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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

基本信息

批准号：
8793099
负责人：
Andrew T Gewirtz
金额：
$ 19.09万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/8793099
关键词：
Accounting Anatomy Antibodies Antibody Response 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 Health 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 research study response tool trafficking transcytosis uptake vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): 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 (RANK IEC mice) lack intestinal M cells in their Peyer's patches. Preliminary studies show that conventionally housed RANK IEC 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 RANK IEC 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.

描述（由申请人提供）：伊加是人体内合成的主要免疫球蛋白分子。这种伊加的大部分由驻留在肠固有层中的浆细胞产生，并且作为分泌型IgA穿过上皮并进入管腔，分泌型IgA有助于建立和维持与稳定驻留在人胃肠道中的肠道细菌的稳态。小肠派尔集合淋巴结是诱导伊加反应的重要解剖部位。为了刺激伊加的产生，肠道细菌和细菌抗原必须首先被抗原取样细胞摄取。有两种抗原取样途径是解释细菌和细菌抗原最初如何被吸收到派尔集合淋巴结中的候选者：微折叠（M）细胞介导的吸收和单核吞噬细胞（包括树突细胞和巨噬细胞）对管腔细菌的直接取样。M细胞是在覆盖小肠和结肠中的有组织淋巴结构（包括派尔集合淋巴结和分离的淋巴滤泡）的滤泡相关上皮（FAE）中发现的专门的抗原取样上皮细胞。该项目的目标是使用小鼠模型系统，以确定M细胞是否发挥主导作用相比，其他潜在的抗原采样途径在启动分泌型伊加的生产。细胞因子RANKL是启动肠隐窝中未定型上皮前体细胞向M细胞分化的必要和充分条件。因此，肠上皮RANK条件性缺失的小鼠（RANK IEC小鼠）在派伊尔集合淋巴结中缺乏肠M细胞。初步研究表明，常规饲养的RANK IEC小鼠在粪便伊加产生量和肠道固有层中伊加+浆细胞密度方面存在显著缺陷。本项目将使用无菌小鼠和用一组确定的厌氧肠道细菌（Altered Schaedler植物群或ASF）消化的小鼠，以确定这组确定的细菌的分泌型伊加产生是否也依赖于M细胞的细菌摄取。指导所提出的实验的中心假设是，M细胞介导的抗原取样占诱导肠淋巴组织部位的大多数肠道细菌取样，从而启动正常分泌型IgA的有效诱导。对细菌抗原的反应。该提案的第一个目的是确定肠道M细胞的缺乏对无菌小鼠分泌型伊加产生的影响。第二个目的是表征向M细胞缺陷型RANK IEC小鼠和对照同窝仔中引入一组确定的肠道微生物群（ASF）后的分泌型伊加反应。对肠道免疫系统如何通过M细胞介导的抗原采样促进肠道内稳态的机制见解可能有助于开发改进的口服疫苗接种策略和治疗人类炎症性肠病的新方法。