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Encephalitis patient-derived monoclonal GABA(A) receptor antibodies cause epileptic seizures

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Item Type:Article
Title:Encephalitis patient-derived monoclonal GABA(A) receptor antibodies cause epileptic seizures
Creators Name:Kreye, J. and Wright, S.K. and van Casteren, A. and Stoeffler, L. and Machule, M.L. and Reincke, S.M. and Nikolaus, M. and van Hoof, S. and Sanchez-Sendin, E. and Homeyer, M.A. and Gómez, C.C. and Kornau, H.C. and Schmitz, D. and Kaindl, A.M. and Boehm-Sturm, P. and Mueller, S. and Wilson, M.A. and Upadhya, M.A. and Dhangar, D.R. and Greenhill, S. and Woodhall, G. and Turko, P. and Vida, I. and Garner, C.C. and Wickel, J. and Geis, C. and Fukata, Y. and Fukata, M. and Prüss, H.
Abstract:Autoantibodies targeting the GABA(A) receptor (GABA(A)R) 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 GABA(A)R 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 GABA(A)R 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 GABA(A)Rs independent of Fc-mediated effector functions and provide an animal model for GABA(A)R 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, Mice, Rats
Source:Journal of Experimental Medicine
ISSN:0022-1007
Publisher:Rockefeller University Press
Volume:218
Number:11
Page Range:e20210012
Date:1 November 2021
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/).
Official Publication:https://doi.org/10.1084/jem.20210012
PubMed:View item in PubMed

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