T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)可以引起脑出血、癫痫甚至死亡。目前疾病进展和出血机制不祥，且无有效的药物治疗。申请人对CCM进行长期深入的研究，证实B细胞在CCM中的作用，而T细胞调节的免疫反应在疾病中的作用不详。我们发现病变内的T细胞被活化及相关细胞因子可能与内皮细胞(ECs)凋亡、GLI2/KLF4轴等相关。因此我们假设病变中的T细胞被活化，并通过多种途径引起ECs损伤，同时激活GLI2/KLF4轴，增加ECs渗透性，促进CCM进展和出血。本课题拟研究：1、人CCM病变中T细胞是寡克隆扩增；2、T细胞参与ECs凋亡损伤；3、T细胞介导的免疫反应激活GLI2/KLF4轴，影响ECs增殖、内皮间质转化和渗透性，促使CCM进展和出血；4、阻断T细胞调节的免疫反应，可以逆转CCM进展和出血。本研究从新的角度，探讨T细胞调节的免疫反应在CCM中的作用，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) predisposes patients to a risk of a cerebral hemorrhage, epilepsy, and even death. The molecular mechanisms involved in the pathophysiology of CCM lesional growth and hemorrhage await further characterization. There is no known drug therapy to alter the course of this disease. The applicant has deeply engaged in clarifying immune response within the CCM disease for many years. We have demonstrated that B cells play a role in the CCM disease. However, the role of T cells within CCM disease remains unclear. Our studies showed the activation of T cells and their cytokines may relate to endothelial apoptosis, and GLI2/KLF4 axis. We hypothesize that T cells within CCM lesions are activated. Those activated T cells could cause endothelium injury in the CCM lesions via the multiple pathways, increasing vascular endothelial proliferation and permeability via the activation of GLI2/KLF4 axis, promoting lesional growth and hemorrhage. Our proposal will investigate: 1) T cells aggregated in the CCM lesions are oligoclonal expansion. 2) T cells are involved in the apoptotic injury of endothelial cells in the CCM lesions. 3) T cells mediated immune response activates the GLI2/KLF4 axis, promoting endothelial proliferation, EndMT, and permeability, thus leading to CCM lesional growth and hemorrhage. 4) In vivo, inhibition of T cells mediated immune response could rescue the CCM lesional growth and hemorrhage. This project, from a novel perspective, explores the mechanistic implications of T cells mediated immune response in the CCM disease. It lays a theoretical foundation to apply immunotherapy in this disease and provides novel targets for treating this disease. This project has a certain clinical translational meaning.