Adaptive Immune Response to Gut Microbiota in Juvenile & Adult Spondyloarthritis

肠道炎症和脊柱关节炎（SpA）之间的联系早已被认识到。同样， 肠道微生物群在炎症性肠病（IBD）中的作用是很好的认识， SpA正在崛起。然而，SpA患者的植物群含量是否异常尚不清楚 （生态失调），或是否免疫反应，否则正常的植物群介导肠道 炎症IBD和SpA的数据都表明，适应性免疫失调在IBD和SpA中的作用。 这两种疾病的发病机制，也有证据支持IBD的发病机制中的生态失调。 因此，我们预测SpA患者将有一个异常的适应性（B和T细胞）免疫反应， 有限的细菌抗原组，并将另外显示异常的粪便植物群含量。这两 本提案将检验各种假设。在目标1中，我们将鉴定针对肠道的体液免疫靶点， 使用新的抗原微阵列，然后对选择的细菌进行靶向筛选。在目标2中，我们将 通过16 S核糖体DNA测序和宏基因组评估异常花含量 儿童和成人SpA肠道菌群的测序。在目标3中，我们将进行T细胞 在暴露于潜在的抗肿瘤药物之前和之后的T细胞受体（TCR）寡克隆性的功能研究和分析 靶抗原。所有这些目标都是相互关联的，因为将研究目标2中鉴定的细菌抗原 目标1和目标3中确定的靶点，目标1中确定的B细胞靶点也将在目标3中研究。这些研究将有助于 确定了SpA患者对肠道细菌的适应性淋巴细胞应答改变的作用（与 对照受试者），以及探索改变的肠道微生物群在 SpA.这些研究的结果将是确定一组有限的细菌抗原相关的 以及确定适应性免疫反应的作用， 在SpA。因此，这项研究将为SpA的发病机制提供新的见解，并建议 潜在的新的生物标志物，用于诊断和监测疾病，甚至治疗的目标， 我们学会操纵微生物群和/或对微生物群的适应性免疫反应。

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.