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.

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.

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.