ATF3通过Tfh调控B细胞活化的机制及在IBD中的病理意义

Disruption of gut mucosa integrity represents important mechanism of inflammatory bowl diease (IBD). In the gut-related lymphoid tissues, T follicular helper T cells (Tfh) provide help in the formation of germinal center (GC) and B cells activation, which leads to production of secretory IgA. IgA play essential role in the maintenance of mocosa integrity and gut immune homeostasis. The mechanism dictating Tfh development and GC-B activation in the gut remains largely unknown. In our preliminary study, we found that ATF3 is closely associated with IBD and changes in Tfh and GC-B in the gut may be involved in. The experimental evidence include: Mice deficient in ATF3 displayed severer IBD symptoms, the levels of Tfh and GC-B in Peyer’s patches , as well as IgA production from plasma cells and its content in fecal, were significantly decreased, when compared with wild-type littermates. Adoptive transfer of IgA-producing plasma cell relieved the IBD symptoms in ATF3-deficient mice. We therefore propose that “ATF3 represent a novel regulator of Tfh development and GC-B response in gut, its deficiency could cause impaired IgA production and severer IBD disease”. In order to test it, we first establish the relationship between ATF3 and IBD susptibility, then investigate the role of ATF3 in the regulation of gut Tfh development and GC formation; identify the key target of ATF3 in Tfh to clarify its molecular mechanism; finally we will utilize CD4-conditional ATF3 knock-out mice and adoptive transfer strategies, to confirm that Tfh/GC-B mediate the effect of ATF3 in IBD pathogenesis. The implementation of this proposal will uncover the importance of ATF3 in IBD and its underlying mechanism, as well as identify novel regulator of gut Tfh development and GC response, which will provide therapeutic target for IBD immunotherapy.

肠粘膜屏障破坏是炎症性肠病（IBD）的重要发病机制。肠道Tfh辅助生发中心B细胞（GC-B）活化并产生分泌型IgA，是维持肠粘膜屏障的首要防线，然而相应的分子调控机制尚待阐明。我们前期发现，ATF3基因敲除小鼠IBD症状显著加重，肠道派氏淋巴结中Tfh计数，生发中心GC-B及其分泌的IgA水平均显著下降。输入分泌IgA的浆细胞可缓解ATF3-KO的IBD症状。据此提出“ATF3通过调控肠道Tfh及GC-B活化，进而影响IgA分泌及IBD发生”。为验证此假说，我们拟首先确定ATF3与IBD易感性之间的关系，进而研究ATF3对肠道Tfh及 GC-B细胞活化的作用，探讨ATF3调控肠道Tfh发育的分子机制；最后通过体内实验，确定肠道Tfh/GC-B介导了ATF3在IBD发生中的作用。项目的实施将揭示肠道Tfh调控GC-B活化的分子机制，为IBD的免疫治疗提供新策略和新靶标。

肠粘膜屏障破坏是炎症性肠病（IBD）的重要发病机制。肠道Tfh辅助生发中心B细胞（GC-B）活化并产生分泌型IgA，是维持肠粘膜屏障的首要防线，然而相应的分子调控机制尚待阐明。我们前期发现，ATF3基因敲除小鼠IBD症状显著加重，肠道派氏淋巴结中Tfh计数，生发中心GC-B及其分泌的IgA水平均显著下降。输入分泌IgA的浆细胞可缓解ATF3-KO的IBD症状。据此提出“ATF3通过调控肠道Tfh及GC-B活化，进而影响IgA分泌及IBD发生”。为验证此假说，我们拟首先确定ATF3与IBD易感性之间的关系，进而研究ATF3对肠道Tfh及 GC-B细胞活化的作用，探讨ATF3调控肠道Tfh发育的分子机制；最后通过体内实验，确定肠道Tfh/GC-B介导了ATF3在IBD发生中的作用。项目的实施将揭示肠道Tfh调控GC-B活化的分子机制，为IBD的免疫治疗提供新策略和新靶标。

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