FZD7/NFATc1转录活性调控溃疡性结肠炎中传统型/非传统型肠上皮内淋巴细胞免疫平衡的机制研究

Ulcerative colitis is characterized by relapses and remissions,corresponding with repeated damage and repair process of intestinal mucosal immunedynamic equilibrium. Finding a critical pathway of the intestinal mucosal immune homeostasis will be a breakthrough in the treatment of ulcerative colitis. Based on previous work which found that unconventionalintestinal intraepithelial lymphocytes inhibited by FZD7/NFATc1 transcriptional activity change might be involved in the activation of inflammatory bowel disease, this project performs a preliminary analysis about the axis of down-regulation of FZD7/NFATc1 transcriptional activity→suppression of TGF-β activation→balance offset of unconventional intestinal intraepithelial lymphocytes→damage of immune dynamic equilibrium. And the possibility of FZD7/NFATc1 transcriptional activity alternation can be considered as diagnostic markers of gene/protein imprints on disease activity in ulcerative colitis, together with the possibility of reversal of balance offset on unconventional intestinal intraepithelial lymphocytes as a new strategy of treatment are also discussed. From a brand new view of epithelial lymphocyte imbalance, the project enters into the disease difficulty that ulcerative colitis-specific intestinal mucosal immune dynamic equilibrium damages and repairs repeatedly, and provides new inspirations for the diagnosis and treatment of ulcerative colitis.

活动期和缓解期反复交替为溃疡性结肠炎病程的特征，与之对应的是肠黏膜免疫动态平衡的反复破坏和修复。寻找到维持肠黏膜免疫动态平衡的关键通路将会成为治疗溃疡性结肠炎的突破进展。本项目基于前期工作中发现的FZD7/NFATc1转录活性改变抑制溃疡性结肠炎非传统型肠上皮内淋巴细胞可能参与疾病的激活机制，通过初步分析FZD7/NFATc1转录活性下调→TGF-β活化抑制→非传统型肠上皮内淋巴细胞平衡偏移→免疫动态失衡这一作用轴，探讨FZD7/NFATc1转录活性改变能否成为溃疡性结肠炎疾病活动的诊断标志物以及逆转非传统型肠上皮内淋巴细胞平衡偏移作为疾病治疗新策略的可能性。该项目从崭新的非传统型肠黏膜上皮内淋巴细胞失衡的角度切入溃疡性结肠炎特异的肠黏膜免疫动态平衡反复破坏和修复这一疾病难点，为溃疡性结肠炎的诊治提供新的启迪。

本课题立足于 FZD7/NFATc1 转录活性及表达量改变介导的传统型（Type A）和非传统型（Type B）肠上皮内淋巴细胞平衡的偏移和重塑这一全新基点切入溃疡性结肠炎活动期与缓解期交替的机制，并由FZD7所处的WNT通路出发，进一步发现了WNT经典及非经典通路的此消彼涨与溃疡性结肠炎免疫动态平衡紊乱间的联系。课题将非传统型（Type B）肠上皮内淋巴细胞与溃疡性结肠炎免疫动态平衡结合，初步证明FZD7/NFATc1转录活性变异导致非传统型（Type B）肠上皮内淋巴细胞平衡偏移的可能机制，分析FZD7/NFATc1转录活性变异影响溃疡性结肠炎传统型（Type A）和非传统型（Type B）肠上皮内淋巴细胞平衡偏移的作用途径，初步了解FZD7启动子异常甲基化→FZD7表达降低→NFATc1转录活性降低→TGF-β活化受抑制→非传统型（Type B）肠上皮内淋巴细胞抑制→免疫动态平衡破坏这一作用模式。非经典WNT通路的代表性分子标志物FZD5、WNT5A、NFATc1在结肠炎IEL中显著升高。非经典WNT信号因子WNT5A作用于IEL细胞后，细胞表面抑制性标志物LAG3、LY49E、NKG2A表达量下调而激活态标志物CD69及FASL表达量上调。同时伴随着IFN-γ表达上调。阻断非经典WNT通路或加入经典WNT通路信号因子可逆转IEL细胞的促炎状态。上述发现提示WNT经典及非经典通路在IEL为代表的肠道免疫环境中可能起拮抗作用。通过在肠粘膜活检标本中的验证，发现了溃疡性结肠炎患者的肠上皮黏膜中检测NFATc1入核及激活与疾病活动度及呈正相关。提示NFATc1在传统型（Type A）和非传统型（Type B）肠上皮内淋巴细胞平衡偏移和重塑可成为溃疡性结肠炎疾病缓解和复发指示标志。