Encephalitis patient-derived monoclonal GABA(A) receptor antibodies cause epileptic seizures
JOURNAL OF EXPERIMENTAL MEDICINE(2021)
摘要
Autoantibodies targeting the GABA(A) receptor (GABA(A)R) 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(A)R mAbs from cerebrospinal fluid cells bound to various epitopes involving the alpha 1 and gamma 2 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(A)R 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(A)Rs independent of Fc-mediated effector functions and provide an animal model for GABA(A)R 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.
更多查看译文
关键词
monoclonal gabaa receptor,epileptic seizures,antibodies,patient-derived
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要