HLA-B27基因与肠道微生物群交互作用对强直性脊柱炎免疫炎症的影响及雷公藤红素干预作用的研究

HLA-B27 is the strongest susceptibility gene for ankylosing spondylitis (AS).We previously analyzed more than 12000 kinds of compounds by a high throughput drug screening platform and identified Celastrol as the strongest inhibitor for B27 promoter activity. Gut microbiota have been suggested playing an important role on autoimmunity. Previous study indicated intestinal flora composition will be changed in individual carrying B27 gene;however, the exact pathological role is unclear. We propose the "B27 shaped microbiota" concept and hypothesis that "B27 shaped microbiota", formed by the interaction between genes and the environmental factor, affect the immune and inflammatory process in AS and Celastrol could regulate "B27 shaped microbiota" on AS. We keep HLA-B27 transgenic rat in our lab. Using this animal model, we will analyze the effect of "B27 shaped microbiota" on T cell response, dendritic cells development, antigen presented role of HLA-B27 and the intestinal mucosal barrier function.In addition, we will clarify the new mechanism of Celastrol on AS by targeted "B27 shaped microbiota".This study will pave a new way for understanding the pathogenesis of AS.

HLA-B27是与强直性脊柱炎(ankylosing spondylitis, AS)关联最强的易感基因，近来发现携带B27基因会影响肠道某些菌群构成，确切的病理作用尚不清楚。我们前期通过高通量药物筛选平台分析了12000多种化合物，发现对B27启动子活性抑制最强的是雷公藤红素。肠道微生物群是目前免疫学中关注的热点，我们提出“B27型微生物群”概念，假说：基因和环境交互作用形成“B27型微生物群”，影响AS免疫炎症过程；雷公藤红素通过调控“B27型微生物群”发挥治疗作用。本课题组保存有HLA-B27转基因鼠，我们将以此为工具，从多层次分析“B27型微生物群”对AS模型鼠T细胞免疫反应、树突状细胞功能和HLA-B27抗原递呈作用及肠粘膜屏障功能的影响；同时从“B27型微生物群”这一新靶点阐明雷公藤红素作用机制。本研究将可能从新的视角揭示AS发病机制，为AS防治提供新思路、新方法。

HLA-B27是与强直性脊柱炎(ankylosing spondylitis, AS)关联最强的易感基因，近来发现携带B27基因会影响肠道某些菌群构成，确切的病理作用尚不清楚。我们前期通过高通量药物筛选平台分析了12000多种化合物，发现对B27启动子活性抑制最强的是雷公藤红素。肠道微生物群是目前免疫学中关注的热点，我们提出“B27型微生物群”概念，假说：基因和环境交互作用形成“B27型微生物群”，影响AS免疫炎症过程；雷公藤红素通过调控“B27型微生物群”发挥治疗作用。通过临床和动物研究，我们在B27阳性的AS患者及动物身上都找到了几种可能的“B27型微生物群”；我们也证实了雷公藤红素在动物身上减轻强直性脊柱炎疾病活动度及免疫效应的同时，显著改变肠道菌群的结构和丰富度，保护肠道粘膜，调节肠道微生态的失衡，这可能与其对于“B27型微生物群”的作用有关。本研究成果将具有一定理论意义和潜在的应用前景。为进一步开展筛选其他以“肠道微生物群”为靶标的中药或化合物的研究提供新方法和新技术平台。