Department of Medicine, University of California, San Francisco, CA, USA; Department of Physiology, University of California, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, CA, USA; Department of Physiology, University of California, San Francisco, CA, USA.
Exp Neurol. 2014 May;255:145-53. doi: 10.1016/j.expneurol.2014.03.004. Epub 2014 Mar 14.
Neuromyelitis optica (NMO) pathogenesis involves binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) present in serum to AQP4 on astrocytes, which causes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Human immunoglobulin G (hIgG) is effective for treatment of humorally mediated neurological autoimmune diseases and has been reported to improve disease outcome in a limited number of NMO patients. Here, we investigated hIgG actions on NMO-IgG pathogenicity using an in vivo rat model of NMO and in vitro assays. In rats administered NMO-IgG by intracerebral injection, the size of neuroinflammatory demyelinating lesions was reduced by ~50% when hIgG was administered by intraperitoneal injection to reach levels of 10-25mg/mL in rat serum, comparable with human therapeutic levels. In vitro, hIgG at 10mg/mL reduced by 90% NMO-IgG-mediated CDC following addition of NMO-IgG and human complement to AQP4-expressing cells. The hIgG effect was mainly on the classical complement pathway. hIgG at 10mg/mL also reduced by up to 90% NMO-IgG-mediated ADCC as assayed with human natural killer cells as effector cells. However, hIgG at up to 40mg/mL did not affect AQP4 cell surface expression or its supramolecular assembly in orthogonal arrays of particles, nor did it affect NMO-IgG binding to AQP4. We conclude that hIgG reduces NMO-IgG pathogenicity by inhibition of CDC and ADCC, providing a mechanistic basis to support further clinical evaluation of its therapeutic efficacy in NMO.
视神经脊髓炎（NMO）的发病机制涉及血清中存在的抗水通道蛋白-4（AQP4）自身抗体（NMO-IgG）与星形胶质细胞上的 AQP4 结合，导致补体依赖性细胞毒性（CDC）和抗体依赖性细胞毒性（ADCC）。人免疫球蛋白 G（hIgG）可有效治疗体液介导的神经自身免疫性疾病，并已报道在有限数量的 NMO 患者中改善疾病结局。在这里，我们使用 NMO 的体内大鼠模型和体外测定研究了 hIgG 对 NMO-IgG 致病性的作用。在通过脑内注射给予 NMO-IgG 的大鼠中，当通过腹腔内注射给予 hIgG 以达到大鼠血清中 10-25mg/mL 的水平时，神经炎症性脱髓鞘病变的大小减少了约 50%，与人类治疗水平相当。在体外，当将 NMO-IgG 和人补体添加到表达 AQP4 的细胞中时，hIgG 在 10mg/mL 时可将 NMO-IgG 介导的 CDC 减少 90%。hIgG 的作用主要在经典补体途径上。当用人自然杀伤细胞作为效应细胞进行测定时，hIgG 在 10mg/mL 时还可将 NMO-IgG 介导的 ADCC 减少高达 90%。然而，hIgG 高达 40mg/mL 时不会影响 AQP4 细胞表面表达或其在正交排列的颗粒中的超分子组装，也不会影响 NMO-IgG 与 AQP4 的结合。我们得出结论，hIgG 通过抑制 CDC 和 ADCC 来降低 NMO-IgG 的致病性，为支持进一步评估其在 NMO 中的治疗效果的临床评价提供了机制基础。
