Identification and Characterization of GABAA Receptor Autoantibodies in Autoimmune Encephalitis

• Published in: The Journal of neuroscience Vol. 34; no. 24; pp. 8151 - 8163
• Main Authors: Ohkawa, T., Satake, S., Yokoi, N., Miyazaki, Y., Ohshita, T., Sobue, G., Takashima, H., Watanabe, O., Fukata, Y., Fukata, M.
• Format: Journal Article
• Language: English
• Published: Society for Neuroscience 11-06-2014
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4415-13.2014

Autoimmune forms of encephalitis have been associated with autoantibodies against synaptic cell surface antigens such as NMDA- and AMPA-type glutamate receptors, GABAB receptor, and LGI1. However, it remains unclear how many synaptic autoantigens are yet to be defined. Using immunoproteomics, we identified autoantibodies against the GABAA 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 beta 3 subunit of the GABAA receptor. The beta 3-subunit-containing GABAA 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 beta 3 subunit was knocked down. Our developed multiplex ELISA testing showed that both patients had similar levels of GABAA 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 GABAA 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' GABAA receptor antibodies play a central role in the patients' symptoms. Therefore, this study establishes anti-GABAA receptor encephalitis and expands the pathogenic roles of GABAA receptor autoantibodies.