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 当肠道免疫时，炎症性肠病（IBD）发生在普通敏感的个体中 系统失去了对共生微生物群的身份不明元素的容忍度。等离子体细胞（PC）衍生的分泌 免疫球蛋白A（SIGA）是我们能够与我们的主要机制之一 微生物群。尽管如此，不足以理解B细胞/免疫球蛋白A （IGA）IBD期间的系统。封闭白细胞细胞表面整合素的抗体已成为广泛的 使用的策略用于治疗IBD。这些药物之一（vedolizumab），特异性地阻断了整联蛋白α4β7，a 分子对于白细胞流向肠道至关重要。我们发现B细胞更多地携带该整联蛋白 小鼠和人类中的T细胞以及批判性地依赖于该分子传播到肠道。因此，小鼠 缺乏β7整联蛋白链的肠道B细胞不足和粪便IgA缺陷，导致改变的话 他们在两种慢性IBD小鼠模型中的肠道菌群和更糟糕的IBD。尽管这可能归因于 整联蛋白α4β7缺陷，缺乏αeβ7整联蛋白的小鼠腔IgA不足持续存在，尽管在这些小鼠B中B 细胞可以正常达到肠道。我们最近发现了一个先前未描述的肠道PC子集 ExpressαEβ7，主要定位于隐窝的底部。我们提出某些肠道PC表达αeβ7， 这使他们能够与肠上皮细胞进行对接，并直接继电器IgA的最有效的运输 到肠腔。我们认为，这种新的IGA运输方式对维护起着至关重要的作用 IBD期间的肠腔中的IgA，因此在微生物菌群上。在当前的建议中，我们将 几个重要的问题仍未得到答复。 1。这些细胞在哪里，它们在哪里 起源？ 2。它们如何影响小鼠IBD的严重性和3。他们对控制的贡献是什么 IBD期间的肠道细菌菌群。这项投资很重要，因为它开始解决B细胞的作用 以及它们对β7整合蛋白对肠道的关键依赖性，并维持所需的IgA水平 控制IBD期间某些病原微生物。了解淋巴细胞整联蛋白在界面中的作用 在微生物群和其宿主之间可能会更好地理解当前抗整合蛋白 治疗剂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 那触发了IBD。