中文摘要
新近数据显示滤泡辅助T细胞（TFH）不仅调节B细胞分化而且也参与炎症。目前完全不清楚TFH尤其TFH17细胞发育分化及其在肾小球肾炎发生发展过程中的作用和分子机制的调节。虽然已经明确TH17介入炎症，但是不清楚TFH17是否介入肾小球肾炎的病理发展？本研究拟以抗GBM抗体诱导的肾小球损伤模型在IL-10缺陷鼠表现更严重的肾小球肾炎的预初数据基础上，对IL-10如何调节TFH17细胞发育分化及其在肾小球肾炎病理发展过程中的作用机制进行研究。用FACS， WB，ELISA，组织切片，PCR等免疫学方法从蛋白和核酸水平探讨IL-10在细胞及分子水平调节TFH17细胞的发育分化作用，佐以WT和IL-10缺陷鼠，加上脾细胞，CD4+ T细胞及TFH细胞转移至Rag1-/-鼠并用抗GBM抗体诱导出肾小球肾炎模型后，对TFH17细胞的体内体外发育分化及其参与免疫性肾小球肾炎疾病的可能机制进行研究和证实。
英文摘要
Resent data showed that follicular helper T cells (TFH) were key regulators in not only B cell differentiation but also inflammation, but how TFH cells including TFH17 regulate inflammatory responses including glomerulonephritis (GN) remain unclear. Although it is clear that TH17 cells play a pathologic role in the pathogenesis of several inflammatory diseases, the contribution of TFH17 cells in the development of GN are still not fully understood. Herein, we shall focus on mechanism of what IL-10 deficient mice exhibit exacerbation of GN after induction with anti-glomerular basement membrane globulin (anti-GBM), with enhanced inflammatory TFH and TH17 cells responses by methods of FACS, WB, ELISA, histology and PCR. We further study the reason of what Rag1-/- mice reconstituted with IL-10-/- CD4+ T cells develop more severe GN after induction of anti-GBM glomerulonephritis, with more kidneys injury in mouse GN model. To explain the mechanism how IL-10 regulate TFH17 cells differentiation and its function in autoimmune diseases. This study could explain how T cell-derived IL-10 plays a critical suppressive role in the control of pathogenic TFH17 cell differentiation and highlights the importance of IL-10 as protection against GN development.
结题摘要
新近数据显示滤泡辅助T细胞（TFH）不仅调节B细胞分化而且也参与炎症。目前完全不清楚TFH尤其TFH17细胞发育分化及其在肾小球肾炎发生发展过程中的作用和分子机制的调节。虽然已经明确TH17介入炎症，但是不清楚TFH17是否介入肾小球肾炎的病理发展？本研究拟以抗GBM抗体诱导的肾小球损伤模型在IL-10缺陷鼠表现更严重的肾小球肾炎的预初数据基础上，对IL-10如何调节TFH17细胞发育分化及其在肾小球肾炎病理发展过程中的作用机制进行研究。用FACS， WB，ELISA，组织切片，PCR等免疫学方法从蛋白和核酸水平探讨IL-10在细胞及分子水平调节TFH17细胞的发育分化作用，佐以WT和IL-10缺陷鼠，加上脾细胞，CD4+ T细胞及TFH细胞转移至Rag1-/-鼠并用抗GBM抗体诱导出肾小球肾炎模型后，对TFH17细胞的体内体外发育分化及其参与免疫性肾小球肾炎疾病的可能机制进行研究和证实。我们已完成的研究工作证明IL-10可显著抑制炎症性TFH/TFH17的产生；TFH细胞高表达有CD40L, ICOS, PD-1及相应趋化因子受体并分泌促炎性细胞因子IL-23等, 这些分子通过与表达有相应受配体的其它免疫细胞相互作用, 进而扩大了免疫应答反应。此研究数据可以很好的解释和证实IL-10缺陷鼠在抗基底膜抗体诱导的肾小球肾炎模型鼠体内表现有比WT鼠更严重的肾炎症状,进而可以阐明TFH/TFH17细胞参与炎症的分子机制.具有明显的临床意义。