Home > Publications Database > Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures. > print

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024 7 _ |a 10.1084/jem.20210012
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037 _ _ |a DZNE-2021-01512
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Kreye, Jakob
|0 P:(DE-2719)2811468
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|e First author
245 _ _ |a Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures.
260 _ _ |a New York, NY
|c 2021
|b Rockefeller Univ. Press
336 7 _ |a article
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520 _ _ |a 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.
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Antibodies, Monoclonal: immunology
|2 MeSH
650 _ 2 |a Autoantibodies: immunology
|2 MeSH
650 _ 2 |a Autoantigens: immunology
|2 MeSH
650 _ 2 |a Cells, Cultured
|2 MeSH
650 _ 2 |a Encephalitis: immunology
|2 MeSH
650 _ 2 |a Epilepsy: immunology
|2 MeSH
650 _ 2 |a HEK293 Cells
|2 MeSH
650 _ 2 |a Hippocampus: immunology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Neurons: immunology
|2 MeSH
650 _ 2 |a Receptors, GABA-A: immunology
|2 MeSH
650 _ 2 |a Seizures: immunology
|2 MeSH
700 1 _ |a Wright, Sukhvir K
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700 1 _ |a Casteren, Adriana
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700 1 _ |a Stöffler, Laura
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700 1 _ |a Machule, Marie-Luise
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700 1 _ |a Reincke, Momsen
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700 1 _ |a Nikolaus, Marc
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700 1 _ |a Hoof, Scott
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700 1 _ |a Sanchez Sendin, Elisa
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700 1 _ |a Schmitz, Dietmar
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700 1 _ |a Kaindl, Angela M
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700 1 _ |a Boehm-Sturm, Philipp
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700 1 _ |a Mueller, Susanne
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700 1 _ |a Wilson, Max A
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700 1 _ |a Dhangar, Divya R
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700 1 _ |a Greenhill, Stuart
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700 1 _ |a Woodhall, Gavin
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700 1 _ |a Turko, Paul
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700 1 _ |a Vida, Imre
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700 1 _ |a Garner, Craig Curtis
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700 1 _ |a Wickel, Jonathan
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700 1 _ |a Geis, Christian
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700 1 _ |a Fukata, Yuko
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700 1 _ |a Fukata, Masaki
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700 1 _ |a Prüß, Harald
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773 _ _ |a 10.1084/jem.20210012
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