有专门的抗体类型：一种称为IgG的抗体主要对付病毒和细菌，而另一种称为IgE的抗体是为了防御寄生虫而产生的。然而，在世界上寄生虫感染不再构成挑战的地区，这些IgE抗体是针对我们称为过敏原的物质产生的。有产生高水平IgE倾向的人特别容易患过敏症，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定的部分，存在于IgE中，而不是IgG中，这赋予了它特殊的性质。特别是，它会使IgE分子非常紧密地粘附在细胞上，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，它具有相同的效果，其中包括突然的炎症反应，当过敏原如草花粉，蜂毒或特定食物，例如花生，进入体内时。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。我们在这一领域工作的一个目标是开发改进的药物来治疗这些疾病。然而，我们还需要了解人类免疫系统，例如IgG和IgE类型反应的“极化”，以及为什么只有我们所知的某些分子作为过敏原才会引起IgE反应。解决这个问题的一种方法是从进化的角度。鸟类没有IgG或IgE，而是有一种称为IgY的抗体。事实上，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IgY样抗体，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，然而鸟类在免疫反应中对病毒和寄生虫的反应不同，尽管只有一种抗体。我们建议研究鸡的IgY，因为它们具有最好的非哺乳动物免疫系统。去年发表的鸡基因组完整DNA序列大大加强了这些研究。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，我们是第一个确定IgY的这种“受体”的人。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，从而帮助我们了解，也许然后预防人体中不必要的IgE过敏反应。因此，这项研究的成果之一是提高对人类免疫系统及其进化的理解，并为人类医学带来未来的好处。然而，提高对鸡免疫系统的认识并非没有其自身的好处。禽肉是人类疾病的重要来源，而鸡的细菌性疾病的控制主要是基于不加选择地使用抗生素;抗生素的过度使用严重降低了它们在控制人类细菌感染方面的有效性，正如耐药性“超级细菌”菌株的出现所显示的那样。更好地了解鸡的免疫系统可能会导致更好的方法来控制这些商业上重要的动物的细菌感染。鸡和其他鸟类也可能携带病毒，反过来威胁人类，例如最近爆发的禽流感，提高鸟类免疫力的知识可能有助于我们了解这种传播过程是如何发生的。

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.