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...

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Published inAnnals of neurology Vol. 85; no. 5; pp. 771 - 776
Main Authors Wenke, Nina Kerstin, Kreye, Jakob, Andrzejak, Ewa, 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
Format Journal Article
LanguageEnglish
Published Hoboken, USA John Wiley & Sons, Inc 01.05.2019
Wiley Subscription Services, Inc
Subjects
Animals
Anti-N-Methyl-D-Aspartate Receptor Encephalitis - blood
Anti-N-Methyl-D-Aspartate Receptor Encephalitis - pathology
Antibodies
Autoantibodies
Autoantibodies - blood
Brief Communication
Brief Communications
Cerebrospinal fluid
Encephalitis
Glutamic acid receptors
HEK293 Cells
Hippocampus
Hippocampus - chemistry
Hippocampus - metabolism
Hippocampus - pathology
Humans
Immunoglobulins
Lymphocytes B
Mice
N-Methyl-D-aspartic acid receptors
Neurons - chemistry
Neurons - metabolism
Protein Binding - physiology
Protein Structure, Secondary
Receptors, N-Methyl-D-Aspartate - blood
Receptors, N-Methyl-D-Aspartate - chemistry
Signs and symptoms
Time dependence
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Summary: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
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These authors contributed equally to the work.
ISSN:0364-5134
1531-8249
DOI:10.1002/ana.25460