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

大多数属于免疫系统的细胞位于肠壁。尽管如此，全世界每年仍有数百万人死于肠道感染，如果我们要与此类疾病作斗争，我们需要知道如何指导肠道免疫系统识别并阻止导致疾病的细菌。目前这是有问题的。我们认为，造成这种情况的原因是我们未能回答一个基本问题，特别是“正常的人类肠道抗体反应是如何驱动的？”有能力制造抗体的细胞被称为B细胞，它们一直在骨髓中新鲜产生。每一种抗体都有自己独特的形状，而且有大量不同的潜在形状。每个B细胞表面只有一种形状的抗体。B细胞把抗体放在细胞表面，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。一种是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T细胞的帮助下，B细胞被激活，T细胞是免疫反应的组织者。B细胞分裂得很快。它们的抗体可以适应，以产生与激活它们的形状更好的匹配。这种依赖于T细胞的B细胞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，以备相同形状再次出现；因此，这种类型的反应对于预防感染的疫苗是最有效的。另一种产生抗体的途径并不依赖于抗体本身的形状，而是涉及到B细胞表面分子对细菌表面特征形状的识别。这是可能的，因为细菌的表面与哺乳动物细胞的表面非常不同。B细胞表面的细菌成分受体是已知的，但到目前为止，人类肠道B细胞的状态尚不清楚。这个项目的首要目标就是确定这一点。T细胞在一定程度上增强了这些反应，但不涉及生发中心的产生。它们不能产生最合适的抗体或记忆细胞，因此这不是激活有效疫苗接种的有用途径。最近的一项小鼠实验发现，如果从B细胞表面去除特异性抗体，如预期的那样，在淋巴结或脾脏中不会形成生发中心。然而，令人惊讶的是，生发中心确实在肠道中形成。这意味着驱动肠道生发中心的因素与淋巴结和脾脏中的因素不同，可能不会产生特异性抗体。因此，我们认为有效接种肠道疫苗的尝试失败了，因为控制肠道生发中心形成的规则是不同的，在正常条件下不一定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动作，根据上述刺激的性质，这可能会有所不同。这是通过信号分子实现的，这些信号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，比如开始分裂或开始产生抗体。这些信号的组成和状态根据细胞表面刺激的性质不同而不同。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中的抗体反应。这样我们就能更好地研制出一种疫苗，有效地预防肠道感染。

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.