Adaptive Immune Response to Gut Microbiota in Juvenile & Adult Spondyloarthritis

幼年肠道菌群的适应性免疫反应

• 批准号: 8475814
• 负责人: CHARLES O ELSON
• 金额: $ 29.54万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475814
• 关键词: Adolescent; Adult; Antigen Targeting; Antigens; B-Lymphocytes; Bacteria; Bacterial Antigens; Biological Markers; Child; Clinical Research; DNA Sequence; Data; Diagnosis; Disease; Enteral; Exposure to; Immune response; Immunologics; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Lead; Learning; Link; Lymphocyte; Mediating; Monitor; Outcome Study; Pathogenesis; Patients; Research; Ribosomal DNA; Role; Spondylarthritis; T-Cell Receptor; T-Lymphocyte; Technology; Testing; adaptive immunity; gut microbiota; insight; metagenome; metagenomic sequencing; microbial; microbiome; multidisciplinary; novel; novel strategies; response; screening

The link between intestinal inflammation and spondyloarthritis (SpA) has long been recognized. Likewise, the role for intestinal microbiota in inflammatory bowel disease (IBD) is well appreciated, and a similar role in SpA is emerging. It is unknown, however, whether the contents of the flora are abnormal in SpA patients (dysbiosis), or whether the immunologic response to an otherwise normal flora mediates intestinal inflammation. Data in both IBD and SpA suggest a role for dysregulated adaptive immunity in the pathogenesis of both diseases, and there is also evidence supporting dysbiosis in the pathogenesis of IBD. Therefore, we predict that SpA patients will have an abnormal adaptive (B and T cell) immune response to a limited set of bacterial antigens and will additionally demonstrate abnormal fecal flora contents. Both of these hypotheses will be tested in this proposal. In Aim 1, we will identify humoral immunologic targets to enteric antigens using a novel antigen microarray followed by targeted screening of select bacteria. In Aim 2, we will evaluate for abnormal floral content through 16S ribosomal DNA sequencing followed by metagenome sequencing of the enteric microflora of children and adults with SpA. In Aim 3, we will perform T cell functional studies and analysis of T cell receptor (TCR) oligoclonality before and after exposure to potential target antigens. All of these aims are inter-connected, as bacterial antigens identified in Aim 2 will be studied in Aims 1 and 3, and B cell targets identified in Aim 1 will also be studied in Aim 3. These studies will help to establish a role for an altered adaptive lymphocyte response to intestinal bacteria in SpA patients (compared to control subjects), as well as explore a potential role for an altered gut microbiota in the pathogenesis of SpA. The outcome of these studies will be the identification of a limited set of bacterial antigens associated with and potentially causative of the disease, as well as identifying a role for the adaptive immune response in SpA. Thus, this research will provide novel insights into the pathogenesis of SpA as well as suggest potential new biomarkers useful for diagnosis and monitoring of the disease, and even targets of therapy as we learn to manipulate the microbiota and/or the adaptive immune response to the microbiota.

长期以来，已经认识到肠道炎症与脊椎关节炎（SPA）之间的联系。同样， 肠道菌群在炎症性肠病（IBD）中的作用受到很好的赞赏，并且在 水疗中心正在出现。但是，尚不清楚菌群的含量是否异常 （营养不良），或者对原本正常植物的免疫学反应是否介导肠道 炎。 IBD和水疗中的数据都表明在适应性免疫失调中的作用 两种疾病的发病机理，也有证据支持IBD发病机理中营养不良的证据。 因此，我们预测水疗患者对A的适应性异常（B和T细胞）的免疫反应异常 有限的细菌抗原，将表现出异常的粪便菌群含量。这两个 假设将在此提案中进行检验。在AIM 1中，我们将确定肠道免疫学目标 使用新型的抗原微阵列进行抗原，然后对精选细菌进行靶向筛查。在AIM 2中，我们将 通过16S核糖体DNA测序评估异常的花卉含量，然后进行元基因组 Spa儿童和成人的肠菌群测序。在AIM 3中，我们将执行T细胞 暴露于潜力之前和之后，T细胞受体（TCR）寡聚的功能研究和分析 靶抗原。所有这些目标都是相互连接的，因为将研究AIM 2中鉴定的细菌抗原 在AIM 1和AIM 1中确定的B细胞目标中也将在AIM 3中进行研究。这些研究将有助于 确立改变自适应淋巴细胞对水疗患者肠道细菌反应的作用（比较 控制受试者），并探索改变肠道菌群改变的潜在作用 温泉。这些研究的结果将是鉴定有限的细菌抗原相关的细菌抗原 与该疾病有关并有可能导致疾病，并确定适应性免疫反应的作用 在水疗中心。因此，这项研究将提供有关水疗发病机理的新见解，并暗示 潜在的新生物标志物可用于诊断和监测疾病，甚至是治疗的靶标 我们学会操纵微生物群和/或对微生物群的自适应免疫反应。