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Neurology. 2015 Mar 24;84(12):1233-41. doi: 10.1212/WNL.0000000000001326. Epub 2015 Jan 30.

Antibodies to GABAA receptor α1 and γ2 subunits: clinical and serologic characterization.

Author information

1
From the Nuffield Department of Clinical Neurosciences (P.P., R.P., S.M., A.N., S.R.I., C.B., D.B., B.L., P.W., A.V.) and the Department of Physiology, Anatomy and Genetics (H.B.K.), University of Oxford; St George's Healthcare NHS Trust (J.A.C.), Tooting, London; the Centre for Neuroscience & Trauma, Blizard Institute (A.M.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; and The Walton Centre Foundation Trust (A.J.), Liverpool, UK.
2
From the Nuffield Department of Clinical Neurosciences (P.P., R.P., S.M., A.N., S.R.I., C.B., D.B., B.L., P.W., A.V.) and the Department of Physiology, Anatomy and Genetics (H.B.K.), University of Oxford; St George's Healthcare NHS Trust (J.A.C.), Tooting, London; the Centre for Neuroscience & Trauma, Blizard Institute (A.M.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; and The Walton Centre Foundation Trust (A.J.), Liverpool, UK. angela.vincent@ndcn.ox.ac.uk.

Abstract

OBJECTIVE:

To search for antibodies against neuronal cell surface proteins.

METHODS:

Using immunoprecipitation from neuronal cultures and tandem mass spectrometry, we identified antibodies against the α1 subunit of the γ-aminobutyric acid A receptor (GABAAR) in a patient whose immunoglobulin G (IgG) antibodies bound to hippocampal neurons. We searched 2,548 sera for antibodies binding to GABAAR α, β, and γ subunits on live HEK293 cells and identified the class, subclass, and GABAAR subunit specificities of the positive samples.

RESULTS:

GABAAR-Abs were identified in 40 of 2,046 (2%) referred sera previously found negative for neuronal antibodies, in 5/502 (1%) previously positive for other neuronal surface antibodies, but not in 92 healthy individuals. The antibodies in 40% bound to either the α1 (9/45, 20%) or the γ2 subunits (9/45, 20%) and were of IgG1 (94%) or IgG3 (6%) subclass. The remaining 60% had lower antibody titers (p = 0.0005), which were mainly immunoglobulin M (IgM) (p = 0.0025), and showed no defined subunit specificity. Incubation of primary hippocampal neurons with GABAAR IgG1 sera reduced surface GABAAR membrane expression. The clinical features of 15 patients (GABAAR α1 n = 6, γ2 n = 5, undefined n = 4) included seizures (47%), memory impairment (47%), hallucinations (33%), or anxiety (20%). Most patients had not been given immunotherapies, but one with new-onset treatment-resistant catatonia made substantial improvement after plasma exchange.

CONCLUSIONS:

The GABAAR α1 and γ2 are new targets for antibodies in autoimmune neurologic disease. The full spectrum of clinical features, treatment responses, correlation with antibody specificity, and in particular the role of the IgM antibodies will need to be assessed in future studies.

PMID:
25636713
PMCID:
PMC4366091
DOI:
10.1212/WNL.0000000000001326
[Indexed for MEDLINE]
Free PMC Article
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