Cellular and molecular mechanisms of blood-brain barrier disruption in anti-AQP4-antibody mediated neuromyelitis optica

视神经脊髓炎谱系疾病(NMOSD)是一种慢性致残性中枢神经系统自身免疫性疾病。水通道蛋白-4(Aquaporin-4，AQP4)以前被认为是多发性硬化症的一种变异体，其特征是严重的和反复的视神经和脊髓病变，最近在大约70%的NMOSD患者中被确定为体液免疫反应的靶抗原。AQP4是一种在星形细胞末端足部高度表达的水通道，因此定位于紧邻脑毛细血管的位置。这些患者早期的NMO损害以免疫介导的星形胶质细胞破坏和AQP4表达减少为特征。通过磁共振成像(MRI)，NMOSD患者的中枢神经系统损害显示Gd-DTPA持续且强化的强化，表明血脑屏障(BBB)的主要破坏。在本项目中，我们致力于确定与抗AQP4自身免疫相关的NMOSD中血脑屏障破坏的时间进程和细胞和分子介质。我们将利用一个特征良好的实验模型，该模型基于局部脑内注射重组人抗AQP4抗体到啮齿动物体内，再现人类疾病的关键特征。在该模型中获得的初步结果表明，粒细胞可能在破坏血脑屏障和促进NMOSD损伤诱导方面发挥主要作用。通过应用药理学和遗传操作，结合对血脑屏障的功能和分子评估，我们将深入了解NMOSD的血脑屏障破坏和病变形成的机制，以及粒细胞在这些过程中的作用。实验结果将在具有良好特征的抗AQP4血清阳性的NMOSD患者的活检和尸检组织上得到验证。

Neuromyelitis optica spectrum disorders (NMOSD) are chronic disabling CNS autoimmune diseases. Previously regarded a variant of multiple sclerosis characterized by severe and recurrent affection of the optic nerves and spinal cord, aquaporin-4 (AQP4) has recently been identified as the target antigen of the humoral immune response in around 70% of the patients with NMOSD. AQP4 is a water channel highly expressed on astrocytic end-feet and thus localized immediately adjacent to brain capillaries. Early NMO lesions in these patients are characterized by immune-mediated destruction of astrocytes and diminished AQP4 expression.By magnetic resonance imaging (MRI), CNS lesions of patients with NMOSD show a prolonged and intensified enhancement with gadolinium-DTPA, indicating a major disruption of the blood-brain barrier (BBB). In the present project, we strive to determine the time course and cellular and molecular mediators of BBB disruption in NMOSD related to anti-AQP4 autoimmunity. We will take advantage of a well-characterized experimental model based on focal intracerebral injection of recombinant human anti-AQP4 antibodies into rodents, reproducing key features of the human disease. Preliminary results obtained in this model indicate that granulocytes might play a major role in disrupting the BBB and facilitating NMOSD lesion induction. By applying pharmacologic and genetic manipulations accompanied by functional and molecular assessment of the BBB, we will gain insights into the mechanisms of BBB disruption and lesion formation in NMOSD and the contribution of granulocytes to these processes. Experimental results will be validated on biopsy and autopsy tissue from well characterized anti-AQP4-seropositive NMOSD patients.