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A cell\u2010based assay (CBA) with GluK2\u2010expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2\u2010ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2\u2010expressing HEK293 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients\u2019 antibodies precipitated GluK2. GluK2 antibody\u2010specificity was confirmed by CBA, immunoprecipitation, GluK2\u2010immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno\u2010absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (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 the samples showed mild reactivity with non\u2010kainate receptors (alpha\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid receptors [AMPAR] and N\u2010methyl\u2010D\u2010aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2\u2010abs among patients with anti\u2010AMPAR (5\/71) or anti\u2010NMDAR encephalitis (1\/73). GluK2\u2010abs internalized GluK2 in HEK293 cells and neurons; these antibody\u2010effects were reversible in neurons. A significant reduction of GluK2\u2010mediated currents was observed in cells treated with patients\u2019 GluK2 serum following the time frame of antibody\u2010mediated GluK2 internalization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>GluK2\u2010abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021;90:107\u2013123<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26098","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T14:00:31Z","timestamp":1620223231000},"page":"101-117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Encephalitis with Autoantibodies against the Glutamate Kainate Receptors <scp>GluK2<\/scp>"],"prefix":"10.1002","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7644-7517","authenticated-orcid":false,"given":"Jon","family":"Landa","sequence":"first","affiliation":[{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) Hospital Cl\u00ednic, Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Guasp","sequence":"additional","affiliation":[{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) Hospital Cl\u00ednic, 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