Autoantibodies targeting the GABA_A receptor (GABA_AR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient-derived mAbs. Five GABA_AR mAbs from cerebrospinal fluid cells bound to various epitopes involving the α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABA_AR mAbs and Fab fragments into rodents induced a severe phenotype with seizures and increased mortality, reminiscent of encephalitis patients’ symptoms. Our results demonstrate direct pathogenicity of autoantibodies on GABA_ARs independent of Fc-mediated effector functions and provide an animal model for GABA_AR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and can serve as tools for the development of antibody-selective immunotherapies.

中文翻译：

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脑炎患者来源的单克隆 GABA A 受体抗体导致癫痫发作

靶向 GABA _A受体 (GABA _A R) 的自身抗体标志着一种自身免疫性脑炎，表现为频繁的癫痫发作和精神运动异常。鉴于与其他自身抗体的常见重叠以及缺乏来自患者的 mAb，它们的致病作用仍未明确定义。来自脑脊液细胞的五种 GABA _{A R mAb 与涉及 α1 和 γ2 受体亚基的各种表位结合，具有可变的结合强度和部分竞争性。}mAb 选择性地降低神经元培养物中的 GABA 能电流，而不会导致受体内化。脑室输注 GABA _AR mAbs 和 Fab 片段进入啮齿动物会引起严重的癫痫发作和死亡率增加的表型，这让人想起脑炎患者的症状。_{我们的结果证明了 GABA A} Rs自身抗体的直接致病性独立于 Fc 介导的效应功能，并提供了 GABA _A R 脑炎的动物模型。它们进一步为使用抗体耗竭的临床治疗提供科学依据，并可作为开发抗体选择性免疫疗法的工具。