B细胞调节的免疫反应在脑海绵状血管畸形（CCM）中的机制性研究

脑海绵状血管畸形（CCM）是脑血管畸形的一种，由其导致的脑出血可致严重的并发症甚至死亡。CCM发病机制尚不明确，尚无有效的药物治疗。申请人对CCM进行长期深入的研究发现，CCM中有免疫细胞、免疫复合体和补体存在、和T-B细胞聚集等，这些与内皮细胞(EC)渗透性紧密相关。B细胞耗竭减少了CCM病变进展和脑出血，但机制不详。我们假设免疫复合体和抗体依赖的补体激活沉积在EC上, 通过细胞内多个信号通路的活化, 增加了EC的增殖和渗透性, 促使CCM病变的进展和出血。本课题拟研究 1、在转基因鼠中阻断T-B细胞聚集，阐明B细胞发挥作用是否由T细胞辅助；2、哪种补体激活途径参与CCM病变进展、出血；3、体内外实验探讨免疫复合体激活多信号转导通路，使EC繁殖和渗透性增加的机制。本研究从新的角度，试图探讨B细胞调节的免疫反应在CCM中的作用机制，为CCM治疗提供新靶点和理论依据，有一定转化意义。

The cerebral cavernous malformation (CCM) is a common cerebrovascular anomaly. Cerebral hemorrhage caused by CCM can lead to serious complication, and even death. The molecular mechanisms involved in the pathophysiology of CCM await characterization. There is no known medicine treatment to alter the course of this disease. The applicant has performed the long-run and deep study on the CCM diseases, including the infiltration of immunocompetent cells, immune complex and complement deposits, and T-B aggregates in CCM lesions. This phenomenon is associated with vascular endothelial permeability. In our data, we found B cell depletion therapy could reduce CCM lesional progression and hemorrhage. However, the definitive mechanism of B cell-mediated immune response in the CCM disease is unclear. We hypothesize that immune complex and antibody-dependent complement activation on the endothelia, increasing the vascular endothelial proliferation and permeability via the activation of cellular multiple signaling pathways, promoting CCM lesional progression and hemorrhage. This proposal will investigate 1. In our recently developed Pdcd10+/-Trp53-/- mice, the investigation of T- cells being readily available to provide help for B- cells via the inhibition of T-B aggregates. 2. Which complement pathway(s) involved in the lesional progression and hemorrhage of CCM diseases. 3. In vitro and in vivo study, the investigation of the mechanistic role of the immune complex in the promotion of vascular endothelial proliferation and permeability, via the activation of multiple signaling pathways. With a fresh perspective, this study would provide proof of principle of its mechanistic implications of B cell mediated immune response in the CCM disease. It lays a theoretical foundation of immunotherapy in this disease and provides a new target for treating this disease. This project has a certain significance of transformation.