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.

肠道炎症和脊柱炎(SpA)之间的联系早已被认识到。同样， 肠道微生物区系在炎症性肠病(IBD)中的作用得到了很好的认识，在 水疗中心正在兴起。然而，目前尚不清楚SpA患者的菌群内容是否异常。 (生物失调)，或者对其他正常菌群的免疫反应是否调节肠道 发炎。IBD和SpA的数据都表明调节失调的适应性免疫在 这两种疾病的发病机制，也有证据支持失调在IBD的发病机制。 因此，我们预测SpA患者将会有异常的适应性(B和T细胞)免疫反应。 有限的一套细菌抗原，并将另外显示异常的粪便菌群内容。这两个都是 假设将在这项提案中得到检验。在目标1中，我们将确定肠道免疫的体液免疫靶点。 使用新的抗原微阵列检测抗原，然后对选定的细菌进行有针对性的筛选。在目标2中，我们将 通过16S核糖体DNA测序和后基因组组评估异常花内容物 患有spa的儿童和成人肠道微生物区系的测序。在目标3中，我们将执行T细胞 电击前后T细胞受体(TCR)寡克隆的功能研究与分析 靶标抗原。所有这些目标都是相互关联的，因为将研究目标2中确定的细菌抗原。 在目标1和目标3中，目标1中确定的B细胞目标也将在目标3中进行研究。这些研究将有助于 确定SpA患者肠道细菌适应性淋巴细胞反应改变的作用(比较 以控制受试者)，以及探索肠道微生物区系改变在致病机制中的潜在作用 水疗中心。这些研究的结果将是确定一组有限的相关细菌抗原。 以及确定获得性免疫反应的作用 在水疗中心。因此，这项研究将为Spa的发病机制提供新的见解，并提示 潜在的新的生物标志物有助于疾病的诊断和监测，甚至是治疗的目标 我们学会了操纵微生物区系和/或对微生物区系的适应性免疫反应。