Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2

Abstract

Objective: To report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2) in patients with autoimmune encephalitis, and describe the clinical features, IgG subclass, subunit targets, and antibody pathogenicity. Methods: Sera and CSF from 2 patients with similar brain immunostaining were used to precipitate the antigen from cultures of rat cerebellar neurons. A cell-based assay (CBA) with GluK2-expressing HEK293 cells was used to test 127 patients with unclassified neuropil antibodies, 477 with different neurological disorders, and 23 normal subjects. The IgG subclass was characterized by CBA. The effects of antibodies were determined by confocal microscopy in cultured neurons, and by electrophysiology in GluK2-expressing HEK293 cells. Results: Patients' antibodies precipitated GluK2. CBA identified 8 patients with GluK2-only antibodies, all IgG1. Six presented with acute encephalitis and clinical or MRI features of predominant cerebellar involvement and 2 developed other syndromes (1 with cerebellar involvement). Overall, 4/8 patients developed cerebellitis (2 with severe edema, compression of the 4th ventricle, and hydrocephalus). In 6 additional patients, GluK2 antibodies coexisted with AMPA (5) or NMDAR (1) antibodies and the syndrome was driven by the concurrent antibodies. GluK2 antibodies internalized GluK2 receptors in rat hippocampal neurons, and these effects were reversible. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' serum following the time frame of antibody-mediated GluK2 internatization. Interpretation: GluK2 antibodies associate with an encephalitis with prominent clinical and radiological cerebellar involvement. The antibody-mediated structural and electrophysiological effects are predominantly caused by internalization of Gluk2-containing kainate receptors.