TY  - JOUR
AU  - Kreye, Jakob
AU  - Wright, Sukhvir K
AU  - Casteren, Adriana
AU  - Stöffler, Laura
AU  - Machule, Marie-Luise
AU  - Reincke, Momsen
AU  - Nikolaus, Marc
AU  - Hoof, Scott
AU  - Sanchez Sendin, Elisa
AU  - Homeyer, Marie Alice
AU  - Cordero Gomez, Cesar
AU  - Kornau, Hans-Christian
AU  - Schmitz, Dietmar
AU  - Kaindl, Angela M
AU  - Boehm-Sturm, Philipp
AU  - Mueller, Susanne
AU  - Wilson, Max A
AU  - Upadhya, Manoj A
AU  - Dhangar, Divya R
AU  - Greenhill, Stuart
AU  - Woodhall, Gavin
AU  - Turko, Paul
AU  - Vida, Imre
AU  - Garner, Craig Curtis
AU  - Wickel, Jonathan
AU  - Geis, Christian
AU  - Fukata, Yuko
AU  - Fukata, Masaki
AU  - Prüß, Harald
TI  - Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures.
JO  - Journal of experimental medicine
VL  - 218
IS  - 11
SN  - 0022-1007
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DZNE-2021-01512
SP  - e20210012
PY  - 2021
AB  - 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.
KW  - Animals
KW  - Antibodies, Monoclonal: immunology
KW  - Autoantibodies: immunology
KW  - Autoantigens: immunology
KW  - Cells, Cultured
KW  - Encephalitis: immunology
KW  - Epilepsy: immunology
KW  - HEK293 Cells
KW  - Hippocampus: immunology
KW  - Humans
KW  - Mice
KW  - Neurons: immunology
KW  - Receptors, GABA-A: immunology
KW  - Seizures: immunology
LB  - PUB:(DE-HGF)16
C6  - pmid:34546336
C2  - pmc:PMC8480667
DO  - DOI:10.1084/jem.20210012
UR  - https://pub.dzne.de/record/162857
ER  -