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

基本信息

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
项目类别：
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

项目摘要

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.

七、项目概要当肠道免疫系统受到影响时，遗传易感个体就会出现炎症性肠病 (IBD) 系统失去了对浆细胞（PC）衍生的分泌物中未知成分的耐受性。免疫球蛋白 A (sIgA) 是我们能够与自身环境共存的主要机制之一。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已成为一种广泛应用的抗体。其中一种药物（维多珠单抗）可特异性阻断整合素 α4β7，这是一种治疗 IBD 的策略。对白细胞运输到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。与小鼠和人类的 T 细胞相比，并且严重依赖这种分子运输到肠道。缺乏 β7 整合素链的人存在肠道 B 细胞缺陷和粪便 IgA 缺陷，如果在两种慢性 IBD 小鼠模型中，它们的肠道菌群和 IBD 更严重，但这可能是由于整合素 α4β7 缺陷，在缺乏 αEβ7 整合素的小鼠中，管腔 IgA 缺陷持续存在，尽管在这些小鼠中 B 我们最近发现了一个以前未描述的肠道 PC 子集，它可以正常到达肠道。表达 αEβ7，主要定位于隐窝基部。我们认为某些肠道 PC 表达 αEβ7，这使得它们能够与肠上皮细胞对接并直接中继 IgA 以实现最有效的运输我们相信这种新的 IgA 运输方式对于维持肠道功能起着至关重要的作用。在当前的提案中，我们将研究肠腔中 IgA 的变化以及 IBD 期间微生物菌群的变化。其中几个解决了尚未解答的重要问题：1.这些细胞位于何处以及它们是什么。 2. 它们如何影响小鼠 IBD 的严重程度？ 3. 它们对控制 IBD 有何贡献？这项研究非常重要，因为它开始探讨 B 细胞的作用。以及它们对 β7 整合素的关键依赖，以回到肠道并维持所需的 IgA 水平，控制 IBD 期间的某些致病微生物。了解淋巴细胞整合素在界面处的作用。微生物群与其宿主之间的关系可能有助于更好地了解当前的抗整合素如何发挥作用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从而引发炎症性肠病 (IBD)。