从调控B细胞活化的ERα-miRNA-TLR7内分泌免疫环路研究解毒祛瘀滋肾方改善SLE免疫失衡的机制

Systemic lupus erythematosus is a multisystemic autoimmune disease that usually occurs in women of childbearing age. Estrogen activated B cells play an important role in the pathogenesis of systemic lupus erythematosus. ERα -miRNA-TLR7 immune loop is closely related to kidney essence deficiency, heat toxin and blood stasis in SLE. Our research team found that Jiedu Quyu Zhijshen prescription (LCD) has better clinical curative effect, it can regulate ERα transcription activity and TLR7 signal pathway of immune cells and improve SLE disease activity. So we wonder if LCD upregulate related miRNAs by inhibiting Erα and thus inhibit TLR7? Therefore, we propose the hypothesis that: LCD can B cells activity by regulating the ERα -miRNA-TLR7 endocrine immune loop , and improve the imbalance of SLE immunity, thus exerting its synergistic and attenuated effects. To analyze whether LCD can upregulate mir146a and mir3148 by inhibiting ERα of B cell, and then inhibite the activation of B cell induced by TLR7 and the recombination of autoantibody associated immunoglobulin. This project has important scientific value to clarify the mechanism of Chinese medicine to correct the imbalance of B cell immunity, to enrich the theory of yin and yang balance of traditional Chinese medicine, and to find effective drug target.

系统性红斑狼疮（SLE）是好发于育龄期女性的自身免疫病，雌激素可活化自身反应性B细胞、促进SLE发生发展。SLE肾精亏虚为本，热毒血瘀为标的病机与ERα-miRNA-TLR7环路的致病机制密切相关。本团队研究发现，解毒祛瘀滋肾方(LCD)有确切的临床疗效，能调控ERα转录活性、抑制TLR7、改善SLE病情。那么，LCD是不是通过抑制ERα而上调相关miRNA，进而抑制TLR7来发挥作用呢？我们假设：LCD可能通过调控ERα-miRNA-TLR7环路而抑制B细胞活化，进而改善SLE免疫失衡状态。现拟利用现代生物学技术，分析LCD是否通过抑制B细胞的ERα而上调miR146a和miR3148，进而抑制TLR7导致的B细胞活化和免疫球蛋白类别转换重组，并促进Breg细胞分化。本项目对明确中医药纠正B细胞免疫失衡的作用机制具有重要的科学价值，对于丰富中医阴阳平衡理论、寻找有效药物靶点具有重要意义。

系统性红斑狼疮（systemic lupus erythematosus, SLE）是一种累及人体多系统的自身免疫性疾病。雌激素可促进自身反应性B细胞活化并分泌自身抗体，在SLE发病中具有重要作用。受雌激素调控的miRNA是否能通过影响SLE B细胞的TLR7信号进而影响自身抗体的产生还不明确。本研究主要研究解毒祛瘀滋肾方（JQZF）是否通过调控ERα-miRNA-TLR7内分泌免疫环路而调节B细胞活化，改善SLE免疫失衡而发挥其增效减毒作用。研究结果表明：JQZF可抑制B细胞ERα的表达，同时上调B细胞的miR146a，并可通过上调B细胞miR146a表达而抑制TLR7信号通路，可以通过抑制B细胞TLR7影响B细胞活化。总之，本项目研究阐明了ERα-miRNA-TLR7内分泌免疫环路对SLE发展与转归的重要作用，揭示了解毒祛瘀滋肾方可通过抑制ERα而上调B细胞的miR146a，进而通下调B细胞 TLR7的表达而抑制分泌自身抗体B细胞的活化、自身抗体相关免疫球蛋白类别转换重组，促进Breg细胞分化，纠正SLE的免疫失衡状态。本项目对明确中医药纠正B细胞免疫失衡的作用机制具有重要的科学价值，对于丰富中医阴阳平衡理论、寻找有效药物靶点具有重要意义。