Immunometabolism of IgA-Microbiota Interaction in Gut Homeostasis and Inflammation

IgA-微生物群相互作用在肠道稳态和炎症中的免疫代谢

• 批准号: 10218003
• 负责人: ANDREA CERUTTI
• 金额: $ 46.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218003
• 关键词: 16S ribosomal RNA sequencing; Adaptor Signaling Protein; Affinity; Antibodies; Antigens; Architecture; Autoimmune Diseases; B Cell Proliferation; B-Cell Development; B-Lymphocytes; Bacteria; Binding; Biology; Blood; Blood specimen; Cell Communication; Cell Differentiation process; Cell Line; Cells; Collaborations; Data; Defect; Event; FRAP1 gene; Family; Feces; Genes; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Gnotobiotic; Homeostasis; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Knock-out; Lesion; Link; Mediating; Metabolic Diseases; Modality; Molecular; Mus; Nature; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Plasma Cells; Plasmablast; Production; Property; Protein Isoforms; Proteins; Receptor Signaling; Regulation; Resources; Role; Secretory Immunoglobulin A; Shapes; Signal Transduction; Sirolimus; Sorting - Cell Movement; Specimen; Syndrome; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Tissue Sample; Tissues; Toll-like receptors; activation-induced cytidine deaminase; bacterial community; base; commensal bacteria; commensal microbes; congenital immunodeficiency; dysbiosis; experimental study; fitness; gut bacteria; gut homeostasis; gut microbiota; host microbiota; human model; inflammatory disease of the intestine; insight; microbial; microbiota; mouse model; patient subsets; plasma cell differentiation; preservation; programs; receptor; recruit; response; sensor; stool sample

The commensal microbiota establishes a mutualistic relationship with the gut immune system by activating B cells via T cell-dependent (TD) and T cell-independent (TI) pathways that generate secretory immunoglobulin A (SIgA) with high and low affinity for antigen, respectively. High-affinity (HA)-SIgA emerges from a relatively well- understood TD pathway involving CD40L and is generally viewed as essential for gut homeostasis due to its specific recognition of bacterial cells. However, recent studies indicate that also (LA)-SIgA from a poorly understood TI pathway specifically recognizes commensal bacteria. Additional evidence shows that HA-SIgA coats colitogenic bacteria in patients with inflammatory bowel disease (IBD), raising the possibility that gut homeostasis requires balanced HA-SIgA and LA-SIgA responses. This proposal will combine an in-depth analysis of primary immunodeficiency (PID) specimens with studies of knockout, germfree and gnotobiotic mouse models to dissect the regulation, microbiota reactivity and function of LA-SIgA and HA-SIgA responses. Preliminary data show that TI production of LA-SIgA involves CD40-independent activation of gut B cells by TACI, a BAFF/APRIL receptor that triggers IgM-to-IgA class switching through the kinase mTOR. Additional preliminary evidence shows that TACI deficiency impairs microbiota diversity and gut homeostasis by decreasing the coating of bacterial cells by LA-SIgA. Here, we hypothesize that TACI and CD40 orchestrate LA-SIgA and HA-SIgA responses through mTOR-regulated TI and TD pathways targeting non-overlapping consortia of gut bacteria. Three specific aims are proposed. Aim 1 is to elucidate the regulation of LA-SIgA and HA-SIgA responses by TACI and CD40 and dissect their reactivity for the gut microbiota. Aim 2 is to characterize the composition and function of bacterial communities targeted by LA-SIgA and HA-SIgA antibodies; Aim 3 is to dissect the functional interplay of LA-SIgA and HA-SIgA responses induced by TACI and CD40 with B cell signals from mTOR. This kinase activates B cells by engaging TACI through MyD88. The proposed studies (Project 3) will take advantage of cells, stool and tissues made available by this consortium and of the complementary and integrative expertise of the Cunningham-Rundles group, which evaluates the role of TACI in B cell proliferation and differentiation (Project 1), the Meffre group (Project 2), which explores the role of TACI and other key antibody- regulating molecules in B cell tolerance, and the Casanova group (Project 4), which seeks to identify new causative genes in PIDs.

肠道微生物群与肠道免疫系统建立了互惠关系。 通过T细胞依赖性（TD）和T细胞非依赖性（TI）激活B细胞 产生具有高和低亲和力的分泌性免疫球蛋白A（SIgA）的途径 抗原，分别。高亲和力（HA）-SIgA出现在一个相对良好的- 已知涉及CD 40 L的TD途径，并且通常被认为是肠道免疫必需的。 由于其对细菌细胞的特异性识别，其具有体内平衡。但最近的研究 这表明来自一种知之甚少TI途径的（LA）-SIgA也特异性地 识别肠道细菌。其他证据表明，HA-SIgA涂层 炎症性肠病（IBD）患者中的大肠杆菌， 肠道内稳态需要平衡的HA-SIgA和LA-SIgA反应的可能性。 该提案将联合收割机结合原发性免疫缺陷（PID）的深入分析 用于研究基因敲除、无菌和无菌小鼠模型的标本， LA-SIgA和HA-SIgA反应的调节、微生物群反应性和功能。 初步数据表明，TI生产LA-SIgA涉及CD 40非依赖性 TACI激活肠道B细胞，TACI是一种BAFF/APRIL受体，可触发IgM至伊加类 通过激酶mTOR进行转换。初步证据显示， 缺乏通过减少涂层而损害微生物群多样性和肠道内稳态 细菌细胞的LA-SIgA。在这里，我们假设TACI和CD 40协调 通过mTOR调节的TI和TD途径的LA-SIgA和HA-SIgA应答 针对非重叠的肠道细菌群。提出了三个具体目标。 目的1是阐明TACI对LA-SIgA和HA-SIgA反应的调节， CD 40，并分析其对肠道微生物群的反应性。目标2是表征 LA-SIgA和HA-SIgA靶向细菌群落的组成和功能 目的3是剖析LA-SIgA和HA-SIgA的功能相互作用， TACI和CD 40诱导的应答与来自mTOR的B细胞信号。该激酶 通过MyD 88与TACI结合激活B细胞。拟议研究（项目3） 将利用该财团提供的细胞、粪便和组织， Cunningham-Rundles集团的互补和综合专业知识， 评估TACI在B细胞增殖和分化中的作用（项目1）， Meffre小组（项目2），探索TACI和其他关键抗体的作用- 调节B细胞耐受性的分子，以及Casanova组（项目4）， 试图在PID中发现新的致病基因。