Evolution of antibody affinity modification in fishes

接种疫苗的两个预期结果是：1)免疫记忆，由此长期免疫记忆细胞的数量大量增加，这些细胞将能够识别你接种过疫苗的疾病。2)通过调整用于识别病原体的分子的基因，提高对疾病生物体的识别。后一种过程被称为抗体亲和成熟，它涉及我们基因组的一个选择部分的有意突变，希望改进它编码的抗体的设计，这样它们就能更好地与生物体接触过的病原体结合。基因组突变是一件微妙的事情，必须严格监管，以免意外突变导致癌症或自身免疫性疾病。我们的研究研究突变过程发生的条件。具体来说，我们研究这个系统是如何在能够产生抗体的最原始的生物中运作的——鱼。鲨鱼和鱼类似乎有一种非常简单的方法来改变它们的抗体基因。通过研究更简单的系统（与哺乳动物相比），我们希望了解系统如何工作的最基本的细胞和分子必需品，以及导致它出错的原因，就像在许多自身免疫性疾病中一样。在自身免疫性疾病中，抗体基因被改变了，所以它们把我们自己的组织误认为是病原体的组织。在哺乳动物中发生这种情况的条件与鱼类驱动突变过程的情况相似。鱼类正常发生的情况可能与某些哺乳动物疾病相似，研究鱼类可能为理解人类自身免疫的发展打开一扇窗。具体来说，我们正在研究一种突变系统，它可以调整现有的抗体，使它们更适合它们识别的病原体。我们的第一个目标是验证鱼类是否具有与哺乳动物相同的突变系统（即鱼类是研究哺乳动物突变系统的模型系统）。这包括研究组织中抗体基因中积累的突变，我们认为这一过程正在发生。我们的第二个目标是研究如何检查发生突变的细胞，以确保它们不会产生针对自身的抗体，即自身免疫抗体。在这一点上，他们已经被判了死刑，如果他们仍然不能识别病原体，他们就会死。一些参与“检查”的细胞在鱼类中似乎是不同的，我们正在验证这一点。最后，我们正在开发转基因细胞和鱼，可用于研究抗体亲和成熟的其他成分。这些细胞和鱼经过基因工程改造，可以“点亮”所有AID活跃的细胞，从而使我们能够观察到存在于半透明斑马鱼体内的与突变系统有关的细胞。

Two desired outcomes of vaccination are: 1) immunologic memory, whereby there is a large increase in the number of long-lived immune memory cells that will be able to recognize the disease that you were vaccinated against. 2) improved recognition of disease organism by tweaking the genes of the molecules used to recognize the pathogen. This latter process termed antibody affinity maturation involves the intentional mutation of a select part of our genome in the hopes of improving the design of the antibodies that it encodes, so they can better bind to a pathogen that the organism has been exposed to. Mutation of the genome is a delicate business that must be tightly regulated so that unintended mutation doesn't lead to cancers or autoimmune diseases. Our research studies the conditions in which the mutation process takes place. Specifically we study how this system operates in the most primitive of organisms that are able to make antibodies - the fishes. Sharks and fishes seem to have a very simplified method of altering their antibody genes. By studying the simpler system (compared to mammals) we hope to understand the most basic cellular and molecular necessities for how the system works, and what can cause it to go wrong as it does in many autoimmune diseases. In autoimmune diseases the antibody genes are altered so they mistake our own tissues for that of a pathogen. The conditions under which this happens in mammals look similar to how fish drive the mutation process. It is possible that what occurs normally in fish parallels what happens in some mammalian diseases, and studying fish may open windows to understanding the development of auto-immunity in humans. Specifically we are studying a mutational system that tweaks existing antibodies and makes them a better fit for the pathogen that they recognize. Our first goal is to verify that fish have the same sort of mutational system as mammals (i.e. that fish are a model system to study mammalian mutational systems). This involves studying the mutations that accumulate in the antibody genes from tissues in which we believe the process is happening. Our second goal is to study how cells that have undergone mutations are checked to make sure they are not making antibodies to self i.e. autoimmune antibodies. At this point they have been sentenced to death and if they can't still recognize the pathogen then they will die. Some of the cells involved in the 'checking' appear to be different in fish and we are verifying that point. Lastly we are developing transgenic cells and fish that can be used to study other components of the antibody affinity maturation. The cells and fish are genetically engineered to 'light-up' all cells in which AID is active thereby allowing us to observe the cells involved in the mutational system as they exist in translucent zebrafish.