神经轴突导向分子Plexin B2负向调控自发性生发中心的机制及在干预系统性红斑狼疮中的验证研究

有效调控自发性生发中心（Spt-GC）维持外周B细胞稳态是干预系统性红斑狼疮（SLE）的新方向。本项目前期发现，在无外来抗原刺激的免疫稳态下，Spt-GC B细胞高表达轴突导向分子Plexin B2，敲除该分子后Spt-GC B细胞比例显著增加，我们推测其对Spt-GC的负向调控作用，可能成为干预SLE的新靶点。本项目将研究稳态下，Plexin B2对Spt-GC形成、凋亡、分化、功能等影响，阐明其对Spt-GC的负向调控机制；构建条件性敲除小鼠，鉴定并验证Plexin B2的配体及二者的结合方式；测序分析Spt-GC B细胞内Plexin B2下游关键分子，探究其与Plexin B2在调控Spt-GC中的关系；验证Plexin B2与配体负向调控Spt-GC在干预SLE中的应用。本研究将为Plexin B2通过负向调控Spt-GC维持B细胞稳态，成为干预SLE的新靶点奠定理论与应用基础。

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Robust spontaneous germinal center (Spt-GC) is one of the major abnormal sites contributing to the pathogenesis of SLE. Strict control of Spt-GC is an important way to maintain the homeostasis of peripheral B cells and prevent SLE. In recent years, B cell-centered immune intervention has become a new hot spot. An early microarray screening study found that an axon guiding molecule Plexin B2 was highly expressed on T cell-dependent germinal center, and the output and affinity maturation of plasma cells were impaired after knockout of the molecule. In the present project, we found that Plexin B2 was also highly expressed on Spt-GC under steady state, however, Spt-GC B cells were increased after Plexin B2 knockout, suggesting a negative regulatory effect on Spt-GC and B cell homeostasis of Plexin B2. In this project, we will first investigate the effects of Plexin B2 on the formation, apoptosis and function of Spt-GC, then explore its ligand, interaction mode and molecular mechanism, finally observe the intervention effect on SLE mice. To elucidate the role and mechanism of Plexin B2 and its ligand in the regulation of Spt-GC will provide a theoretical basis for the treatment for SLE.