Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710000, China.
Brain Behav Immun. 2017 Oct;65:173-182. doi: 10.1016/j.bbi.2017.04.023. Epub 2017 May 2.
Neuromyelitis optica spectrum disorder is primarily an anti-aquaporin 4 autoantibody-mediated, central nervous system-restricted channelopathy. Patients frequently develop central nervous system-restricted lesions even though autoantigen aquaporin 4 in neuromyelitis optica spectrum disorder is broadly distributed in the central nervous system and peripheral organs. The cause of such tissue-specific immune response remains largely unknown. We confirmed here that CD59, an inhibitory regulator of the complement membrane attack complex, is expressed and co-localized with aquaporin 4 in peripheral organs but is only minimally expressed in astrocytes in the central nervous system. In addition, we further found that CD59 overexpression in mouse brains decreased demyelination, blocked the loss of astrocytes and aquaporin 4, and inhibited membrane attack complex formation and infiltration of inflammatory cells. Inactivation of CD59 in mouse peripheral aquaporin 4-expressing cells and tissues led to complement-dependent cytotoxicity. In accordance with the mouse data, human samples presented higher expression of CD59 in many aquaporin 4-expressing peripheral tissues but not in astrocytes. Silencing or blocking CD59 in aquaporin 4-expressing human tracheal epithelial and skeletal muscle cells induced membrane attack complex formation and cytotoxicity, which suggests a protective role of CD59 in anti-aquaporin 4 antibodies-mediated complement toxicity. Our findings suggest that low CD59 expression in astrocytes may contribute to central nervous system-restricted lesions in neuromyelitis optica spectrum disorder. Restoring CD59 expression in astrocytes may serve as a novel therapeutic target of neuromyelitis optica spectrum disorder.
视神经脊髓炎谱系疾病主要是一种抗水通道蛋白 4 自身抗体介导的、中枢神经系统受限的通道病。尽管视神经脊髓炎谱系疾病中的自身抗原水通道蛋白 4 在中枢神经系统和外周器官中广泛分布，但患者经常会出现中枢神经系统受限的病变。这种组织特异性免疫反应的原因在很大程度上仍然未知。我们在这里证实，CD59 是补体膜攻击复合物的抑制调节因子，在外周器官中表达并与水通道蛋白 4 共定位，但在中枢神经系统中的星形胶质细胞中仅微量表达。此外，我们还进一步发现，在小鼠大脑中过表达 CD59 可减少脱髓鞘、阻止星形胶质细胞和水通道蛋白 4 的丢失，并抑制膜攻击复合物的形成和炎症细胞的浸润。在小鼠外周表达水通道蛋白 4 的细胞和组织中失活 CD59 会导致补体依赖性细胞毒性。与小鼠数据一致，人类样本在许多表达水通道蛋白 4 的外周组织中表达更高的 CD59，但在星形胶质细胞中则不然。在表达水通道蛋白 4 的人气管上皮细胞和骨骼肌细胞中沉默或阻断 CD59 会诱导膜攻击复合物的形成和细胞毒性，这表明 CD59 在抗水通道蛋白 4 抗体介导的补体毒性中具有保护作用。我们的研究结果表明，星形胶质细胞中 CD59 的低表达可能导致视神经脊髓炎谱系疾病中的中枢神经系统受限病变。恢复星形胶质细胞中的 CD59 表达可能成为视神经脊髓炎谱系疾病的一种新的治疗靶点。
