Neuromyelitis optica (NMO) is an autoimmune disease that primarily targets astrocytes. Autoantibodies (NMO-IgG) against the water channel protein, aquaporin 4 (AQP4), are a serologic marker in NMO patients, and they are known to be responsible for the pathophysiology of the disease. In the brain, AQP4 is mainly expressed in astrocytes, especially at the end-feet, where they form the blood-brain barrier. Following the interaction between NMO-IgG and AQP4 in astrocytes, rapid AQP4 endocytosis initiates pathogenesis. However, the cellular and molecular mechanisms of astrocyte destruction by autoantibodies remain largely elusive. We established an in vitro human astrocyte model system using induced pluripotent stem cells (iPSCs) technology in combination with NMO patient-derived serum and IgG to elucidate the cellular and functional changes caused by NMO-IgG. Herein, we observed that NMO-IgG induces structural alterations in mitochondria and their association with the endoplasmic reticulum (ER) and lysosomes at the ultrastructural level, which potentially leads to impaired mitochondrial functions and dynamics. Indeed, human astrocytes display impaired mitochondrial bioenergetics and autophagy activity in the presence of NMO-IgG. We further demonstrated NMO-IgG-driven ER membrane deformation into a multilamellar structure in human astrocytes. Together, we show that NMO-IgG rearranges cellular organelles and alter their functions and that our in vitro system using human iPSCs offers previously unavailable experimental opportunities to study the pathophysiological mechanisms of NMO in human astrocytes or conduct large-scale screening for potential therapeutic compounds targeting astrocytic abnormalities in patients with NMO.

中文翻译：

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人 iPSC 衍生星形胶质细胞中的视神经脊髓炎 (NMO)-IgG 驱动的细胞器重组

视神经脊髓炎 (NMO) 是一种主要针对星形胶质细胞的自身免疫性疾病。针对水通道蛋白水通道蛋白 4 (AQP4) 的自身抗体 (NMO-IgG) 是 NMO 患者的血清学标志物，并且已知它们与该疾病的病理生理学有关。在大脑中，AQP4 主要在星形胶质细胞中表达，尤其是在足底，它们在那里形成血脑屏障。在星形胶质细胞中 NMO-IgG 和 AQP4 相互作用后，快速的 AQP4 内吞作用启动发病机制。然而，自身抗体破坏星形胶质细胞的细胞和分子机制在很大程度上仍然难以捉摸。我们使用诱导多能干细胞 (iPSCs) 技术结合 NMO 患者来源血清和 IgG 建立了体外人星形胶质细胞模型系统，以阐明 NMO-IgG 引起的细胞和功能变化。在此，我们观察到 NMO-IgG 在超微结构水平上诱导线粒体结构改变及其与内质网 (ER) 和溶酶体的关联，这可能导致线粒体功能和动力学受损。事实上，在 NMO-IgG 存在的情况下，人星形胶质细胞表现出受损的线粒体生物能学和自噬活性。我们进一步证明了 NMO-IgG 驱动的 ER 膜变形为人星形胶质细胞的多层结构。一起，