Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures

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.

Publication DOI: https://doi.org/10.1084/jem.20210012
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > Aston Institute of Health & Neurodevelopment (AIHN)
College of Health & Life Sciences
College of Health & Life Sciences > Clinical and Systems Neuroscience
Additional Information: © 2021 Kreye et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
Uncontrolled Keywords: Medicine(all)
Publication ISSN: 1540-9538
Last Modified: 14 May 2024 07:53
Date Deposited: 27 Sep 2021 11:04
Full Text Link:
Related URLs: https://rupress ... edFrom=fulltext (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2021-09-21
Accepted Date: 2021-08-17
Authors: Kreye, Jakob
Wright, Sukhvir K (ORCID Profile 0000-0002-5464-3779)
van Casteren, Adriana
Stöffler, Laura
Machule, Marie-Luise
Reincke, S Momsen
Nikolaus, Marc
van Hoof, Scott
Sanchez-Sendin, Elisa
Homeyer, Marie A
Cordero Gómez, César
Kornau, Hans-Christian
Schmitz, Dietmar
Kaindl, Angela M
Boehm-Sturm, Philipp
Mueller, Susanne
Wilson, Max A
Upadhya, Manoj A (ORCID Profile 0000-0002-2032-1472)
Dhangar, Divya R (ORCID Profile 0000-0002-0363-627X)
Greenhill, Stuart (ORCID Profile 0000-0002-5038-5258)
Woodhall, Gavin (ORCID Profile 0000-0003-1281-9008)
Turko, Paul
Vida, Imre
Garner, Craig C
Wickel, Jonathan
Geis, Christian
Fukata, Yuko
Fukata, Masaki
Prüss, Harald

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