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

控制人类肠道相关淋巴组织中 B 细胞命运决定的检查点。

• 批准号: MR/L009382/1
• 负责人: Jo Spencer
• 金额: $ 48.11万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL009382%2F1
• 关键词: Checkpoint; governing; cell; fate; decisions

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.

抗体是在血液中循环的小蛋白质分子，也会分泌到湿润的身体表面，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它们。与细菌结合的抗体可以中和它们，阻止它们造成伤害，或者抗体可以针对细菌，由免疫系统的其他组成部分攻击。抗体是由B细胞产生的，B细胞在它们的表面显示它们能产生的抗体。每个B细胞都是独一无二的，并且在其表面显示其自身特殊形状的抗体。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。编码抗体的遗传物质在B细胞发育过程中被洗牌，因此产生了大量的抗体遗传密码。因此，无论哪种细菌或疫苗进入人体，都会有一个B细胞显示出与之匹配的抗体。以随机事件的方式产生B细胞抗体多样性的过程的一个缺点是，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，检查点在B细胞发育过程中清除具有有害特异性的B细胞。没有人确切知道检查点是什么——尤其是在人类身上，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，作为未成熟的B细胞（过渡性1型[T1]细胞）释放到血液中，在成为成熟的naïve B细胞之前成熟为过渡性2型（T2）细胞。在每个阶段，具有有害抗体特异性的B细胞的百分比都在减少，这必须涉及某种检查点。我们已经证明，处于发育T2阶段的B细胞优先进入负责保护肠道的免疫系统部分（肠道相关淋巴组织[GALT]）。GALT富含肠道中无害细菌的碎片，这些细菌驱动抗体的产生，这些抗体注定要通过粘液进入肠道。与大多数免疫系统的其他部分不同，高尔特从出生后不久就一直处于活跃状态。当T2未成熟B细胞处于这种状态时，一些被激活。由于大多数B细胞在某些时候可能会通过肠道，这必然会产生后果，因为如果没有GALT激活的B细胞，B细胞群就会成熟。为了进一步了解这一过程，我们希望回答以下4个问题：当B细胞在GALT中激活时，它们是活的还是死的？被激活的细胞是被选择性地移除和处理还是以某种方式实际使用？2. 被激活的B细胞和未被激活的B细胞的抗体反应性有什么不同吗？这将有助于我们了解这一过程对发育中的B细胞群的影响，以及这一过程如何可能塑造整个成熟的B细胞群。T2细胞在GALT中被激活后会产生抗体进入肠道粘液吗？4. GALT不断被肠道细菌碎片激活。被激活的T2细胞亚群是否在调节这一过程中发挥了某种作用？这个项目很重要，因为它研究了我们已经发现的人类B细胞发育的一个阶段，这在以前是完全不知道的。我们有证据表明，这一阶段的失败导致有害抗体的产生。我们必须了解我们所发现的系统的基本特性，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法，以最大限度地影响人类健康。

项目成果

Human marginal zone B cell development from early T2 progenitors.

• DOI: 10.1084/jem.20202001
• 发表时间: 2021-04-05
• 期刊: The Journal of experimental medicine
• 作者: Tull TJ;Pitcher MJ;Guesdon W;Siu JHY;Lebrero-Fernández C;Zhao Y;Petrov N;Heck S;Ellis R;Dhami P;Kadolsky UD;Kleeman M;Kamra Y;Fear DJ;John S;Jassem W;Groves RW;Sanderson JD;Robson MG;D'Cruz DP;Bemark M;Spencer J
• 通讯作者: Spencer J

Human intestinal lymphoid tissue in time and space.

时间和空间上的人体肠道淋巴组织。

• DOI: 10.1038/s41385-018-0120-6
• 发表时间: 2019
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Spencer J

Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue.

• DOI: 10.1038/s41467-018-06089-1
• 发表时间: 2018-09-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Zhao Y;Uduman M;Siu JHY;Tull TJ;Sanderson JD;Wu YB;Zhou JQ;Petrov N;Ellis R;Todd K;Chavele KM;Guesdon W;Vossenkamper A;Jassem W;D'Cruz DP;Fear DJ;John S;Scheel-Toellner D;Hopkins C;Moreno E;Woodman NL;Ciccarelli F;Heck S;Kleinstein SH;Bemark M;Spencer J
• 通讯作者: Spencer J

Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus.

免疫球蛋白轻链等位基因包含在全身性红斑狼疮中。

• DOI: 10.1002/eji.201545599
• 发表时间: 2015-08
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Fraser LD;Zhao Y;Lutalo PM;D'Cruz DP;Cason J;Silva JS;Dunn-Walters DK;Nayar S;Cope AP;Spencer J
• 通讯作者: Spencer J