Departments of Medicine and Physiology, University of California, 1246 Health Sciences East Tower, 513 Parnassus Ave, San Francisco, CA, 94143-0521, USA.
Department of Neurology, Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
Acta Neuropathol Commun. 2019 Jul 11;7(1):112. doi: 10.1186/s40478-019-0766-7.
Cellular injury in AQP4-IgG seropositive neuromyelitis spectrum disorder (herein called NMO) involves AQP4-IgG binding to astrocytes, resulting in astrocyte injury by complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) mechanisms. The rapid disease progression, severe tissue damage, and abundant leukocyte infiltration seen in some NMO patients suggest a more direct mechanism for demyelination and neurologic deficit than secondary injury from astrocyte loss. Here, we report evidence for an 'ADCC bystander mechanism' in NMO involving injury to nearby cells by leukocytes following their activation by AQP4-bound AQP4-IgG on astrocytes. In model cocultures containing AQP4-expressing and null CHO cells, AQP4-IgG and complement killed bystander null cells to ~ 100 μm away from AQP4-expressing cells; AQP4-IgG and NK cells produced bystander killing to ~ 300 μm, with perforin deposition seen on injured null cells. Bystander cytotoxicity was also seen with neutrophil-mediated ADCC and in astrocyte-neuron cocultures. Mechanistic studies, including real-time imaging, suggested that leukocytes activated by an AQP4-dependent ADCC mechanism injure bystander cells by direct targeted exocytosis on neighboring cells and not by diffusion of soluble granule contents. In support of this conclusion, ADCC bystander injury was preferentially reduced by an RGDS peptide that inhibits integrin adhesion. Evidence for ADCC bystander injury to oligodendrocytes and neurons was also found in mice following intracerebral injection of AQP4-IgG and NK cells, which was inhibited by RGDS peptide. These results establish a novel cellular pathogenesis mechanism in AQP4-IgG seropositive NMO and provide evidence that inflammatory mechanisms can cause widespread tissue damage in NMO independently of the secondary effects from astrocyte loss.
AQP4-IgG 阳性视神经脊髓炎谱系疾病（以下简称 NMO）中的细胞损伤涉及 AQP4-IgG 与星形胶质细胞结合，通过补体依赖性细胞毒性（CDC）和抗体依赖性细胞毒性（ADCC）机制导致星形胶质细胞损伤。一些 NMO 患者的疾病快速进展、严重组织损伤和大量白细胞浸润表明，脱髓鞘和神经功能缺损的机制比星形胶质细胞丢失引起的继发性损伤更为直接。在这里，我们报告了 NMO 中存在“ADCC 旁观者机制”的证据，涉及到白细胞在被 AQP4 结合的 AQP4-IgG 激活后，通过与星形胶质细胞上的 AQP4 结合的 AQP4-IgG 对附近细胞造成损伤。在包含表达 AQP4 和无 AQP4 的 CHO 细胞的模型共培养物中，AQP4-IgG 和补体可杀死距离表达 AQP4 的细胞 100μm 以外的无 AQP4 细胞；AQP4-IgG 和 NK 细胞产生的旁观者杀伤距离为 300μm，损伤的无 AQP4 细胞上可见穿孔素沉积。中性粒细胞介导的 ADCC 和星形胶质细胞-神经元共培养物中也观察到旁观者细胞毒性。包括实时成像在内的机制研究表明，通过 AQP4 依赖性 ADCC 机制激活的白细胞通过直接针对邻近细胞的靶向胞吐作用而不是通过可溶性颗粒内容物的扩散来损伤旁观者细胞。支持这一结论的是，通过抑制整合素粘附的 RGDS 肽优先减少了 ADCC 旁观者损伤。在向脑内注射 AQP4-IgG 和 NK 细胞后，在小鼠中也发现了对少突胶质细胞和神经元的 ADCC 旁观者损伤的证据，该损伤可被 RGDS 肽抑制。这些结果确立了 AQP4-IgG 阳性 NMO 中的一种新型细胞发病机制，并提供了证据表明炎症机制可以独立于星形胶质细胞丢失的继发效应，导致 NMO 中广泛的组织损伤。
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