encephalitis patient derived monoclonal gabaa receptor antibodies cause epileptic seizures

• DOI: 10.1084/jem.20210012
• Publication Date: 2021-01-01
• Authors: Masaki Fukata; Masaki Fukata; Divya R Dhangar; Sukhvir Wright; Sukhvir Wright; Adriana van Casteren; Stuart D. Greenhill; S. Momsen Reincke; Scott van Hoof; Scott van Hoof; Scott van Hoof; Marie-Luise Machule; Marie-Luise Machule; Susanne Mueller; Laura Stöffler; Laura Stöffler; César Cordero Gómez; César Cordero Gómez; Angela M. Kaindl; Dietmar Schmitz; Dietmar Schmitz; Paul Turko; Philipp Boehm-Sturm; Gavin L. Woodhall; Marie A Homeyer; Marie A Homeyer; Yuko Fukata; Yuko Fukata; Elisa Sanchez-Sendin; Elisa Sanchez-Sendin; Elisa Sanchez-Sendin; Harald Prüss; Harald Prüss; Harald Prüss; Manoj A. Upadhya; Christian Geis; Jonathan Wickel; Imre Vida; Max A Wilson; Marc Nikolaus; Marc Nikolaus; Hans-Christian Ko...; Hans-Christian Ko...; Craig C. Garner; Jakob Kreye
• Keywords: immunology [Autoantigens]; immunology [Seizures]; Autoantigens; Hippocampus; Article; Mice; Seizures; immunology [Autoantibodies]; immunology [Receptors, GABA-A]; Animals; Humans; ddc:610; immunology [Encephalitis]; Cells, Cultured; immunology [Hippocampus]; Autoantibodies; Neurons; Epilepsy; Antibodies, Monoclonal; Receptors, GABA-A; immunology [Antibodies, Monoclonal]; HEK293 Cells; immunology [Epilepsy]; Encephalitis; immunology [Neurons]; Function and Dysfunction of the Nervous System

Autoantibodies targeting the GABAA receptor (GABAAR) 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 GABAAR 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 GABAAR 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 GABAARs independent of Fc-mediated effector functions and provide an animal model for GABAAR 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.