Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABA <sub>A</sub> receptor encephalitis
Simone M. Brändle, Manuela Cerina, Susanne Weber, Kathrin Held, Amélie F. Menke, Carmen Alcalá, David Gebert, Alexander M. Herrmann, Hannah Pellkofer, Lisa Ann Gerdes, Stefan Bittner, Frank Leypoldt, Bianca Teegen, Lars Komorowski, Tania Kümpfel, Reinhard Hohlfeld, Sven G. Meuth, Bonaventura Casanova, Nico Melzer, Eduardo Beltrán, Klaus Dornmair
Abstract
Significance Antibodies recognizing the neuronal gamma-aminobutyric acid A receptor (GABA A -R) cause severe encephalitis by triggering internalization of the antibody–receptor complexes in inhibitory synapses, which leads to hyperexcitability and dysfunction of neuronal networks. From the cerebrospinal fluid of a patient with GABA A -R encephalitis we cloned a highly expressed antibody and showed that it binds the GABA A -R and influences signal transduction in neurons, explaining clinical symptoms. Using several experimental techniques, we confirmed that the antibody cross-reacts to an oncoprotein which is known to be involved in several malignancies. We showed that cross-reactivity to this oncoprotein may also be detected in two other GABA A -R patients, suggesting that such cross-reactivity is presumably a key event in the pathogenesis of GABA A -R encephalitis.