Integrin αEβ7-dependent IgA transcytosis during homeostasis and IBD

7.项目总结 炎症性肠病(IBD)发生在遗传易感人群中，当肠道免疫时 系统对共生微生物区系中的未知元素失去耐受性。浆细胞(PC)分泌 免疫球蛋白A(SIgA)是我们能够与我们的 微生物区系。尽管如此，对B细胞/免疫球蛋白A的了解还不够重视 (IGA)系统在IBD期间。阻断白细胞细胞表面整合素的抗体已成为一种广泛的- 使用了治疗IBD的策略。其中一种药物(Vedolizumab)，专门阻断整合素α4β7，a 一种对白细胞进入肠道至关重要的分子。我们发现B细胞更多地携带这种整合素 比小鼠和人类的T细胞更重要，并严重依赖这种分子来运输到肠道。因此，老鼠 缺乏β7整合素链的人有肠道B细胞缺陷和粪便Ig A缺陷，这会导致以下情况的改变 两种慢性IBD小鼠模型的肠道菌群和更严重的IBD。尽管这可以归因于 整合素α4β7缺陷，腔免疫球蛋白A缺陷在缺乏αEβ7整合素的小鼠中持续存在，尽管在这些小鼠B 正常情况下，细胞可以到达肠道。我们最近发现了一个以前未描述的肠道PC子集 ExpressαEβ7，主要定位于墓穴底部。我们建议某些肠道PC表达αEβ7， 这使它们能够与肠道上皮细胞对接，并直接依靠IgA进行最有效的运输 转移到肠腔。我们认为，这种新的免疫球蛋白A运输方式对维持 在IBD期间，肠腔中的IgA对微生物区系也有影响。在目前的提案中，我们将 有几个解决了仍然没有得到回答的重要问题。1.这些牢房位于哪里？它们的位置是什么 起源？2.它们如何影响小鼠IBD的严重程度？3.它们对控制IBD有什么贡献 IBD期间肠道菌群的变化。这项研究具有重要意义，因为它开始解决B细胞的作用 以及它们对β7整合素的严重依赖以定位于肠道，并维持所需的 控制IBD期间的某些致病微生物。理解淋巴细胞整合素在界面上的作用 微生物区系与其宿主之间的关系可能有助于更好地理解当前的反整合素是如何 治疗工作并导致新的干预措施，以防止对微生物区系的失控免疫反应 这会引发IBD。

7. Project Summary Inflammatory bowel disease (IBD) arises in genetically-susceptible individuals when the intestinal immune system loses tolerance to unidentified elements of the commensal microbiota. Plasma cell (PC)-derived secretory immunoglobulin A(sIgA) is one of the main mechanisms through which we are able to coexist with our microbiota. Despite this, insufficient emphasis has been placed on understanding the B cell/immunoglobulin A (IgA) system during IBD. Antibodies that block integrins on the cell surface of white cells have become a widely- used strategy for the treatment of IBD. One of these drugs (vedolizumab), specifically blocks integrin α4β7, a molecule which is critical for the traffic of white cells to the intestine. We find that B cells carry this integrin more than T cells in mice and humans and critically depend on this molecule to traffic to intestine. Therefore, mice that lack the β7 integrin chain have an intestinal B cell deficit and a stool IgA deficit that leads to alterations if their intestinal flora and worse IBD in two chronic IBD mouse models. Although this could be attributed to an integrin α4β7 defect, the luminal IgA deficit persists in mice that lack αEβ7 integrin, although in these mice B cells can reach the intestine normally. We recently found a previously undescribed subset of intestinal PC that express αEβ7, localized primarily to the base of the crypts. We propose that certain intestinal PC express αEβ7, which allows them to dock with intestinal epithelial cells and directly relay IgA for its most efficient transport to the intestinal lumen. We believe that this new mode of IgA transport plays a critical role for the maintenance of IgA in intestinal lumen and therefore on the microbial flora during IBD. In the current proposal we will several address important questions that remain unanswered. 1. Where are these cells located and what is their origin? 2. How do they influence the severity of IBD in mice and 3. What is their contribution on the control of the intestinal bacterial flora during IBD. This investigation is significant as it begins to address the role of B cells and their critical dependence on β7 integrins to home to the intestine and maintain the required IgA levels that control certain pathogenic microbes during IBD. Understanding the role of lymphocyte integrins at the interface between the microbiota and its host may lead to a better understanding of how do current anti-integrin therapeutics work and lead to new interventions to prevent the uncontrolled immune response to the microbiota that triggers IBD.