探讨锌指家族转录因子对系统性红斑狼疮患者I型干扰素基因特征的调控和疾病的影响

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease affecting 5 million people worldwide. SLE patients suffer chronic immune-mediated inflammatory damage in multiple organs, resulting in morbidity and a marked reduction in life expectancy. SLE is strongly associated with dysregulated cytokine production, characterised by an interferon (IFN)-stimulated gene (ISG) signature. Moreover, this IFN response is believed to play an important role in disease development and/or progression. By determining transcription binding motifs that are enriched in the promoters of gene transcripts that are elevated in SLE patients, we have identified a role for the PLZF (promyelocytic leukaemia zinc finger) and Bcl6 (B cell lymphoma 6) transcription factors in the ISG signature. These two related transcription factors bind to the same motif in gene promoters, but with distinctly different outcomes. We previously demonstrated that PLZF induces a specific subset of IFN-regulated genes (6). More recently, we identified that Bcl6 represses the IFN response. We hypothesisse that this opposing activity of PLZF and Bcl6 is of consequence to the regulation of ISG expression that underlies SLE pathology (Fig. 1). We will test this hypothesis by analysis of the expression and transcriptional activity of each factor in peripheral blood mononuclear cells from SLE patients during flares and states of inactive disease. We will also test the contribution of PLZF and Bcl6 to the IFN signature and the progression of disease in murine models using transgenic murine lines that are ablated for these transcription factors. These studies will determine whether Bcl6 and PLZF contribute to pathology in SLE, thereby identifying a route for therapeutic treatment of this complex disease.

系统性红斑狼疮（SLE）是严重的自身免疫性疾病，SLE的发生主要以干扰素（IFN）刺激基因（ISG）为特征,通过检测SLE患者中富集基因转录物启动子,我们确定了ISG标签中早幼粒细胞白血病锌指蛋白（promyelocytic leukaemia zinc finger,PLZF）和B细胞淋巴瘤6（B cell lymphoma 6,Bcl6）转录因子的重要作用。我们曾发现PLZF诱导特定的ISG (Immunity 2009)，我们又发现PLZF在表观遗传学水平调控炎症信号（PNAS & Nat Commun 2015),还确定Bcl6可抑制IFN应答。基于此我们提出假说PLZF和Bcl6的这种相反的活性是SLE病理学基础下ISG表达调节的结果，将通过分析SLE患者的每种因子的表达和转录活性，利用基因敲除小鼠来检测PLZF和Bcl6对IFN应答及疾病进展的作用，找到治疗这种复杂疾病的新方法

系统性红斑狼疮（SLE）是严重的自身免疫性疾病，SLE的发生主要以干扰素（IFN）刺激基因（ISG）为特征，通过检测SLE患者中富集基因转录物启动子，我们确定了ISG标签中早幼粒细胞白血病锌指蛋白（promyelocytic leukaemia zinc finger，PLZF）和B细胞淋巴瘤6（B cell lymphoma 6，Bcl6）转录因子的重要作用。我们曾发现PLZF正调节ISG（Immunity），又发现PLZF在表观遗传学水平负调控炎症信号（PNAS & Nat Commun），还确定Bcl6可抑制IFN应答。基于此我们提出假说PLZF和Bcl6的这种相反的活性是SLE病理学基础下ISG表达调节的结果，通过分析SLE患者的每种因子的表达和转录活性，利用基因敲除小鼠来检测PLZF和Bcl6对IFN应答及疾病进展的作用，找到治疗这种复杂疾病的新方法。有点令人惊讶的是在本研究中，我们使用姥鲛烷诱导的实验性狼疮模型探讨了PLZF（ZBTB16）在SLE发展中的作用。结果发现，与原来的预测相反，髓细胞敲除的PLZF小鼠出现了更严重的狼疮样综合征。ZBTB16flox/flox（LysmCRE+）小鼠在接受原始烷攻击后表现出显着更高的死亡率。此外，显着的细胞过多和间质性肾炎在 ZBTB16-/-小鼠的肾小球中很明显。此外，ZBTB16-/-小鼠肾脏中免疫细胞浸润增强和促炎介质水平升高, 但I型IFN表达差异不明显。总之，我们的研究证明了PLZF在SLE发展中的关键作用，并表明调节炎性体信号可能有助于控制自身免疫性疾病（包括狼疮）中的炎症损伤，而不是依赖于调节干扰素及ISG。