Microbiota, Tertiary Lymphoid Structures and Chronic Inflammation in the Human Gut

微生物群、三级淋巴结构和人类肠道慢性炎症

• 批准号: 10154604
• 负责人: Milena Bogunovic
• 金额: $ 25.39万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10154604
• 关键词: Address; Adult; Affect; Animal Model; Antibody Response; Antigen-Presenting Cells; Antigens; Area; Atherosclerosis; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding; Biology; Cell Fraction; Cell Separation; Cell model; Cell surface; Cells; Chronic; Chronic Disease; Chronic Gastritis; Clinical; Coin; Colitis; Collaborations; Colorectal Cancer; Crohn' s disease; Data Set; Defect; Dendritic Cells; Development; Disease; Drug or chemical Tissue Distribution; Excision; Flow Cytometry; Functional disorder; Future; Gastroenterology; Gastrointestinal tract structure; Gene Expression; Generations; Genetic; Graft Rejection; Heterogeneity; Human; Immune; Immune response; Immunoglobulin A; Immunoglobulin G; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Life; Link; Lymphoid; Malignant Neoplasms; Metagenomics; Methodology; Microbe; Microscopy; Molecular; Mononuclear; Mucous Membrane; Mus; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway Analysis; Patients; Phagocytes; Phenotype; Plasma Cells; Population; Positioning Attribute; Prognostic Factor; Publications; Publishing; Reaction; Reporting; Resources; Salmonella; Salmonella infections; Science; Shotguns; Site; Specificity; System; T-Lymphocyte; Testing; Tissues; Ulcerative Colitis; Viral; bacteriome; cancer type; checkpoint therapy; commensal microbes; gastrointestinal; graft vs host disease; gut microbiota; host-microbe interactions; human model; lymph nodes; macrophage; medical schools; microbial; microbiota; mucosal site; multidisciplinary; multiple omics; novel therapeutic intervention; novel therapeutics; pathobiont; response; salmonella colitis; secondary lymphoid organ; tertiary lymphoid organ; transcriptome sequencing; virome

PROJECT SUMMARY Tertiary lymphoid structures (TLS) are ectopic disorganized lymphoid aggregates with the cellular composition resembling secondary lymphoid organs. Although the exact function of TLS remains elusive, the accumulated evidence suggests that TLS significantly contribute to the pathogenesis of chronic disorders including autoimmune and inflammatory diseases, graft versus host disease, transplant rejection, and various types of cancer. Therefore, better understanding of the composition of TLS and specificity of the immune response that they initiate in the context of a specific disease may help decode the disease pathogenesis and provide novel therapeutic strategies. Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is thought to result from the dysregulated immune response to commensal microbes driven by a convergence of genetic, environmental and microbial factors. Studies in humans and animal models indicate that IBD pathogenesis is associated with dysregulated mononuclear phagocyte (MP) system and abnormal T and B cell responses. We recently identified the mechanisms that drive TLS development in mice with Salmonella colitis. In this new study we will take advantage of our expertise, established collaboration and clinical resources available at UMass Medical School (UMMS) to understand the mechanisms that drive TLS development and function in human IBD. Our overarching hypothesis is that TLS in IBD are dysregulated towards a preferential generation of local proinflammatory IgG response instead of IgA and are induced by specific inflammatory MP subsets in response to pathobionts that colonize the mucosa. To test the hypothesis, we are going to analyze intestinal surgical resections from patients with IBD by applying a combination of multi-OMICs approaches. Our actively collaborating multi-disciplinary team that consists of experts in MP biology, computational biomedicine, bacterial microbiome, virome, gastroenterology and clinical GI pathology is uniquely positioned to address the following specific aims: Aim 1. Establish cellular composition and predict intercellular interactions in TLS in human IBD; Aim 2. Identify pathobionts that drive TLS formation via MP activation in human IBD. As the outcome of this project, we will establish a model of cell-cell and cell-microbe interactions and identify key regulatory molecules required for development of intestinal TLS in human IBD. Short term, these results will provide a basis for our future R01 proposal that will test computational predictions of host-microbial interactions and link them to disease pathogenesis with the underlying rationale to identify novel therapeutic avenues aimed at TLS in IBD. In the long term, information and methodology gained from this study will be applied to other inflammatory and autoimmune conditions as well as cancers in which TLS formation is evident.

项目摘要 第三级淋巴结构（TLS）是与细胞组成的异位混乱的淋巴聚集体 类似于继发性淋巴器官。尽管TLS的确切功能仍然难以捉摸，但积累 有证据表明，TLS显着有助于慢性疾病的发病机理 自身免疫性和炎症性疾病，移植物与宿主疾病，移植排斥和各种类型 癌症。因此，更好地理解TL的组成和免疫反应的特异性 它们在特定疾病的背景下发起可能有助于解码疾病发病机理并提供新颖 治疗策略。 包括克罗恩病（CD）和溃疡性结肠炎（UC）的炎症性肠病（IBD）为 被认为是由于对共生微生物的失调免疫响应而导致的。 遗传，环境和微生物因素。人类和动物模型的研究表明IBD 发病机理与失调的单核吞噬细胞（MP）系统和异常T和B细胞有关 回答。我们最近确定了驱动沙门氏菌炎小鼠TLS发育的机制。 在这项新研究中，我们将利用我们的专业知识，建立的合作和临床资源 可在UMass医学院（UMMS）获得，以了解推动TLS开发和 人类IBD的功能。我们的总体假设是，IBD中的TLS因优先考虑而失调 局部促炎IgG反应而不是IgA产生，并由特定的炎症MP诱导 子集响应于粘膜定居的病原体。为了检验假设，我们将分析 通过采用多词方法的组合，来自IBD患者的肠道手术切除术。我们的 积极合作由MP生物学专家，计算生物医学专家组成的多学科团队， 细菌微生物组，病毒蛋白，胃肠病学和临床胃肠道病理学是独特的定位 遵循特定目的： 目标1。建立细胞组成并预测人IBD中TLS中的细胞间相互作用； 目标2。确定通过人IBD中MP激活驱动TLS形成的病原体。 作为该项目的结果，我们将建立一个细胞 - 细胞和细胞 - 微生物相互作用的模型以及 确定人IBD中肠道TLS开发所需的关键调节分子。短期，这些 结果将为我们未来的R01提案提供基础，该建议将测试宿主微生物的计算预测 相互作用并将其与疾病发病机理与基本原理联系起来，以鉴定新的疗法 针对IBD的TLS大道。从长远来看，这项研究中获得的信息和方法将是 应用于其他炎症和自身免疫性条件以及TLS形成的取消。