Integrin αEβ7-dependent IgA transcytosis during homeostasis and IBD

稳态和 IBD 期间整合素 αEβ7 依赖性 IgA 转胞吞作用

• 批准号: 10591538
• 负责人: Jesus Rivera-Nieves
• 金额: $ 64.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591538
• 关键词: Acceleration; Address; Affect; Area; B-Lymphocytes; Bacteria; Blocking Antibodies; Cell Compartmentation; Cell physiology; Cell surface; Cells; Chronic; Colitis; Cytometry; Data; Dedications; Defect; Dependence; Diffusion; Disease model; Docking; E-Cadherin; Elements; Epithelial Cells; Epithelium; Epitopes; Event; Family; Feces; Financial Hardship; Growth; Healthcare Systems; Home; Homeostasis; Homing; Human; Ileitis; Immune; Immune response; Immune system; Immunofluorescence Immunologic; Immunoglobulin A; Immunoglobulin-Secreting Cells; Immunophenotyping; Individual; Inflammatory Bowel Diseases; Integrin alpha Chains; Integrins; Interleukin-10; Intervention; Intestines; Investigation; Lamina Propria; Leukocytes; Ligands; Lymphocyte; Maintenance; Manuscripts; Mediating; Modeling; Mononuclear; Morbidity - disease rate; Morphology; Mucosal Immune System; Mucous body substance; Mus; North America; Pathogenesis; Pathogenicity; Persons; Pharmaceutical Preparations; Phenotype; Plasma Cells; Play; Polymeric Immunoglobulin Receptors; Predisposition; Regulation; Role; Secretory Immunoglobulin A; Severities; Severity of illness; Surface; System; T-Lymphocyte; TNF gene; Therapeutic; Translating; Work; attenuation; base; beta diversity; cell motility; commensal microbes; dimer; disorder control; effector T cell; gut microbiota; integrin alpha4beta7; intestinal epithelium; microbial; microbiota; mouse model; mucosal addressin cell adhesion molecule-1; novel; pathogenic microbe; prevent; recruit; stem cell niche; transcriptomics; transcytosis; treatment strategy

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.

7.项目摘要 炎症性肠病（IBD）发生在遗传易感个体，当肠道免疫功能低下时， 系统失去对共生微生物群中未识别成分的耐受性。浆细胞（PC）源性分泌 免疫球蛋白A（sIgA）是我们能够与我们的人共存的主要机制之一。 微生物群尽管如此，对B细胞/免疫球蛋白A的理解还不够重视 (IgA)系统在IBD期间。阻断白色细胞表面整联蛋白的抗体已成为一种广泛的免疫抑制剂。 采用的治疗IBD的策略。其中一种药物（Vedolizumab）特异性阻断整合素α4β7， 这种分子对于白色细胞进入肠道至关重要。我们发现，B细胞携带这种整合素更多， 比小鼠和人类的T细胞更重要，并且严重依赖这种分子运输到肠道。因此，老鼠 缺乏β7整联蛋白链的人有肠B细胞缺陷和粪便伊加缺陷，如果 肠道植物群和更严重的IBD在两个慢性IBD小鼠模型。尽管这可能归因于 整合素α4β7缺陷，在缺乏αEβ7整合素的小鼠中持续存在管腔伊加缺陷，尽管在这些小鼠中B 细胞可以正常到达肠道。我们最近发现了一个以前未描述的肠道PC亚群， 表达αEβ7，主要定位于隐窝的基部。我们认为某些肠PC表达αEβ7， 这使得它们能够与肠上皮细胞对接，并直接传递伊加，以实现最有效的运输 到肠腔。我们认为这种新的伊加转运方式在维持免疫系统中起着关键作用。 伊加在肠腔中，因此在IBD期间对微生物植物群的影响。在目前的提案中，我们将 有几个问题涉及尚未得到解答的重要问题。1.这些细胞位于何处，它们的 起源？2.它们如何影响小鼠IBD的严重程度和3.他们对控制 IBD期间肠道细菌植物群。这项研究是重要的，因为它开始解决B细胞的作用 以及它们对β7整联蛋白的关键依赖，以归巢到肠道并维持所需的伊加水平， 在IBD期间控制某些病原微生物。了解淋巴细胞整合素在界面的作用 微生物群和宿主之间的联系可能会导致更好地理解目前的抗整合素是如何 治疗有效，并导致新的干预措施，以防止对微生物群的不受控制的免疫反应， 引发炎症性肠病