Intestinal M Cells and Secretory IgA Response to Defined Gut Microbiota

肠道 M 细胞和分泌型 IgA 对特定肠道微生物群的反应

• 批准号: 8684523
• 负责人: Andrew T Gewirtz
• 金额: $ 24.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684523
• 关键词: Accounting; Anatomic Sites; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Bacteria; Bacterial Antigens; Bacterial Translocation; Biological Models; Bypass; Cell Differentiation process; Cells; Colon; Data; Dendritic Cells; Development; Drug Formulations; Enteral; Enterobacteriaceae; Epithelial; Epithelial Cells; Epithelium; Event; Flow Cytometry; Gastrointestinal tract structure; Generations; Genes; Germ-Free; Gnotobiotic; Goals; Gut associated lymphoid tissue; Homeostasis; House mice; Housing; Human; Human body; Immune response; Immune system; Immunoglobulin A; Immunoglobulins; Individual; Inflammatory Bowel Diseases; Intestines; Kinetics; Knockout Mice; Knowledge; Laboratories; Lamina Propria; Lymphoid; Lymphoid Follicle; Lymphoid Tissue; M cell; Maintenance; Measures; Mediating; Minor; Mononuclear; Mucosal Immune Responses; Mus; Oral; Paper; Parents; Particulate; Pathway interactions; Phagocytes; Plasma Cells; Play; Process; Production; Publishing; Research; Role; Sampling; Secretory Immunoglobulin A; Site; Small Intestines; Structure; Structure of aggregated lymphoid follicle of small intestine; TNFSF11 gene; Testing; Universities; Weaning; acrosome stabilizing factor; base; commensal microbes; cytokine; density; gut microbiota; improved; insight; intestinal crypt; intestinal epithelium; intestinal homeostasis; intraepithelial; macrophage; mouse model; novel strategies; oral vaccine; precursor cell; prevent; public health relevance; research study; response; tool; trafficking; transcytosis; uptake; vaccination strategy

Project Summary/Abstract IgA is the predominant immunoglobulin molecule synthesized in the human body. Most of this IgA is produced by plasma cells residing in the intestinal lamina propria and is transported across the epithelium and into the lumen as secretory IgA that helps to establish and maintain homeostasis with the commensal bacteria that stably reside in the human gastrointestinal tract. Intestinal Peyer's patches are important anatomic sites for the induction of IgA responses. In order to stimulate the production of IgA, commensal bacteria and bacterial antigens must first be taken up by antigen-sampling cells. There are two antigen-sampling pathways that are candidates to explain how bacteria and bacterial antigens are initially taken up into Peyer's patches: microfold (M) cell-mediated uptake and direct sampling of luminal bacteria by mononuclear phagocytes (including both dendritic cells and macrophages). M cells are specialized antigen-sampling epithelial cells that are found in the follicle-associated epithelium (FAE) covering organized lymphoid structures in the small intestine and colon including Peyer's patches and isolated lymphoid follicles. The goal of this project is to use a mouse model system to determine if M cells play a dominant role compared to other potential antigen-sampling pathways in the initiation of secretory IgA production. The cytokine RANKL is necessary and sufficient to initiate M cell differentiation from uncommitted epithelial precursor cells in intestinal crypts. As a result, mice with a conditional deletion of RANK in the intestinal epithelium (RANKIEC mice) lack intestinal M cells in their Peyer's patches. Preliminary studies show that conventionally housed RANKIEC mice have significant deficiencies in the amount of fecal IgA produced and the density of IgA+ plasma cells present in the intestinal lamina propria. This project will use germ-free mice and mice recolonized with a defined set of anaerobic enteric bacteria (Altered Schaedler Flora or ASF) to determine whether secretory IgA production to this defined set of bacteria is also dependent on bacterial uptake by M cells. The central hypothesis guiding the proposed experiments is that M cell-mediated antigen sampling accounts for most sampling of commensal bacteria at the site of inductive intestinal lymphoid tissues, thereby initiating the efficient induction of the normal secretory IgA response to bacterial antigens. The first aim of the proposal is to determine the impact of absence of intestinal M cells on secretory IgA production by germ-free mice. The second aim is to characterize the secretory IgA response to introduction of a defined set of commensal microbiota (ASF) into M cell-deficient RANKIEC mice and control littermates. Mechanistic insights into how M cell-mediated antigen sampling by the gut immune system promotes intestinal homeostasis may be useful in developing improved oral vaccination strategies and new approaches to the treatment of human inflammatory bowel disease.

项目摘要/摘要 免疫球蛋白是人体内合成的主要免疫球蛋白分子。这种免疫球蛋白的大部分是由 由驻留在肠道固有层的浆细胞，并通过上皮运输到 管腔作为分泌型IgA，帮助建立和维持与共生细菌的动态平衡 稳定地驻留在人类胃肠道中。肠Peyer‘s补片是重要的解剖部位 诱导免疫球蛋白A应答。为了刺激IgA的产生，共生菌和细菌 抗原必须首先被抗原采样细胞摄取。有两条抗原采样路径，分别是 解释细菌和细菌抗原最初是如何进入Peyer氏斑的候选者：微折叠 (M)单核吞噬细胞(包括两者)对腔细菌的细胞介导摄取和直接取样 树突状细胞和巨噬细胞)。M细胞是一种特殊的抗原采样上皮细胞，在 覆盖在小肠和结肠中的有组织的淋巴样结构的滤泡相关上皮(FAE) 包括佩耶氏斑和孤立的淋巴滤泡。这个项目的目标是使用鼠标模型 与其他潜在的抗原采样途径相比，确定M细胞是否发挥主导作用的系统 分泌型免疫球蛋白A产生的启动。细胞因子RANKL是启动M细胞的必要条件和充分条件 肠隐窝中未定植的上皮前体细胞的分化。其结果是，携带一种 肠上皮(RANKIEC小鼠)中缺少肠M细胞的RANK条件缺失 佩尔的斑块。初步研究表明，常规饲养的RANKIEC小鼠具有显著的 肠道中存在的粪便IgA生成量和IgA+浆细胞密度不足 固有层。该项目将使用无菌小鼠和用一套明确的厌氧菌重新克隆的小鼠。 肠道细菌(改变的Schaedler菌群或ASF)来确定分泌性IgA的产生是否达到这一定义 一组细菌也依赖于M细胞对细菌的摄取。指导建议的中心假设 实验表明，M细胞介导的抗原采样占共生菌采样的大部分 诱导肠道淋巴组织的位置，从而启动正常分泌的有效诱导 对细菌抗原的免疫球蛋白反应。该提案的第一个目标是确定缺少 肠道M细胞对无菌小鼠分泌免疫球蛋白A的影响。第二个目标是描述 将一组已定义的共生微生物区系(ASF)引入M细胞缺陷的分泌型IgA反应 RANKIEC小鼠和对照窝产仔。对M细胞介导的抗原采样如何通过 肠道免疫系统促进肠道内环境平衡可能有助于改善口腔 治疗人类炎症性肠病的疫苗接种策略和新方法。