title: Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis.
abstract: Autoimmune forms of encephalitis have been associated with autoantibodies against synaptic cell surface antigens such as NMDA- and AMPA-type glutamate receptors, GABA(B) receptor, and LGI1. However, it remains unclear how many synaptic autoantigens are yet to be defined. Using immunoproteomics, we identified autoantibodies against the GABA(A) receptor in human sera from two patients diagnosed with encephalitis who presented with cognitive impairment and multifocal brain MRI abnormalities. Both patients had antibodies directed against the extracellular epitope of the β3 subunit of the GABA(A) receptor. The β3-subunit-containing GABA(A) receptor was a major target of the patients' serum antibodies in rat hippocampal neurons because the serum reactivity to the neuronal surface was greatly decreased by 80% when the β3 subunit was knocked down. Our developed multiplex ELISA testing showed that both patients had similar levels of GABA(A) receptor antibodies, one patient also had a low level of LGI1 antibodies, and the other also had CASPR2 antibodies. Application of the patients' serum at the time of symptom presentation of encephalitis to rat hippocampal neuron cultures specifically decreased both synaptic and surface GABA(A) receptors. Furthermore, treatment of neurons with the patients' serum selectively reduced miniature IPSC amplitude and frequency without affecting miniature EPSCs. These results strongly suggest that the patients' GABA(A) receptor antibodies play a central role in the patients' symptoms. Therefore, this study establishes anti-GABA(A) receptor encephalitis and expands the pathogenic roles of GABA(A) receptor autoantibodies.
authors.affiliation: Division of Membrane Physiology, Department of Cell Physiology, and Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan;
authors.forename: Toshika
authors.initials: T
authors.lastname: Ohkawa
authors.affiliation: Division of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; and Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan;
authors.forename: Shin'Ichiro
authors.initials: S
authors.lastname: Satake
authors.affiliation: Division of Membrane Physiology, Department of Cell Physiology, and Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan;
authors.forename: Norihiko
authors.initials: N
authors.lastname: Yokoi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
authors.forename: Yu
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Neurology, Suiseikai Kajikawa Hospital, Hiroshima 730-0046, Japan; and.
authors.forename: Tomohiko
authors.identifier: http://orcid.org/0000-0002-3915-2963
authors.initials: T
authors.lastname: Ohshita
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takashima
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Watanabe
authors.affiliation: Division of Membrane Physiology, Department of Cell Physiology, and Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; yfukata@nips.ac.jp mfukata@nips.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fukata
authors.affiliation: Division of Membrane Physiology, Department of Cell Physiology, and Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; yfukata@nips.ac.jp mfukata@nips.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukata
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001927:Brain Diseases / Q000097:blood* / Q000150:complications / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003072:Cognition Disorders / Q000209:etiology; D004660:Encephalitis; D005260:Female; D050031:Hashimoto Disease / Q000097:blood* / Q000150:complications / Q000276:immunology* / Q000473:pathology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000276:immunology; D051381:Rats; D011963:Receptors, GABA-A / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D018377:Neurotransmitter Agents; D011506:Proteins; D011963:Receptors, GABA-A; C090468:TP53BP2 protein, human
keywords: GABAA receptor; autoantibody; autoimmune encephalitis; cognitive impairment; seizure; thymoma