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

抗 AQP4 抗体介导的视神经脊髓炎血脑屏障破坏的细胞和分子机制

• 批准号: 391468659
• 负责人: Professorin Dr. Christine Stadelmann-Nessler
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/391468659?language=en
• 关键词: Cellular; molecular; mechanisms; blood; brain

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.

神经瘤性频谱疾病（NMOSD）是慢性禁用CNS自身免疫性疾病。先前被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，Aquaporin-4（AQP4）最近被确定为大约70％NMOSD患者的体液免疫反应的靶抗原。 AQP4是在星形胶质细胞末端高表达的水通道，因此位于脑毛细血管附近的位置。这些患者中的早期NMO病变的特征是免疫介导的星形胶质细胞破坏并减少了AQP4的表达。通过磁共振成像（MRI），NMOSD患者的CNS病变表现出长时间的延长且用gadolinium-dtpa增强，表明了血液中的大脑（BBB）（BBB）（BBB）的增强。在本项目中，我们努力确定与抗AQP4自身免疫相关的NMOSD中BBB破坏的时间过程，细胞和分子介体。我们将利用基于重组人类抗AQP4抗体的局灶性脑内注射到啮齿动物中的特征良好的实验模型，从而再现了人类疾病的关键特征。在此模型中获得的初步结果表明，粒细胞可能在破坏BBB并促进NMOSD病变诱导方面起主要作用。通过应用药理和遗传操作，伴随着对BBB的功能和分子评估，我们将深入了解NMOSD中BBB破坏和病变形成的机制，以及粒细胞对这些过程的贡献。实验结果将在表征良好的抗AQP4序列阳性NMOSD患者的活检和尸检组织上进​​行验证。