MDA5在I型干扰素通路中发挥双重角色参与皮肌炎发病的机制研究

Dermatomyositis (DM) patients with positive expression of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies are characterized by high mortality and resistant to therapy. However, the etiology of this disorder remains unclear. We previously expressed and purified MDA5 protein in Baculovirus expression system and examined the anti-MDA5 antibody in the sera of patients with DM by ELISA using recombinant MDA5 antigen. We described the clinical manifestations in these anti-MDA5 positive patients. Higher prevalence of the acute subtype of ILD in patients with positive anti-MDA5 antibody resulted in a higher mortality rate. We addressed the type I interferon pathway might have important role in the production of anti-MDA5 antibody. In this project, we focus on the dual pathogenic role of MDA5 involved in type I IFN signaling pathway in DM by vitro studies and animal models. 1. As pattern recognition receptors, intrinsic type I IFN might be produced by MDA5-mediated signaling after virus infection. 2. As self-antigen, MDA5 could produce extrinsic type I IFN mediated by NA-TLR signaling pathway and enhance the development of autoimmune disease. Understanding the functional role of MDA5 and its autoantibody with disease initiation, propagation and expression appears fundamental in providing further insight into pathogenic pathways which in turn may stimulate new therapeutic approaches.

血清抗黑素瘤分化相关基因5（MDA5）抗体阳性的皮肌炎（DM）患者治疗效果差、死亡率高，其发病机制尚不明确。前期研究中我们通过真核系统重组表达MDA5蛋白，建立并完善ELISA方法检测DM患者血清中抗MDA5抗体。我们报道了抗MDA5抗体水平与肺间质病变的发生及严重程度密切相关，其产生与I型干扰素（I型IFN）通路相关。在此基础上本项目拟通过体外实验和动物模型进一步研究抗原MDA5在I型IFN通路中可能发挥双重角色参与DM发病：1.病毒感染后，MDA5作为模式识别受体，通过MDA5信号通路产生内源性I型IFN。2. MDA5作为自身抗原，通过核酸-Toll样受体（NA-TLRs）信号通路产生外源性I型IFN，活化外周血T、B细胞产生更多的自身抗体，加剧病变。本项目将深入探讨MDA5的生物学功能，不仅为阐明DM的发病机制、病情演变提供理论依据，也为探讨DM的靶向生物学治疗提供新的切入点。

在特发性炎症性肌病中，铁蛋白与其他炎症指标（ESR、CRP）、部分血清肌酶（AST、LDH）、ILD的发生以及肺高分辨率CT（HRCT）的影像学之间高度相关，提示其在判断疾病活动性特别是ILD病情严重程度中有重要的临床意义。皮肌炎患者血清IL-6、IL-10和IL-18等细胞因子与炎症指标、皮损和肺间质病变显著相关，在皮肌炎的疾病活动中可能发挥重要作用。研究合并肺间质病变或恶性肿瘤的皮肌炎/临床无肌病性皮肌炎（DM/CADM）患者的差异表达基因及相关信号通路。DM/CADM患者与健康对照、合并肺间质病变或合并恶性肿瘤的DM/CADM与无合并症患者间转录组基因及通路存在差异。抗MDA5抗体不同亚型，临床表现和预后不同。

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