膜锚定补体调节蛋白CD59在视神经脊髓炎中枢神经系统特异性病灶形成中的作用研究

视神经脊髓炎（NMO）是以体液免疫为主介导的中枢神经系统（CNS）自身免疫病，星形胶质细胞水通道蛋白AQP4是患者自身抗体攻击的主要靶抗原。然而，AQP4在机体多个组织广泛存在，但NMO患者却只出现CNS特异性病灶。膜锚定补体调节蛋白会保护细胞免受抗体和补体介导的攻击，据此我们推测星形胶质细胞由于受血脑屏障保护，细胞上的膜锚定补体调节蛋白逐渐退化缺失可能导致了NMO中CNS特异性病灶的形成。我们初步研究发现膜锚定补体调节蛋白CD59在星形胶质细胞上特异性缺失。因此，本研究将系统比较人和小鼠中CD59在不同组织AQP4表达细胞中的表达，利用动物模型探讨星形胶质细胞过表达及其它组织细胞敲低CD59分子对AQP4抗体和补体介导的细胞杀伤作用的影响，明确CD59在NMO的CNS特异性病灶形成中的作用，为阐明NMO疾病CNS特异性病灶形成这一科学问题提供答案，研究结果也将为NMO的治疗发现新的靶点。

Neuromyelitis optica (NMO) is a humoral immunity-mediated central nervous system (CNS) autoimmune disease. The astrocytic water channel protein AQP4 is the major target for autoantibody mediated astrocytes damage. Although AQP4 is widely expressed on different tissues and cells, the NMO patients only have CNS-restricted lesions. It has been reported that the membrane-bounded complement regulatory proteins may protect the cells from antibody and complement mediated cell damage, we hypothesize that the blood-brain-barrier will protect the CNS cell from antibody and complement attacking and the astrocytes will lose membrane-bounded complement regulatory proteins due to the protection during evolution. Our preliminary data have proved that one of the membrane-bounded complement regulatory proteins, CD59, is specifically lost in astrocytes and this observation partially proved our hypothesis. In this project, we aim to systematically compare the expression of CD59 between different AQP4-expressing cell and tissues both in human and mouse. We will also test the effect of AQP4 autoantibody with complement mediated cell damage when overexpressing CD59 in astrocytes or knocking down its expression in other AQP4-bearing cells and tissues in animal model. The results of this project will help to answer the scientific question that why AQP4 antibody with complement mediated NMO is a CNS lesion restricted autoimmune disease. The observation will also help to identify novel therapeutic target.