Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures

Jakob Kreye; Sukhvir K Wright; Adriana van Casteren; Laura Stöffler; Marie-Luise Machule; S Momsen Reincke; Marc Nikolaus; Scott van Hoof; Elisa Sanchez-Sendin; Marie A Homeyer; César Cordero Gómez; Hans-Christian Kornau; Dietmar Schmitz; Angela M Kaindl; Philipp Boehm-Sturm; Susanne Mueller; Max A Wilson; Manoj A Upadhya; Divya R Dhangar; Stuart Greenhill; Gavin Woodhall; Paul Turko; Imre Vida; Craig C Garner; Jonathan Wickel; Christian Geis; Yuko Fukata; Masaki Fukata; Harald Prüss

doi:10.1084/jem.20210012

Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures

Jakob Kreye, Sukhvir K Wright, Adriana van Casteren, Laura Stöffler, Marie-Luise Machule, S Momsen Reincke, Marc Nikolaus, Scott van Hoof, Elisa Sanchez-Sendin, Marie A Homeyer, César Cordero Gómez, Hans-Christian Kornau, Dietmar Schmitz, Angela M Kaindl, Philipp Boehm-Sturm, Susanne Mueller, Max A Wilson, Manoj A Upadhya, Divya R Dhangar, Stuart GreenhillGavin Woodhall, Paul Turko, Imre Vida, Craig C Garner, Jonathan Wickel, Christian Geis, Yuko Fukata, Masaki Fukata, Harald Prüss

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e20210012
Journal	Journal of Experimental Medicine
Volume	218
Issue number	11
DOIs	https://doi.org/10.1084/jem.20210012
Publication status	Published - 21 Sept 2021

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© 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/).

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Encephalitis patient-derived monoclonal GABA
copyright 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/).
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Kreye, J., Wright, S. K., van Casteren, A., Stöffler, L., Machule, M.-L., Reincke, S. M., Nikolaus, M., van Hoof, S., Sanchez-Sendin, E., Homeyer, M. A., Cordero Gómez, C., Kornau, H.-C., Schmitz, D., Kaindl, A. M., Boehm-Sturm, P., Mueller, S., Wilson, M. A., Upadhya, M. A., Dhangar, D. R., ... Prüss, H. (2021). Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures. Journal of Experimental Medicine , 218(11), Article e20210012. https://doi.org/10.1084/jem.20210012

@article{43e2a80da9ec4a4d8862b47b05912e9e,

title = "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.",

author = "Jakob Kreye and Wright, {Sukhvir K} and {van Casteren}, Adriana and Laura St{\"o}ffler and Marie-Luise Machule and Reincke, {S Momsen} and Marc Nikolaus and {van Hoof}, Scott and Elisa Sanchez-Sendin and Homeyer, {Marie A} and {Cordero G{\'o}mez}, C{\'e}sar and Hans-Christian Kornau and Dietmar Schmitz and Kaindl, {Angela M} and Philipp Boehm-Sturm and Susanne Mueller and Wilson, {Max A} and Upadhya, {Manoj A} and Dhangar, {Divya R} and Stuart Greenhill and Gavin Woodhall and Paul Turko and Imre Vida and Garner, {Craig C} and Jonathan Wickel and Christian Geis and Yuko Fukata and Masaki Fukata and Harald Pr{\"u}ss",

note = "{\textcopyright} 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/).",

year = "2021",

month = sep,

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doi = "10.1084/jem.20210012",

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Kreye, J, Wright, SK, van Casteren, A, Stöffler, L, Machule, M-L, Reincke, SM, Nikolaus, M, van Hoof, S, Sanchez-Sendin, E, Homeyer, MA, Cordero Gómez, C, Kornau, H-C, Schmitz, D, Kaindl, AM, Boehm-Sturm, P, Mueller, S, Wilson, MA, Upadhya, MA, Dhangar, DR, Greenhill, S , Woodhall, G, Turko, P, Vida, I, Garner, CC, Wickel, J, Geis, C, Fukata, Y, Fukata, M & Prüss, H 2021, 'Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures', Journal of Experimental Medicine , vol. 218, no. 11, e20210012. https://doi.org/10.1084/jem.20210012

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T1 - Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures

AU - Kreye, Jakob

AU - Wright, Sukhvir K

AU - van Casteren, Adriana

AU - Stöffler, Laura

AU - Machule, Marie-Luise

AU - Reincke, S Momsen

AU - Nikolaus, Marc

AU - van Hoof, Scott

AU - Sanchez-Sendin, Elisa

AU - Homeyer, Marie A

AU - Cordero Gómez, César

AU - Kornau, Hans-Christian

AU - Schmitz, Dietmar

AU - Kaindl, Angela M

AU - Boehm-Sturm, Philipp

AU - Mueller, Susanne

AU - Wilson, Max A

AU - Upadhya, Manoj A

AU - Dhangar, Divya R

AU - Greenhill, Stuart

AU - Woodhall, Gavin

AU - Turko, Paul

AU - Vida, Imre

AU - Garner, Craig C

AU - Wickel, Jonathan

AU - Geis, Christian

AU - Fukata, Yuko

AU - Fukata, Masaki

AU - Prüss, Harald

N1 - © 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/).

PY - 2021/9/21

Y1 - 2021/9/21

N2 - 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.

AB - 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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JO - Journal of Experimental Medicine

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Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures

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