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

项目摘要 三级淋巴样结构（TLS）是一种异位的淋巴样结构， 类似于次级淋巴器官。虽然TLS的确切功能仍然难以捉摸，但累积的 有证据表明TLS对慢性疾病的发病机制有重要作用， 自身免疫性和炎性疾病、移植物抗宿主病、移植排斥和各种类型的 癌因此，更好地了解TLS的组成和免疫反应的特异性， 它们在特定疾病的背景下启动可能有助于解码疾病的发病机制，并提供新的 治疗策略 炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC）， 被认为是由于对肠道微生物的免疫反应失调所致， 遗传、环境和微生物因素。人类和动物模型的研究表明，IBD 发病机制与单核吞噬细胞（MP）系统失调和T、B细胞异常有关 应答我们最近确定了在沙门氏菌结肠炎小鼠中驱动TLS发展的机制。 在这项新的研究中，我们将利用我们的专业知识，建立合作和临床资源 麻省大学医学院（UMMS）提供，以了解推动TLS发展的机制， 在人类IBD中的作用我们的总体假设是，IBD中的TLS向优先的 产生局部促炎性IgG反应而不是伊加，并由特异性炎性MP诱导 亚群对定植在粘膜上的致病菌的反应。为了验证这个假设，我们将分析 通过应用多种OMIC方法的组合，从IBD患者中进行肠道手术切除。我们 积极合作的多学科团队，由MP生物学，计算生物医学， 细菌微生物组，病毒组，胃肠病学和临床GI病理学的独特定位，以解决 具体目标如下： 目标1.在人IBD的TLS中建立细胞组成并预测细胞间相互作用; 目标二。识别通过MP激活驱动TLS形成的致病菌。 作为本项目的成果，我们将建立一个细胞-细胞和细胞-微生物相互作用的模型， 鉴定人IBD中肠TLS发展所需的关键调节分子。短期来看，这些 结果将为我们未来的R 01提案提供基础，该提案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制联系起来，以确定新的治疗方法 针对IBD中TLS的途径。从长远来看，从这项研究中获得的信息和方法将是 适用于其他炎症和自身免疫性疾病以及TLS形成明显的癌症。

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.