E4BP4调控Tfh细胞分化及其在系统性红斑狼疮发病中的作用机制研究

Systemic lupus erythematosus (SLE) is systemic autoimmune disease characterized by multiple organ disorders and abnormal up-regulation of autoantibodies. SLE is complex and persistent, and makes great harm to human’s health. The pathology of SLE is not completely clear. T follicular helper cells (Tfh cells), provides a helper role to B cells differentiation and secretion of immunoglobulins, are recognized as prominent contributors to SLE. Transcription factor E4BP4 has been to implicate in the development and functions of immune cells and regulation in pathogenesis of autoimmune diseases. The role of E4BP4 in pathogenesis of SLE is rarely reported. On the basis of previously results that lack of E4BP4 facilitates Tfh cell differentiation in murine models, this study has scheduled to identify E4BP4 involves in lupus by regulating Tfh cell growth with strategies like polarization of Tfh cells in vivo and in vitro, siRNA transfection in clinical samples and murine models. This study will broaden the understanding of lupus pathogenesis and help identify putative treatment targets of SLE.

系统性红斑狼疮（SLE）是一种以多器官损害以及自身抗体异常增多为特征的自身免疫性疾病，其发病机制不明确，临床表现复杂多变、反复迁延，治疗困难，对人类健康造成了极大危害。最新的研究证实可辅助B细胞产生抗体的滤泡辅助性T细胞（Tfh cells）在SLE的发病中起重要作用。转录因子E4BP4调控多种免疫细胞的分化和功能，E4BP4的功能异常也可导致自身免疫病的发病，但其在SLE发生发展中的作用及机制鲜有研究；基于申请者前期研究发现小鼠中E4BP4的缺失可促进Tfh细胞的分化和功能，本研究拟针对SLE患者和动物模型，采用转基因小鼠，运用体内体外诱导Tfh细胞，siRNA转染免疫细胞等方法，证实E4BP4是调控Tfh细胞分化和功能的重要因子之一，并通过影响Tfh细胞增殖和功能参与SLE发病，对此机制的深入研究将极大丰富我们对SLE发病机制的研究，为SLE新的治疗方法提供思路和实验依据。

滤泡辅助T细胞（T follicular helper cells, Tfh cells）对于生发中心（germinal center, GC）反应的形成是不可或缺的，而滤泡调节T细胞（T follicular regulatory cells, Tfr cells）则抑制Tfh细胞介导的GC反应。Tfh细胞的异常激活与自身免疫性疾病的发病密切相关，如系统性红斑狼疮（systemic lupus erythematosus, SLE）。然而，减轻Tfh细胞过度分化，进而触发自身免疫的分子机制尚不完全清楚。此研究证明了E4BP4可作为转录的“刹车”来抑制Tfh细胞的分化。此外，我们还表明在SLE患者中这种免疫机制受到了损害。我们使用了CD4条件性敲入或敲除E4BP4的小鼠，发现E4BP4抑制了Tfh细胞分化。E4BP4通过招募抑制性表观遗传修饰物HDAC1和EZH2来下调对Bcl6转录的调控。E4BP4磷酸化位点突变体不能有效抑制Tfh细胞的分化。在SLE患者中，我们检测到E4BP4的磷酸化受损，并与疾病活动性呈正相关。这些发现揭示了E4BP4抑制Tfh细胞分化的分子机制，其功能受损与SLE中不受控制的自身免疫反应有关。