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; 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 IgA是人体中合成的主要免疫球蛋白分子。生产大部分IgA 通过驻留在肠道椎板中并在上皮上运输并进入的浆细胞。 腔作为分泌的IgA，有助于建立和维持与共生细菌的体内平衡 稳定居住在人类胃肠道中。肠Peyer的斑块是重要的解剖站点 IgA响应的诱导。为了刺激IgA的产生，共生细菌和细菌 必须首先用抗原采样细胞吸收抗原。有两个抗原采样途径 候选人可以解释细菌和细菌抗原最初如何将其吸入Peyer的斑块：Microfold （M）细胞介导的摄取和单核吞噬细胞对腔细菌的直接采样（包括 树突状细胞和巨噬细胞）。 M细胞是在 小肠和结肠中覆盖有组织的淋巴结构的卵泡相关上皮（FAE） 包括佩耶的斑块和孤立的淋巴卵泡。该项目的目的是使用鼠标模型 与其他潜在的抗原采样途径相比，确定M细胞是否起主要作用的系统 分泌IgA生产的启动。细胞因子RANKL是必要的，足以启动M细胞 在肠道隐窝中与未承诺的上皮前体细胞分化。结果，用 肠上皮（级别IEC小鼠）中等级的条件缺失缺乏肠道M细胞 佩耶的补丁。初步研究表明，常规饲养的等级IEC小鼠具有重要的 产生的粪便IgA量和IgA+等离子体细胞的密度的缺陷 薄片propria。该项目将使用无细菌的小鼠和用定义的厌氧重新定殖的小鼠 肠细菌（改变的Schaedler Flora或ASF）确定分泌的IgA是否产生。 一组细菌还取决于M细胞的细菌摄取。指导提议的中心假设 实验是M细胞介导的抗原采样占共生细菌的大多数取样 电感性肠道淋巴组织的部位，从而有效诱导正常分泌 IgA对细菌抗原的反应。该提案的第一个目的是确定缺乏的影响 无菌小鼠分泌IgA产生的肠道M细胞。第二个目的是表征 分泌的IgA对引入一组定义的共生微生物群（ASF）的反应 排名IEC小鼠和控制同窝仔。关于M细胞介导的抗原采样的机理见解 肠道免疫系统促进肠道稳态可能有用 疫苗接种策略和治疗人类炎症性肠病的新方法。