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

视神经脊髓炎谱系障碍（NMOSD）是慢性致残性中枢神经系统自身免疫性疾病。以前认为是多发性硬化症的一种变体，其特征是视神经和脊髓的严重和复发性影响，最近在大约70%的NMOSD患者中，水通道蛋白-4 （AQP4）被确定为体液免疫反应的靶抗原。AQP4是星形细胞端足高度表达的水通道，因此定位于紧邻脑毛细血管。这些患者的早期NMO病变的特征是免疫介导的星形胶质细胞破坏和AQP4表达减少。通过磁共振成像（MRI）， NMOSD患者的中枢神经系统病变显示钆- dtpa延长和强化强化，表明血脑屏障（BBB）严重破坏。在本项目中，我们努力确定NMOSD中与抗aqp4自身免疫相关的血脑屏障破坏的时间过程和细胞和分子介质。我们将利用基于局灶性脑内注射重组人抗aqp4抗体到啮齿动物的实验模型，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病变诱导中起主要作用。通过对血脑屏障进行功能和分子评估的药理学和遗传学操作，我们将深入了解NMOSD中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NMOSD患者的活检和尸检组织中得到验证。

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.