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.

项目概要/摘要 IgA 是人体内合成的主要免疫球蛋白分子。大部分 IgA 是产生的 由肠固有层中的浆细胞产生，并穿过上皮细胞进入 管腔作为分泌型 IgA，有助于与共生细菌建立和维持体内平衡 稳定地存在于人体胃肠道中。肠派尔氏集结是重要的解剖部位 诱导 IgA 反应。为了刺激 IgA、共生菌和细菌的产生 抗原必须首先被抗原采样细胞吸收。有两种抗原采样途径： 候选人解释细菌和细菌抗原最初如何被吸收到派尔氏淋巴结中：微折叠 (M) 单核吞噬细胞（包括两者）对腔内细菌的细胞介导摄取和直接采样 树突状细胞和巨噬细胞）。 M 细胞是专门的抗原采样上皮细胞，存在于 滤泡相关上皮 (FAE) 覆盖小肠和结肠中有组织的淋巴结构 包括派尔氏集结和孤立的淋巴滤泡。该项目的目标是使用小鼠模型 系统来确定 M 细胞与其他潜在抗原采样途径相比是否发挥主导作用 分泌型 IgA 产生的开始。细胞因子 RANKL 对于启动 M 细胞是必要且充分的 与肠隐窝中未定型的上皮前体细胞分化。结果，具有 肠上皮中 RANK 的条件性缺失（RANK IEC 小鼠）的肠道 M 细胞 派尔氏斑块。初步研究表明，传统饲养的 RANK IEC 小鼠具有显着的 粪便产生的 IgA 量和肠道中 IgA+ 浆细胞的密度不足 固有层。该项目将使用无菌小鼠和用一组定义的厌氧菌重新定殖的小鼠 肠道细菌（Altered Schaedler Flora 或 ASF）可确定分泌型 IgA 产量是否达到此定义 细菌组也依赖于 M 细胞的细菌摄取。指导所提出的中心假设 实验表明，M 细胞介导的抗原采样占共生细菌采样的大部分。 诱导肠道淋巴组织的部位，从而启动正常分泌的有效诱导 IgA 对细菌抗原的反应。该提案的首要目标是确定缺乏 肠道 M 细胞对无菌小鼠分泌型 IgA 产生的影响。第二个目标是表征 将一组确定的共生微生物群 (ASF) 引入 M 细胞缺陷后的分泌型 IgA 反应 RANK IEC 小鼠和对照同窝小鼠。 M 细胞介导的抗原采样的机制见解 肠道免疫系统促进肠道稳态可能有助于改善口腔 疫苗接种策略和治疗人类炎症性肠病的新方法。