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J Neurosci. 2014 Jun 11;34(24):8151-63. doi: 10.1523/JNEUROSCI.4415-13.2014.

Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis.

Author information

1
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;
2
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;
3
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
4
Department of Neurology, Suiseikai Kajikawa Hospital, Hiroshima 730-0046, Japan; and.
5
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
6
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.

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.

KEYWORDS:

GABAA receptor; autoantibody; autoimmune encephalitis; cognitive impairment; seizure; thymoma

PMID:
24920620
DOI:
10.1523/JNEUROSCI.4415-13.2014
[Indexed for MEDLINE]
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