Abstract Details

Excitatory synaptic transmission in the CNS is largely mediated by 3 types of ionotropic glutamate receptors: NMDARs, AMPARs and kainate receptors. Autoimmune encephalitis associated to antibodies against NMDAR and AMPAR are well known, but not with kainate receptor antibodies.

To report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2-abs) in patients with autoimmune encephalitis and describe the clinical-immunological features and antibody effects.

Patients' antibodies precipitated GluK2. GluK2 antibody-specificity was confirmed by CBA, immunoprecipitation, GluK2-immunoabsorption, and GluK2 knockout brain immunohistochemistry. Two of 8 samples showed reactivity with GluK1 or GluK3 subunits that was abrogated after GluK2 immunoabsorption. Six of 8 patients developed acute encephalitis and clinical or MRI features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of 8 samples showed mild reactivity with non-kainate glutamate receptors (AMPAR and NMDAR) leading to identify 6 additional patients with GluK2-abs among patients with anti-AMPAR (5/71) or anti-NMDAR encephalitis (1/73). Patients’ antibodies internalized GluK2-containing receptors in HEK293 cells and neurons; these effects were reversible in neurons. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' GluK2 serum; these functional effects were not mediated by receptor blocking but by antibody-mediated receptor internalization.

GluK2-abs associate with an encephalitis with prominent clinic-radiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2-containing receptors.