Low expression of complement inhibitory protein CD59 contributes to humoral autoimmunity against astrocytes.
Low expression of complement inhibitory protein CD59 contributes to humoral autoimmunity against astrocytes.
复制标题
补体抑制蛋白 CD59 的低表达有助于针对星形胶质细胞的体液自身免疫
DOI：
10.1016/j.bbi.2017.04.023
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Yan Yaping
中科院分区：
文献类型：
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作者：
Wang Zhen;Guo Wen;Liu Yuanchu;Gong Ye;Ding Xiaoli;Shi Kaibin;Thome Rodolfo;Zhang Guang-Xian;Shi Fu-Dong;Yan Yaping
视神经肌萎缩症谱系障碍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限制性通道病。尽管自身抗原水通道蛋白4广泛分布于中枢神经系统和外周器官，但患者经常发生中枢神经系统限制性病变。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，补体膜攻击复合物的抑制性调节剂，表达和共定位与水通道蛋白4在外周器官，但只有最低限度地表达在中枢神经系统的星形胶质细胞。此外，我们进一步发现小鼠脑中CD59过表达减少了脱髓鞘，阻断了星形胶质细胞和水通道蛋白4的丢失，并抑制了膜攻击复合物的形成和炎性细胞的浸润。小鼠外周水通道蛋白4表达细胞和组织中CD59的失活导致补体依赖性细胞毒性。与小鼠数据一致，人样品在许多水通道蛋白4表达外周组织中呈现出较高的CD59表达，但在星形胶质细胞中没有。沉默或阻断表达水通道蛋白4的人气管上皮细胞和骨骼肌细胞中的CD59诱导膜攻击复合物形成和细胞毒性，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，星形胶质细胞中的低表达CD59可能有助于中枢神经系统限制性病变的视神经肌萎缩症谱系障碍。恢复星形胶质细胞中的CD59表达可能作为神经肌病谱系障碍的新治疗靶点。
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.