大疱性类天疱疮血浆外泌体通过miR-148a-3p/DNMT1/Blimp-1轴调控B细胞异常分化的作用及分子机制

大疱性类天疱疮（BP）是典型的器官特异性自身免疫病，严重危害患者健康。B细胞异常活化并分泌大量致病性自身抗体是BP发病的关键因素，而其调控机制不明。研究表明外泌体作为细胞间信息交流的重要载体，可调控B细胞的功能。我们发现，BP血浆外泌体可刺激BP特异性自身抗体的产生并促进B细胞分化，其内含物miR-148a-3p在BP中异常高表达，且可靶向甲基化酶DNMT1。BP患者外周B细胞DNMT1显著下调，转录因子Blimp-1显著上调。由此提出科学假说：BP血浆外泌体通过miR-148a-3p/DNMT-1/Blimp-1轴调控B细胞的异常分化，在致病性自身抗体的产生中发挥重要作用。本项目拟在此基础上，利用体外共培养、流式、ELISA及小鼠模型阐明血浆外泌体通过miR-148a-3p调控B细胞分化的机制。项目的实施将进一步深入揭示BP的发病机制，并为抗体介导的自身免疫病的研究和治疗提供新的思路。

Bullous pemphigoid (BP) is typically an organ-specific autoimmune disease. Abnormal activation of B cells and pathogenic autoantibodies secretion are the hallmarks of BP. However, the mechanism of B cells abnormal activation and differentiation is still unclear. Recent studies have shown that exosomes, as an important carrier of intercellular information exchange, can regulated the function of B cells. In our previous studies, we found that plasma-derived exosomes induced anti-BP180 secretion and B cell differentiation in BP. Furthermore, miR-148a-3p is highly expressed in plasma-derived exosomes in BP, and predicting targetable methylase enzyme, DNMT1. In addition, DNMT1 and Blimp-1 is significantly down-regulated and up-regulated in peripheral B cells of patients with BP, respectively. Based on these findings, we hypothesize that plasma derived-exosomes play an important role in the pathogenic autoantibodies secretion by regulating B cells differentiation through miR-148a-3p/DNMT1/Blimp-1 axis in bullous pemphigoid. On this basis, we will elucidate the mechanism of plasma derived-exosomes miR-148a-3p regulate B cells differentiation by in vitro co-culture, flow cytometry, ELISA and BP mouse model. This project will further reveal the pathogenesis of BP and provide new ideas for the research and treatment of antibody-mediated autoimmune diseases.