Neuroscience and Medical Scientist Training Programs.
Department of Neurology, and.
J Clin Invest. 2019 Apr 8;129(5):2000-2013. doi: 10.1172/JCI122942.
Neuromyelitis optica (NMO) is an autoimmune CNS disorder mediated by pathogenic aquaporin-4 (AQP4) water channel autoantibodies (AQP4-IgG). Although AQP4-IgG-driven complement-dependent cytotoxicity (CDC) is critical for the formation of NMO lesions, the molecular mechanisms governing optimal classical pathway activation are unknown. We investigated the molecular determinants driving CDC in NMO using recombinant AQP4-specific autoantibodies (AQP4 rAbs) derived from affected patients. We identified a group of AQP4 rAbs targeting a distinct extracellular loop C epitope that demonstrated enhanced CDC on target cells. Targeted mutations of AQP4 rAb Fc domains that enhance or diminish C1q binding or antibody Fc-Fc interactions showed that optimal CDC was driven by the assembly of multimeric rAb platforms that increase multivalent C1q binding and facilitate C1q activation. A peptide that blocks antibody Fc-Fc interaction inhibited CDC induced by AQP4 rAbs and polyclonal NMO patient sera. Super-resolution microscopy revealed that AQP4 rAbs with enhanced CDC preferentially formed organized clusters on supramolecular AQP4 orthogonal arrays, linking epitope-dependent multimeric assembly with enhanced C1q binding and activation. The resulting model of AQP4-IgG CDC provides a framework for understanding classical complement activation in human autoantibody-mediated disorders and identifies a potential new therapeutic avenue for treating NMO.
视神经脊髓炎（NMO）是一种由水通道蛋白 4（AQP4）自身抗体（AQP4-IgG）介导的自身免疫性中枢神经系统疾病。虽然 AQP4-IgG 驱动的补体依赖性细胞毒性（CDC）对于 NMO 病变的形成至关重要，但调控最佳经典途径激活的分子机制尚不清楚。我们使用源自患者的重组 AQP4 特异性自身抗体（AQP4 rAbs）来研究 NMO 中 CDC 的分子决定因素。我们鉴定了一组针对独特的细胞外环 C 表位的 AQP4 rAbs，这些 rAbs 在靶细胞上显示出增强的 CDC。靶向改变 AQP4 rAb Fc 结构域，增强或减弱 C1q 结合或抗体 Fc-Fc 相互作用，结果表明最佳的 CDC 是由增加多价 C1q 结合并促进 C1q 激活的多聚体 rAb 平台组装驱动的。阻断抗体 Fc-Fc 相互作用的肽抑制了 AQP4 rAbs 和多克隆 NMO 患者血清诱导的 CDC。超分辨率显微镜显示，具有增强的 CDC 的 AQP4 rAbs 优先在超分子 AQP4 正交阵列上形成有组织的簇，将表位依赖性多聚体组装与增强的 C1q 结合和激活联系起来。AQP4-IgG CDC 的模型为理解人类自身抗体介导的疾病中的经典补体激活提供了一个框架，并确定了治疗 NMO 的潜在新治疗途径。
