Antibodies to GABA(A) receptor alpha 1 and gamma 2 subunits Clinical and serologic characterization

作者：Pettingill Philippa; Kramer Holger B; Coebergh Jan Adriaan; Pettingill Rosie; Maxwell Susan; Nibber Anjan; Malaspina Andrea; Jacob Anu; Irani Sarosh R; Buckley Camilla; Beeson David; Lang Bethan; Waters Patrick; Vincent Angela^*

来源：Neurology, 2015, 84(12): 1233-1241.

DOI：10.1212/WNL.0000000000001326

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 alpha 1 subunit of the gamma-aminobutyric acid A receptor (GABA(A)R) in a patient whose immunoglobulin G (IgG) antibodies bound to hippocampal neurons. We searched 2,548 sera for antibodies binding to GABA(A)R alpha, beta, and gamma subunits on live HEK293 cells and identified the class, subclass, and GABA(A)R subunit specificities of the positive samples.
Results: GABA(A)R-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 alpha 1 (9/45, 20%) or the gamma 2 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 GABA(A)R IgG1 sera reduced surface GABA(A)R membrane expression. The clinical features of 15 patients (GABA(A)R alpha 1 n = 6, gamma 2 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 GABA(A)R alpha 1 and gamma 2 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.

• 出版日期2015-3-24