Regulation of TLR signaling in anti-commensal B cell responses and mucosal inflammation

抗共生 B 细胞反应和粘膜炎症中 TLR 信号传导的调节

• 批准号: 10675251
• 负责人: Oliver James Harrison
• 金额: $ 26万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-19 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675251
• 关键词: Adaptive Immune System; Affect; Antibodies; Antibody Formation; Antibody Repertoire; Antibody Response; Antibody titer measurement; Antigens; Autoimmune Diseases; Autoimmunity; Autophagocytosis; B-Lymphocytes; Bacteria; CD19 gene; Cell Surface Receptors; Cells; Colitis; Complex; Data; Development; Disease; Epithelium; Equilibrium; Exploratory/Developmental Grant; Failure; Generations; Grant; Growth; Homeostasis; Host Defense; Immune; Immune System Diseases; Immune response; Immune signaling; Immunity; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune System; Integrin alphaVbeta3; Integrins; Intestines; Invaded; Knock-out; Knockout Mice; Lead; Ligands; Link; Location; Measures; Mediating; Methods; Mission; Mucositis; Mucous Membrane; Mus; Parasites; Pathology; Pathway interactions; Patients; Peyer' s Patches; Predisposition; Production; Reagent; Receptor Signaling; Regulation; Research; Role; Signal Transduction; Structure of germinal center of lymph node; Surface; Testing; Toll-like receptors; United States National Institutes of Health; Virus; Work; adaptive immune response; autoreactivity; commensal bacteria; commensal microbes; dextran sulfate sodium induced colitis; experimental study; gut inflammation; immune system function; insight; intestinal homeostasis; microbial; microbial colonization; microorganism; novel; pathogen; prevent; response; systemic inflammatory response

Project Summary Mucosal surfaces house numerous commensal and symbiotic bacteria, viruses and other microorganisms, which establish mutually beneficial interactions with their host. This microbial colonization relies on complex interactions with the innate and adaptive immune systems, including the generation of antibodies against commensal bacteria antigens. There is a pressing need to understand how adaptive immune responses to commensals are regulated, and how failure of these mechanisms lead to inflammation and immune pathology. Recent studies have identified a requirement for toll-like receptor (TLR) signaling in B cells in generating anti- commensal antibodies. We have previously shown that the cell surface receptor integrin αvβ3 and components of the autophagy pathway regulate TLR signaling in B cells to prevent overexpansion of autoreactive cells and autoimmunity. In preliminary studies, we have shown that B cell-specific αv-knockout mice (αv-CD19 mice) have increase numbers of spontaneous germinal centers in the intestine and are more susceptible to inflammatory colitis. Based on these data, we hypothesize that αvβ3 regulates B cell responses to commensal bacteria to maintain defense against infection but prevent overactive inflammatory responses. In this application we propose to test this hypothesis by: (1) measuring anti-commensal antibodies and repertoires in αv-CD19 and control mice, and following B cell responses after bacterial colonization; (2) determining the mechanism of increased susceptibility to DSS colitis in αv-CD19 mice. This research is highly significant as it will provide important insights into mechanisms of regulation of anti-commensal antibody responses, and if successful, will establish a new paradigm linking dysregulated TLR signaling in B cells to susceptibility to colitis.

项目摘要 粘膜表面容纳许多共生和共生细菌，病毒和其他微生物，它们 与宿主建立互惠互利的互动。这种微生物定殖依赖于复合物 与先天和适应性免疫系统的相互作用，包括产生抗体 共生细菌抗原。迫切需要了解自适应免疫调查如何 调查受到调节，以及这些机制的失败如何导致创新和免疫病理学。 最近的研究确定了B细胞中Toll样受体（TLR）信号传导的要求 共生抗体。我们先前已经表明，细胞表面受体整联蛋白αVβ3和成分 自噬途径调节B细胞中TLR信号的调节，以防止自动反应性细胞和 自身免疫性。在初步研究中，我们表明B细胞特异性αV-敲除小鼠（αV-CD19小鼠）具有 增加肠中发育中心的发育中心数量，更容易受到炎症的影响 结肠炎。基于这些数据，我们假设αVβ3调节B细胞对共生细菌对 保持防御感染的防御，但防止过度活跃的炎症反应。在此申请中，我们提出 通过：（1）测量αV-CD19和对照中的抗概物抗体和曲目 小鼠，在细菌定植后B细胞反应后； （2）确定增加的机制 αV-CD19小鼠中DSS结肠炎的敏感性。这项研究非常重要，因为它将提供重要的见解 进入调节抗跨抗体反应的机制，如果成功的话，将建立一个新的 将B细胞中TLR信号失调的范式连接到对结肠炎的易感性。