PGRN通过抑制WASP磷酸化负调节B细胞早期激活和功能的机制研究

自身免疫性疾病（AID）是免疫系统对机体自身物质发生应答的疾病，B淋巴细胞异常早期激活与AID发病有关，PGRN高表达于多种AID中抑制AID进展，但是PGRN是否调控B细胞早期激活及功能不清楚。前期结果发现PGRN在B细胞中高表达，PGRN KO小鼠GC B细胞增多，B细胞早期激活过程中BCR扩张及肌动蛋白聚合增强，且肌动蛋白调节蛋白WASP磷酸化水平升高，但PGRN如何调控pWASP及是否通过pWASP调控B细胞早期激活和功能的分子机制不明确。本研究拟通过免疫小鼠检测PGRN对体液免疫应答的影响，骨髓嵌合小鼠验证PGRN参与调控B细胞分化及免疫应答的内在作用，WB、共聚焦检测BCR下游信号分子考察PGRN对BCR信号及肌动蛋白重构的调控，并通过过表达PGRN探讨其调控pWASP的分子机制。最终揭示PGRN通过抑制WASP磷酸化负调节B细胞早期激活及功能，为AID靶向治疗提供理论依据。

Autoimmune diseases (AID) are a kind of disease in which the immune system attacks the healthy cells in the body, the abnormal early activation of B cells is closely related to AID. PGRN is highly expressed in a variety of AID and retarded their progression. However, the effect of PGRN on the early activation and function of B cells is still not clear. Our previous results showed that PGRN was highly expressed in B cells, and the germinal center B cells were increased in PGRN KO mice. During the early activation of B cells, The expansion of B cell and actin remodeling were increased in PGRN KO mice, we also found the phosphorylation of WASP was increased in PGRN KO mice, but the molecular mechanism of how PGRN regulates the pWASP and whether PGRN regulates the early activation and function of B cells by PGRN is unclear. In this study, the role of PGRN on the humoral immune response will be detected after immunization of mice, and we will further investigate the intrinsic role of PGRN in regulating B cell differentiation and humoral immune response by chimera mice, WB and confocal will be used to determine the regulation of PGRN on BCR signalling and actin remodeling, and the molecular mechanism of PGRN regulates pWASP will be studied by overexpression of PGRN in vitro. Then finally reveal that PGRN negatively regulates the early activation and function of B cells by inhibiting WASP phosphorylation. This study aims to provide a theoretical basis for AID targeted therapy.