MicroRNA-17~92调控浆细胞分化和系统性红斑狼疮致病作用机制的研究

Germinal (GC) centers form in peripheral lymphoid organs and are responsible for clearance of invading pathogens and establishment of memory. After activation by a protein antigen and in collaboration with cognate follicular helper T (TFH) cells, B cells proliferate and undergo immunoglobulin class-switch recombination and enter into a GC reaction, where they undergo somatic hypermutation and differentiate into antibody-secreting plasma cells (PCs) and memory cells. However, PCs can also secrete auto-antibodies and contribute to autoimmune disease, including systemic lupus erythematosus (SLE). Accumulation of auto-reactive PCs and auto-antibodies has been reported in SLE patients and murine models. MicroRNAs (miRNAs) have been demonstrated that regulate TFH cell differentiation, GC reaction and immune responses. Altered miRNA expression has been reported in human autoimmune disease, including lupus. Whether miRNAs control PC differentiation and contribute to autoimmune disease by regulating PC differentiation and function are totally unknown. Based on our preliminary data showing that miR-17~92 controlled PC differentiation by regulating the expression of IRF4, Blimp1 and Pax5 and by affecting ERK signaling pathway probably through targeting DUSP2 and PHLPP2. We will further explore whether miR-17~92 regulates PC differentiation by targeting DUSP2 and PHLPP2, and uncover the detailed molecular mechanisms underlies PC differentiation, immune responses and autoimmunity. Completion of our project will not only provide us new insights into the regulation of plasma cell differentiation by miR17~92 and its target genes including DUSP2 and PHLPP2, but also understanding the pathogenesis of autoimmune disease and promoting development of diagnostic markers and therapy.

生发中心(Germinal center, GC)负责清除入侵的病原体和建立免疫记忆。成熟B细胞经抗原活化并通过滤泡辅助型T (TFH) 细胞协助后, 进行增殖和抗体类别转换, 在GC进一步分化为分泌抗体的浆细胞和记忆细胞。浆细胞分泌自身抗体且被证实参与自身免疫病如系统性红斑狼疮(SLE) 的致病机制。MicroRNA调节TFH细胞和GCB细胞的分化及免疫应答。microRNA表达异常已在自身免疫病发现, 但microRNA是否影响浆细胞分化完全不清楚。我们的前期结果发现miR-17~92通过调控浆细胞分化的重要转录因子IRF4, Blimp1和Pax5的表达, 同时调节靶基因DUSP2和PHLPP2的表达和影响浆细胞分化过程所需的ERK和Akt信号通路, 从而调节浆细胞分化。上述课题的完成将对调控浆细胞分化研究提供新的视野和了解自身免疫病致病机制与促进自身免疫病诊断诊断标记和治疗的发展。

生发中心（Germinal center，GC）负责清除入侵的病原体和建立免疫记忆。成熟B细胞经抗原活化并通过滤泡辅助型T（TFH）细胞协助后，进行增殖和抗体类别转换，在GC进一步分化为分泌抗体的浆细胞和记忆细胞。浆细胞分泌自身抗体且被证实参与自身免疫病如系统性红斑狼 疮(SLE) 的致病机制。MicroRNA调节TFH细胞和GCB细胞的分化及免疫应答。microRNA表达异常已在自身免疫病发现，但microRNA是否影响浆细胞分化完全不清楚。我们的结果发现miR-17-92通过调控浆细胞分化的重要转录因子IRF4, Blimp1和Pax5的表达，同时调节靶基因Pten的表达从而影响B细胞生发中心反应。此外，利用CRISPR/Cas9筛选发现miR-17～92能通过调控SOCS3和A20蛋白的表达从而控制浆细胞的分化所必须的NFkB信号通路的应答因此调节浆细胞以及抗体的产生。上述课题的完成将对调控浆细胞分化研究提供新的视野和了解自身免疫病致病机制与促进自身免疫病诊断诊断标记和治疗的发展。