title: Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis.
abstract: SEE ZEKERIDOU AND LENNON DOI101093/AWW213 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Little is known about the cerebrospinal fluid autoantibody repertoire. Antibodies against the NR1 subunit of the NMDAR are thought to be pathogenic; however, direct proof is lacking as previous experiments could not distinguish the contribution of further anti-neuronal antibodies. Using single cell cloning of full-length immunoglobulin heavy and light chain genes, we generated a panel of recombinant monoclonal NR1 antibodies from cerebrospinal fluid memory B cells and antibody secreting cells of NMDAR encephalitis patients. Cells typically carried somatically mutated immunoglobulin genes and had undergone class-switching to immunoglobulin G, clonally expanded cells carried identical somatic hypermutation patterns. A fraction of NR1 antibodies were non-mutated, thus resembling 'naturally occurring antibodies' and indicating that tolerance induction against NMDAR was incomplete and somatic hypermutation not essential for functional antibodies. However, only a small percentage of cerebrospinal fluid-derived antibodies reacted against NR1. Instead, nearly all further antibodies bound specifically to diverse brain-expressed epitopes including neuronal surfaces, suggesting that a broad repertoire of antibody-secreting cells enrich in the central nervous system during encephalitis. Our functional data using primary hippocampal neurons indicate that human cerebrospinal fluid-derived monoclonal NR1 antibodies alone are sufficient to cause neuronal surface receptor downregulation and subsequent impairment of NMDAR-mediated currents, thus providing ultimate proof of antibody pathogenicity. The observed formation of immunological memory might be relevant for clinical relapses.
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Kreye
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.
authors.forename: Nina K
authors.initials: NK
authors.lastname: Wenke
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.
authors.forename: Mariya
authors.initials: M
authors.lastname: Chayka
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Leubner
authors.affiliation: 3Max Planck Institute (MPI) for Infection Biology, Berlin, Germany 4German Cancer Research Center (DKFZ), B Cell Immunology, Heidelberg, Germany.
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Murugan
authors.affiliation: 5Neuroscience Research Center, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Maier
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.
authors.forename: Betty
authors.initials: B
authors.lastname: Jurek
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.
authors.forename: Lam-Thanh
authors.initials: LT
authors.lastname: Ly
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Brandl
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany 5Neuroscience Research Center, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Rost
authors.affiliation: 5Neuroscience Research Center, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stumpf
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Paulina
authors.initials: P
authors.lastname: Schulz
authors.affiliation: 6German Rheumatism Research Centre Berlin (DRFZ), Germany 7Department of Neuropathology, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Radbruch
authors.affiliation: 6German Rheumatism Research Centre Berlin (DRFZ), Germany 8NeuroCure Clinical Research Center, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Anja E
authors.initials: AE
authors.lastname: Hauser
authors.affiliation: 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany 6German Rheumatism Research Centre Berlin (DRFZ), Germany 8NeuroCure Clinical Research Center, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Florence
authors.initials: F
authors.lastname: Pache
authors.affiliation: 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany 8NeuroCure Clinical Research Center, Charité, Universitätsmedizin Berlin, Germany 9Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
authors.affiliation: 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Harms
authors.affiliation: 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany 8NeuroCure Clinical Research Center, Charité, Universitätsmedizin Berlin, Germany 9Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Paul
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany 10Center for Stroke Research (CSB) Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.
authors.forename: Craig
authors.initials: C
authors.lastname: Garner
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany 5Neuroscience Research Center, Charité, Universitätsmedizin Berlin, Germany 11Einstein Center for Neurosciences Berlin, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schmitz
authors.affiliation: 3Max Planck Institute (MPI) for Infection Biology, Berlin, Germany 4German Cancer Research Center (DKFZ), B Cell Immunology, Heidelberg, Germany.
authors.forename: Hedda
authors.initials: H
authors.lastname: Wardemann
authors.affiliation: 1German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany 2Department of Neurology and Experimental Neurology, Charité, Universitätsmedizin Berlin, Germany harald.pruess@charite.de.
authors.forename: Harald
authors.initials: H
authors.lastname: Prüss
keywords: NMDA receptor encephalitis; cerebrospinal fluid; electrophysiology; germline antibodies; monoclonal auto-antibody