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

项目总结 三级淋巴结构(TLS)是具有细胞成分的异位杂乱无序的淋巴集合体 类似于次级淋巴器官。尽管TLS的确切功能仍然难以捉摸，但积累的 有证据表明，TLS在慢性疾病的发病机制中起着重要作用，包括 自身免疫性和炎症性疾病，移植物抗宿主疾病，移植排斥反应，以及各种类型的 癌症。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，可能有助于破译疾病的发病机制，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)，是 被认为是由于对共生微生物的免疫反应失调所致，这种反应是由 遗传、环境和微生物因素。对人类和动物模型的研究表明，IBD 发病机制与单核巨噬细胞(MP)系统紊乱和T、B细胞异常有关 回应。我们最近确定了推动沙门氏菌结肠炎小鼠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、已建立的协作和临床资源 可在UMMS医学院(UMMS)了解推动TLS发展和 在人类IBD中的作用。我们的主要假设是IBD患者的TLS调节失调，倾向于优先 特异性炎性MP诱导的局部促炎症免疫球蛋白应答替代免疫球蛋白 对定植在粘膜上的病原体作出反应的亚群。为了检验这一假设，我们将分析 应用多种组学方法相结合的IBD患者的肠道手术切除。我们的 积极协作由MP生物学、计算生物医学、 细菌微生物群、病毒群、胃肠病学和临床胃肠道病理学具有独特的地位，能够解决 以下是具体目标： 目的1.确定IBD患者TLS的细胞组成并预测细胞间的相互作用； 目的2.鉴定通过MP激活在人IBD形成TLS的病原体。 作为这个项目的成果，我们将建立一个细胞-细胞和细胞-微生物相互作用的模型，并 确定人IBD肠道TLS发生所需的关键调控分子。短期而言，这些 结果将为我们未来的R01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，并将它们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状况，以及明显形成TLS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.