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@ARTICLE{Kreye:162857,
author = {Kreye, Jakob and Wright, Sukhvir K and Casteren, Adriana
and Stöffler, Laura and Machule, Marie-Luise and Reincke,
Momsen and Nikolaus, Marc and Hoof, Scott and Sanchez
Sendin, Elisa and Homeyer, Marie Alice and Cordero Gomez,
Cesar and Kornau, Hans-Christian and Schmitz, Dietmar and
Kaindl, Angela M and Boehm-Sturm, Philipp and Mueller,
Susanne and Wilson, Max A and Upadhya, Manoj A and Dhangar,
Divya R and Greenhill, Stuart and Woodhall, Gavin and Turko,
Paul and Vida, Imre and Garner, Craig Curtis and Wickel,
Jonathan and Geis, Christian and Fukata, Yuko and Fukata,
Masaki and Prüß, Harald},
title = {{E}ncephalitis patient-derived monoclonal {GABAA} receptor
antibodies cause epileptic seizures.},
journal = {Journal of experimental medicine},
volume = {218},
number = {11},
issn = {0022-1007},
address = {New York, NY},
publisher = {Rockefeller Univ. Press},
reportid = {DZNE-2021-01512},
pages = {e20210012},
year = {2021},
abstract = {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.},
keywords = {Animals / Antibodies, Monoclonal: immunology /
Autoantibodies: immunology / Autoantigens: immunology /
Cells, Cultured / Encephalitis: immunology / Epilepsy:
immunology / HEK293 Cells / Hippocampus: immunology / Humans
/ Mice / Neurons: immunology / Receptors, GABA-A: immunology
/ Seizures: immunology},
cin = {AG Prüß / AG Garner / AG Schmitz},
ddc = {610},
cid = {I:(DE-2719)1810003 / I:(DE-2719)1810001 /
I:(DE-2719)1810004},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 351 -
Brain Function (POF4-351)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34546336},
pmc = {pmc:PMC8480667},
doi = {10.1084/jem.20210012},
url = {https://pub.dzne.de/record/162857},
}