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: 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
• 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

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）：IgA 是人体内合成的主要免疫球蛋白分子。大部分 IgA 由肠道固有层中的浆细胞产生，并作为分泌型 IgA 穿过上皮细胞并进入管腔，有助于与稳定存在于人类胃肠道中的共生细菌建立和维持体内平衡。肠派尔氏集结是诱导 IgA 反应的重要解剖部位。为了刺激 IgA 的产生，共生细菌和细菌抗原必须首先被抗原采样细胞吸收。有两种抗原采样途径可以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) 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）对管腔细菌的直接采样。 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) 中，覆盖小肠和结肠中有组织的淋巴结构，包括派尔氏淋巴集结和分离的淋巴滤泡。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，在分泌型 IgA 产生的起始过程中是否发挥主导作用。细胞因子 RANKL 对于启动 M 细胞从肠隐窝中未定型的上皮前体细胞分化是必要且充分的。因此，肠上皮条件性删除 RANK 的小鼠（RANK IEC 小鼠）的派尔氏淋巴集结中缺乏肠 M 细胞。初步研究表明，传统饲养的 RANK IEC 小鼠在粪便 IgA 产生量和肠固有层中 IgA+ 浆细胞密度方面存在显着缺陷。该项目将使用无菌小鼠和重新定植一组特定厌氧肠道细菌（Altered Schaedler Flora 或 ASF）的小鼠来确定这组特定细菌的分泌型 IgA 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道淋巴组织部位共生细菌的大部分取样，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 细胞缺失对无菌小鼠分泌型 IgA 产生的影响。第二个目的是表征将一组确定的共生微生物群 (ASF) 引入 M 细胞缺陷的 RANK IEC 小鼠和对照同窝小鼠中时的分泌型 IgA 反应。关于肠道免疫系统 M 细胞介导的抗原采样如何促进肠道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。

项目成果

TNF-α augments RANKL-dependent intestinal M cell differentiation in enteroid cultures.

TNF-α 增强肠样培养物中 RANKL 依赖性肠 M 细胞分化。

• 发表时间: 2016
• 作者: Wood, Megan B;Rios, Daniel;Williams, Ifor R
• 通讯作者: Williams, Ifor R

An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells.

内源性纳米矿物伴侣将管腔抗原和肽聚糖与肠道免疫细胞结合。

• 发表时间: 2015-04
• 影响因子: 38.3
• 作者: Powell, Jonathan J;Thomas;Thoree, Vinay;Robertson, Jack;Hewitt, Rachel E;Skepper, Jeremy N;Brown, Andy;Hernandez;Midgley, Paul A;Gomez;Grime, Geoffrey W;Kirkby, Karen J;Mabbott, Neil A;Dona
• 通讯作者: Dona