Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 11 2021
01 11 2021
Historique:
received:
18
01
2021
revised:
30
06
2021
accepted:
17
08
2021
entrez:
21
9
2021
pubmed:
22
9
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34546336
pii: 212650
doi: 10.1084/jem.20210012
pmc: PMC8480667
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Autoantibodies
0
Autoantigens
0
Receptors, GABA-A
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 Kreye et al.
Déclaration de conflit d'intérêts
Disclosures: No disclosures were reported.
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