Cargando…

N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody‐mediated synaptic dysfunction. Cerebrospinal fluid–derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected g...

Descripción completa

Detalles Bibliográficos
Autores principales: Wenke, Nina Kerstin, Kreye, Jakob, Andrzejak, Ewa, van Casteren, Adriana, Leubner, Jonas, Murgueitio, Manuela S., Reincke, S. Momsen, Secker, Christopher, Schmidl, Lars, Geis, Christian, Ackermann, Frauke, Nikolaus, Marc, Garner, Craig C., Wardemann, Hedda, Wolber, Gerhard, Prüss, Harald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593665/
https://www.ncbi.nlm.nih.gov/pubmed/30843274
http://dx.doi.org/10.1002/ana.25460
_version_ 1783430096163438592
author Wenke, Nina Kerstin
Kreye, Jakob
Andrzejak, Ewa
van Casteren, Adriana
Leubner, Jonas
Murgueitio, Manuela S.
Reincke, S. Momsen
Secker, Christopher
Schmidl, Lars
Geis, Christian
Ackermann, Frauke
Nikolaus, Marc
Garner, Craig C.
Wardemann, Hedda
Wolber, Gerhard
Prüss, Harald
author_facet Wenke, Nina Kerstin
Kreye, Jakob
Andrzejak, Ewa
van Casteren, Adriana
Leubner, Jonas
Murgueitio, Manuela S.
Reincke, S. Momsen
Secker, Christopher
Schmidl, Lars
Geis, Christian
Ackermann, Frauke
Nikolaus, Marc
Garner, Craig C.
Wardemann, Hedda
Wolber, Gerhard
Prüss, Harald
author_sort Wenke, Nina Kerstin
collection PubMed
description Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody‐mediated synaptic dysfunction. Cerebrospinal fluid–derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline‐configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose‐ and time‐dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771–776
format Online
Article
Text
id pubmed-6593665
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher John Wiley & Sons, Inc.
record_format MEDLINE/PubMed
spelling pubmed-65936652019-07-10 N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit Wenke, Nina Kerstin Kreye, Jakob Andrzejak, Ewa van Casteren, Adriana Leubner, Jonas Murgueitio, Manuela S. Reincke, S. Momsen Secker, Christopher Schmidl, Lars Geis, Christian Ackermann, Frauke Nikolaus, Marc Garner, Craig C. Wardemann, Hedda Wolber, Gerhard Prüss, Harald Ann Neurol Brief Communications Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody‐mediated synaptic dysfunction. Cerebrospinal fluid–derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline‐configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose‐ and time‐dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771–776 John Wiley & Sons, Inc. 2019-04-02 2019-05 /pmc/articles/PMC6593665/ /pubmed/30843274 http://dx.doi.org/10.1002/ana.25460 Text en © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Brief Communications
Wenke, Nina Kerstin
Kreye, Jakob
Andrzejak, Ewa
van Casteren, Adriana
Leubner, Jonas
Murgueitio, Manuela S.
Reincke, S. Momsen
Secker, Christopher
Schmidl, Lars
Geis, Christian
Ackermann, Frauke
Nikolaus, Marc
Garner, Craig C.
Wardemann, Hedda
Wolber, Gerhard
Prüss, Harald
N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit
title N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit
title_full N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit
title_fullStr N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit
title_full_unstemmed N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit
title_short N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit
title_sort n‐methyl‐d‐aspartate receptor dysfunction by unmutated human antibodies against the nr1 subunit
topic Brief Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593665/
https://www.ncbi.nlm.nih.gov/pubmed/30843274
http://dx.doi.org/10.1002/ana.25460
work_keys_str_mv AT wenkeninakerstin nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT kreyejakob nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT andrzejakewa nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT vancasterenadriana nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT leubnerjonas nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT murgueitiomanuelas nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT reinckesmomsen nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT seckerchristopher nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT schmidllars nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT geischristian nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT ackermannfrauke nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT nikolausmarc nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT garnercraigc nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT wardemannhedda nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT wolbergerhard nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit
AT prussharald nmethyldaspartatereceptordysfunctionbyunmutatedhumanantibodiesagainstthenr1subunit