Generation of human intestinal IgA plasma cells: roles of innate and adaptive immunity.

属于免疫系统的大多数细胞位于肠壁。尽管如此，全世界每年仍有数百万人死于肠道感染，如果我们要与这种疾病作斗争，我们需要知道如何引导肠道免疫系统识别和阻止导致疾病的细菌。目前，这是有问题的。我们认为，这是因为我们没有回答一个基本的问题，具体地说，‘正常的人类肠道抗体反应是如何驱动的？’有能力产生抗体的细胞被称为B细胞，它在骨髓中一直是新鲜的。每种抗体都有自己的个体形状，潜在的个体形状也有很大的变化。每个B细胞都有表面只有一种形状的抗体。B细胞将抗体放在细胞表面，但除非B细胞被激活，否则不会发育成释放抗体的细胞。B细胞可以通过多种途径被激活。其中一个要求抗体的确切形状必须与虫子的形状相匹配，就像锁和钥匙一样。在免疫反应组织者T细胞的帮助下，B细胞被激活。B细胞分裂得非常快。它们的抗体可以适应，以产生与激活它们的形状更匹配的抗体。这种T细胞依赖的B细胞的激活，允许抗体的形状适应，被称为生发中心反应，它产生最适合的抗体和记忆B细胞，一旦再次出现相同的形状，这些B细胞就准备好了；因此，这种类型的反应对预防感染的疫苗最有效。另一种产生抗体的途径并不那么依赖抗体本身的形状，而是涉及B细胞表面的分子识别细菌表面的特征形状。这是可能的，因为例如细菌的表面与哺乳动物细胞的表面非常不同。B细胞表面细菌成分的受体是已知的，但到目前为止，人类肠道B细胞的状态尚不清楚。这个项目的第一个目标就是确定这一点。这些反应在一定程度上被T细胞增强，但不涉及生发中心的产生。它们不会产生最合适的抗体或记忆细胞，因此这不是有效疫苗接种的有效激活途径。最近用小鼠进行的一项实验指出，如果如预期的那样从B细胞表面去除特定的抗体，淋巴或脾中就不会形成生发中心。然而，令人惊讶的是，在肠道中确实形成了生发中心。这意味着驱动肠道生发中心的因素不同于淋巴和脾中的生发中心，可能不会产生特定的抗体。因此，我们认为，有效接种肠道疫苗的尝试失败了，因为管理肠道生发中心形成的规则不同，在正常情况下不一定会产生特定的反应或记忆。当B细胞被激活时，细胞必须将细胞表面的刺激转化为适当的行动，这可能会根据刺激的性质而有所不同，如上所述。这是通过信号分子实现的，这些分子形成了从细胞表面到细胞核的信息链。细胞核包含改变行为的所有信息，例如开始分裂或开始产生抗体。这些信号的成分和状态根据细胞表面刺激的性质而不同。该项目的第二个目标是分析这些信号，以确定是什么驱动了正常人体肠道的抗体反应。然后，我们将处于更好的地位，创造出一种能够有效预防肠道感染的疫苗。

The majority of cells belonging to the immune system are located in the wall of the intestine. Despite this, infections of the intestine kill millions of people each year throughout the world and if we are to fight such diseases we need to know how to direct the intestinal immune system to identify and halt the bugs that cause disease. At the moment this is problematic. We believe that the reason for this is that we have failed to answer a fundamental question, specifically, 'How is the normal human intestinal antibody response driven?' The cells that have the capability to make antibodies are called B cells, which are made fresh in the bone marrow all the time. Each antibody has its own individual shape and there is a massive variety of potential individual shapes. Each B cell has antibody with only a single shape on its surface. B cells put antibody on their cell surface but do not develop into cells that release antibodies unless the B cell is activated. B cells can be activated by a number of routes. One requires that the exact shape of the antibody has to fit, like a lock and key, with the shape of a bug. With the help of T cells, which are organisers of the immune response, the B cells become activated. The B cells divide very fast. Their antibodies can adapt to generate a better fit with the shape that activated them. This T cell dependent activation of B cells that allows the shape of the antibody to adapt, is called a germinal centre response and it generates antibodies with best fit and also memory B cells that are at the ready in case the same shape turns up again; hence this type of response is most effective for vaccination against infections. Another route of antibody production is not so dependent on the shape of the antibody itself, but rather involves the recognition of characteristic shapes on the surfaces of bugs by molecules on the B cell surface. This is possible because the surfaces of bacteria for example are very different to the surfaces of mammalian cells. The receptors for bacterial components on the B cell surface are known, but as yet, the status of human intestinal B cells is not known. The first aim of this project is to determine this. These responses are enhanced by T cells to some degree, but do not involve generation of germinal centres. They do not make best fit antibodies or memory cells and therefore this is not a useful pathway to activate for effective vaccination. A recent experiment using mice noted that if specific antibody is removed from the surface of B cells, as expected, germinal centres do not form in lymph nodes or spleen. However, surprisingly, germinal centres did form in the gut. This implies that the factors that drive germinal centres in the gut are different to those in the lymph nodes and spleen, and might not generate specific antibodies. Therefore we believe that attempts to effectively vaccinate the gut have failed because the rules that govern germinal centre formation in the gut are different and do not necessarily generate specific responses or memory under normal conditions. When B cells are activated, the cells have to convert the stimulus at the cell surface into appropriate action, which may differ according to the nature of the stimulus as described above. This is achieved via signalling molecules that form a chain of messages from the cell surface to the nucleus. The nucleus contains all the information to change behaviour, such as start dividing or start antibody production. The components and state of these signals differ according to the nature of the stimulus at the cell surface. The second aim of this project is to analyse these signals to determine what is driving the antibody response in the normal human intestine. We will then be in a much better position create a vaccine that would effectively protect against intestinal infection.