系统性红斑狼疮(SLE)是一种常见的自身免疫性疾病,其发病机制主要涉及B细胞通过滤泡辅助性T(Tfh)细胞异常活化产生致病性抗体,这需要更有效和安全的治疗方法。双氢青蒿素(DHA)是青蒿素的主要活性成分,具有免疫抑制作用。在这项研究中,体外实验证实,DHA抑制Tfh细胞诱导,削弱其在B细胞分化中的辅助功能;DHA直接抑制B细胞活化,分化,和抗体生产。此外,建立小鼠SLE模型,我们证实DHA显著减轻了SLE和狼疮性肾炎的症状,和降低血清免疫球蛋白(Ig)G,IgM,IgA,和抗dsDNA水平。此外,DHA降低了总Tfh细胞的频率,激活的Tfh细胞,和B细胞淋巴瘤6,和白细胞介素(IL)-21水平在Tfh细胞从脾和淋巴结,以及B细胞的水平,生发中心B细胞,和脾脏中的浆细胞,淋巴结,还有肾脏.此外,DHA通过阻断IL-2诱导的T细胞激酶(ITK)信号及其下游核因子(NF)-κB抑制Tfh细胞,活化T细胞核因子,并激活蛋白质-1通路,并通过阻断布鲁顿酪氨酸激酶(BTK)信号和下游NF-κB和Myc途径直接抑制B细胞。总的来说,我们的结果表明,DHA通过阻断ITK信号传导抑制Tfh细胞,也通过阻断BTK信号传导直接抑制B细胞.因此,减少致病性抗体的产生可能有效治疗SLE。
Systemic lupus erythematosus (SLE) is a common autoimmune disease, and its pathogenesis mainly involves the aberrant activation of B cells through follicular helper T (Tfh) cells to produce pathogenic antibodies, which requires more effective and safe treatment methods. Dihydroartemisinin (DHA) is the main active ingredient of artemisinin and has immunosuppressive effects. In this study, in vitro experiments confirmed that DHA inhibited Tfh cell induction and weakened its auxiliary function in B cell differentiation; furthermore, DHA directly inhibited B cell activation, differentiation, and antibody production. Furthermore, a mouse model of SLE was established, and we confirmed that DHA significantly reduced the symptoms of SLE and lupus nephritis, and decreased serum immunoglobulin (Ig)G, IgM, IgA, and anti-dsDNA levels. Moreover, DHA reduced the frequencies of total Tfh cells, activated Tfh cells, and B cell lymphoma 6, and interleukin (IL)-21 levels in Tfh cells from the spleen and lymph nodes, as well as the levels of B cells, germinal center B cells, and plasma cells in the spleen, lymph nodes, and kidneys. Additionally, DHA inhibited Tfh cells by blocking IL-2-inducible T cell kinase (ITK) signaling and its downstream nuclear factor (NF)-κB, nuclear factor of activated T cell, and activating protein-1 pathways, and directly inhibited B cells by blocking Bruton\'s tyrosine kinase (BTK) signaling and the downstream NF-κB and Myc pathways. Overall, our results demonstrated that DHA inhibited Tfh cells by blocking ITK signaling and also directly inhibited B cells by blocking BTK signaling. Therefore, reducing the production of pathogenic antibodies might effectively treat SLE.