Checkpoint governing B cell fate decisions in human gut-associated lymphoid tissue.

抗体是在血液中循环的小蛋白质分子，也会分泌到潮湿的身体表面，如眼睛和肠道。例如，眼泪、唾液和粘液都含有抗体。抗体通过与细菌结合来对抗细菌。与细菌结合的抗体可以中和它们，以阻止它们造成伤害，或者抗体可以针对细菌，使其受到免疫系统其他组件的攻击。抗体是由B细胞制造的，B细胞在其表面展示它们可以制造的抗体。每个B细胞都是独一无二的，并在其表面显示其独特的抗体形状。为了使每个B细胞及其抗体与下一个不同，B细胞的发育过程包括一些随机事件。在B细胞发育过程中，编码抗体的遗传物质被打乱，从而产生了大量抗体的遗传密码。因此，无论什么细菌或疫苗进入人体，都会有一个B细胞显示适合的抗体。以一种包括随机事件的方式产生B细胞抗体多样性的过程的一个不利之处是，一些B细胞产生的抗体可能是有害的。为了保护身体免受有害抗体的侵害，检查站会在B细胞发育过程中清除具有有害特异性的B细胞。没有人确切地知道检查点是什么--特别是在人类身上，因为很难进行这样的调查。我们知道检查点的存在，是因为人们观察了B细胞在发育过程中产生的抗体。B细胞最初在骨髓中发育，并作为未成熟的B细胞(过渡型1[T1]细胞)释放到血液中，在成为成熟的幼稚B细胞之前成熟为过渡型2(T2)细胞。在每个阶段，具有有害抗体特异性的B细胞的百分比都会下降，这必须涉及到某种类型的检查点。我们已经证明，处于T2发育阶段的B细胞优先进入免疫系统负责保护肠道的部分(肠道相关淋巴组织[GalT])。高尔特特别富含来自肠道的无害细菌片段，这些片段驱动抗体的产生，这些抗体注定会进入肠道的粘液中。与免疫系统的大多数其他部分不同，高尔特从出生后不久就一直活跃。当T2未成熟的B细胞处于这种状态时，一些细胞就会被激活。由于大多数B细胞可能在某个时间点通过肠道，这必然会产生后果，因为如果没有在GALT中激活的B细胞，B细胞群体就会成熟。为了进一步了解这一过程，我们希望回答以下4个问题：1.当B细胞在GALT中被激活时，它们是生存还是死亡？被激活的细胞是否被选择性地移除和处置，或者实际上被以某种方式使用？2.被激活的B细胞的抗体反应性与未被激活的B细胞有什么不同？这将有助于我们了解这一过程对发育中的B细胞群体的影响，以及这一过程可能如何塑造整个成熟的B细胞群体。GALT中被激活的T2细胞是否继续产生抗体，并进入肠道粘液？4.GALT不断被肠道中的细菌碎片激活。被激活的细胞的T2亚群在调节这一过程中有没有某种作用？这个项目很重要，因为它研究了人类B细胞发育的一个阶段，这是我们已经发现的，以前完全不知道的。我们有证据表明，这一阶段的失败会导致有害抗体的产生。我们必须了解我们已经发现的该系统的基本性质，以了解GALT如何防止有害抗体的产生，并找到开发这一领域的最佳方式，以最大限度地影响人类健康。

Antibodies are small protein molecules that circulate in the blood and that are also secreted onto the moist body surfaces such as the eyes and intestines. Tears, saliva and mucus for example all contain antibodies. Antibodies fight bugs by binding to them. Antibody binding to bugs can neutralize them to stop them causing harm, or else antibodies can target bugs for attack by other components of the immune system. Antibodies are made by B cells that display the antibody they can make on their surface. Each B cell is unique and displays its own particular shape of antibody on its surface. In order for each B cell and its antibody to be different to the next one, B cells develop by a process that includes some random events. The genetic material that codes for antibody is shuffled during B cell development so that a massive range of genetic codes for antibodies is generated. As a consequence, no matter what bug or vaccine enters the body there will be a B cell displaying an antibody that fits.A down-side to a process that generates B cell antibody diversity in a way that includes random events, is that some B cells are produced that display antibodies that could be harmful. To protect the body from harmful antibodies, checkpoints remove B cells with harmful specificities as they develop. No one knows exactly what a checkpoints is - especially in humans where it is difficult to do such investigations.We know that checkpoints exist because people have looked at the antibodies that B cells make as they develop. B cells develop initially in the bone marrow and are released into the blood as immature B cells (transitional type 1 [T1] cells) that mature into transitional type 2 (T2) cells before becoming mature naïve B cells. Through each stage, the percentage of B cells that have harmful antibody specificities decreases, and this must involve a checkpoint of some kind. We have shown that B cells at the T2 stage of development preferentially go into the part of the immune system responsible for protecting the intestines (the gut-associated lymphoid tissue [GALT]). GALT is particularly rich in fragments of harmless bugs from the intestine that drive the production of the antibodies that are destined to enter the gut in the mucus. Unlike most of the rest of the immune system, GALT is constantly active from very soon after birth. When the T2 immature B cells are in this setting some become activated. Since most B cells are likely to pass through the gut at some point, this must have consequences because the B cell population would mature without the ones activated in GALT.To understand this process further we wish to answer the following 4 questions:1. When B cells become activated in GALT, do they live or die? Are the cells that are activated selective removed and disposed of or actually used in some way? 2. Is there any difference in the antibody reactivities of the B cells that are activated compared to those that are not? This would help us to understand the affect this process has on the developing B cell population and how this process is likely to shape the entire mature B cell population.3. Are the T2 cells activated in GALT going on to make antibodies that will pass into intestinal mucus? 4. The GALT is constantly activated by bacterial fragments from the gut. Do the T2 subset of cells that are activated have some kind of role in regulating that process?This project is important because it investigates a phase in human B cell development that we have discovered and that was not known at all before. We have evidence that failure of this phase results production of harmful antibodies. We must understand the basic properties of the system we have discovered to understand how GALT protects from harmful antibody production and to find the best way to develop this field for maximum impact on human health.