162857 20240221145957.0 pmid:34546336 pmid pmc:PMC8480667 pmc 0022-1007 ISSN 1540-9358 ISSN 1540-9538 ISSN altmetric:114113592 altmetric 10.1084/jem.20210012 doi DZNE-2021-01512 English 610 Kreye, Jakob P:(DE-2719)2811468 0 First author Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures. New York, NY 2021 Rockefeller Univ. Press article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1708523975_22067 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 0 351 - Brain Function (POF4-351) G:(DE-HGF)POF4-351 POF4-351 POF IV 1 Dataset connected to DataCite, PubMed, , Journals: pub.dzne.de Animals MeSH Antibodies, Monoclonal: immunology MeSH Autoantibodies: immunology MeSH Autoantigens: immunology MeSH Cells, Cultured MeSH Encephalitis: immunology MeSH Epilepsy: immunology MeSH HEK293 Cells MeSH Hippocampus: immunology MeSH Humans MeSH Mice MeSH Neurons: immunology MeSH Receptors, GABA-A: immunology MeSH Seizures: immunology MeSH Wright, Sukhvir K 0000-0002-5464-3779 1 Casteren, Adriana P:(DE-2719)2814218 2 Stöffler, Laura 0000-0003-4724-5112 3 Machule, Marie-Luise P:(DE-2719)2812697 4 Reincke, Momsen P:(DE-2719)2812526 5 Nikolaus, Marc 0000-0002-3678-5159 6 Hoof, Scott P:(DE-2719)2812820 7 Sanchez Sendin, Elisa P:(DE-2719)2812653 8 Homeyer, Marie Alice P:(DE-2719)9001962 9 dzne Cordero Gomez, Cesar P:(DE-2719)9001947 10 dzne Kornau, Hans-Christian P:(DE-2719)2811900 11 Schmitz, Dietmar P:(DE-2719)2810725 12 Kaindl, Angela M 0000-0001-9454-206X 13 Boehm-Sturm, Philipp 0000-0001-8777-4823 14 Mueller, Susanne 0000-0002-5053-2211 15 Wilson, Max A 0000-0003-3317-9433 16 Upadhya, Manoj A 0000-0002-2032-1472 17 Dhangar, Divya R 0000-0002-0363-627X 18 Greenhill, Stuart 0000-0002-5038-5258 19 Woodhall, Gavin 0000-0003-1281-9008 20 Turko, Paul 0000-0002-1305-6711 21 Vida, Imre 0000-0003-3214-2233 22 Garner, Craig Curtis P:(DE-2719)2810922 23 Wickel, Jonathan 0000-0002-5854-3759 24 Geis, Christian 0000-0002-9859-581X 25 Fukata, Yuko 0000-0001-7724-8643 26 Fukata, Masaki 0000-0001-5200-9806 27 Prüß, Harald P:(DE-2719)2810931 28 Last author 10.1084/jem.20210012 Vol. 218, no. 11 PERI:(DE-600)1477240-1 11 e20210012 Journal of experimental medicine 218 2021 0022-1007 VDB oai:pub.dzne.de:162857 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)2811468 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)2814218 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 4 P:(DE-2719)2812697 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)2812526 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 7 P:(DE-2719)2812820 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 8 P:(DE-2719)2812653 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 9 P:(DE-2719)9001962 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 10 P:(DE-2719)9001947 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 11 P:(DE-2719)2811900 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 12 P:(DE-2719)2810725 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 23 P:(DE-2719)2810922 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 28 P:(DE-2719)2810931 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-353 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Clinical and Health Care Research 0 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-351 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Brain Function 1 2021 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-29 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-01-29 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-29 JCR StatID:(DE-HGF)0100 StatID J EXP MED : 2021 2022-11-13 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-13 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-13 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-13 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-13 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-13 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2022-11-13 IF >= 15 StatID:(DE-HGF)9915 StatID J EXP MED : 2021 2022-11-13 I:(DE-2719)1810003 AG Prüß Autoimmune Encephalopathies 0 I:(DE-2719)1810001 AG Garner Synaptopathy 1 I:(DE-2719)1810004 AG Schmitz Network Dysfunction 2 journal VDB I:(DE-2719)1810003 I:(DE-2719)1810001 I:(DE-2719)1810004 UNRESTRICTED