抗dsDNA IgG致病新机制—通过抑制SOCS1信号而诱导肾脏纤维化病变

抗dsDNA抗体是系统性红斑狼疮主要致病抗体之一，与肾损害密切相关，但致病机制不清楚。我们最近发现抗dsDNA IgG特异性识别SOCS1（一种纤维化负向调控因子）的功能区域KIR结构，继而促进纤维化炎症因子合成；还发现一种ALW多肽能高效封闭（>80%）抗dsDNA IgG与抗原结合。因此提出假说：抗dsDNA抗体穿透进入肾脏固有细胞，直接调控基因表达或干扰SOCS1-KIR与JAK2结合，诱导肌成纤维细胞表型；利用ALW多肽可能阻断抗dsDNA IgG的致病效应。本课题拟借助细胞培养、多肽化学修饰、质谱分析等技术，阐明抗dsDNA IgG干扰胞内SOCS1-JAK2信号链的分子机制，并借助MRL/lpr狼疮小鼠模型探讨ALW多肽靶向性阻断抗dsDNA IgG的初步疗效。本研究将揭示抗dsDNA抗体诱导肾组织纤维化的一种致病新机制，还将奠定小分子多肽药物治疗红斑狼疮靶器官损害的理论基础。

Systemic lupus erythematosus is characterized by excessive production of pathogenic autoantibodies including anti-dsDNA antibodies, which induce specific injuries in kideneys. However, the precise mechanim underlying lupus nephritis remains unclear. Recently, we found that anti-dsDNA IgG exhibits high affinity to kinase inhibitory region (KIR) of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of tissue fibrosis. The binding of anti-dsDNA IgG to KIR leads to the production of profibrotic cytokines in cells. Moreover, we identified a peptide (abbreviated as ALW), which blocks the antigenic recognition of anti-dsDNA IgG with an efficiency of >80%. Therefore, we speculate that anti-dsDNA IgG penetrates renal resident cells, modulates gene expression or interferes signal transduction of SOCS1-KIR to JAK2, and then triggers myofibroblast phenotype of normal cells. Also, ALW peptide may effectively inhibit such pathogenic effect of anti-dsDNA IgG. In this study, our aim will be focused on revealing the role of anti-dsDNA IgG in aberrant signal transduction of SOCS1-KIR to JAK2. The main techniques include cell culture, chemical peptide modification, mass spectrometry, etc. Finally, modified ALW peptide will be administrated to MRL/lpr lupus-prone mice, followed by monitoring both therapeutic and side effect. The results from this study will not only elucidate a novel intrinsic mechanism underlying renal fibrotic progresses induced by anti-dsDNA IgG, but also contribute to the development of small-molecule peptide therapies for patients with SLE-related end-organ damage.