Monoclonal Antibodies From Anti-NMDA Receptor Encephalitis Patient as a Tool to Study Autoimmune Seizures

• Type of Material: Article
• Authors: Olga Taraschenko, University of Nebraska Medical Center; Howard S Fox, University of Nebraska Medical Center; Ember Eldridge, University of Nebraska Medical Center; Wenyi Wang, Emory University; Samuel W Dowd, University of Nebraska Medical Center; Fetweh Al-Saleem, Lankenau Institute for Medical Research; Chandana Devi Kattala, Lankenau Institute for Medical Research; Scott K Dessain, Lankenau Institute for Medical Research; Raymond Dingledine, Emory University
• Language: English
• Date: 2021-08-26
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Taraschenko, Fox, Eldridge, Wang, Dowd, Al-Saleem, Kattala, Dessain and Dingledine.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fnins.2021.710650
• Title of Journal or Parent Work: FRONTIERS IN NEUROSCIENCE
• Volume: 15
• Start Page: 710650
• End Page: 710650
• Grant/Funding Information: This work was supported by the American Epilepsy Society (AES) Junior Investigator Research Award and AES-NORSE Institute Seed Grant (OT), the National Institute of Health (NIH) grant R21 NS088148 (SKD), the Lankenau Institute for Medical Research (SKD), and NIH grant R01 NS112308 (RD).
• Keywords: PATHOGENESIS; ACTIVATION; autoimmune seizures; ANTAGONIST; cytokines; neuronal autoantibodies; anti-NMDA receptor encephalitis; SUBUNIT; EPILEPSY; Life Sciences & Biomedicine; BRAIN; Science & Technology; DYSFUNCTION; Neurosciences & Neurology; INFLAMMATION; monoclonal antibodies; Neurosciences; AUTOANTIBODIES; MECHANISMS
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis manifests with precipitous cognitive decline, abnormal movements, and severe seizures that can be challenging to control with conventional anti-seizure medications. We previously demonstrated that intracerebroventricular (i.c.v.) administration of cerebrospinal fluid from affected patients, or purified NMDA receptor antibodies from encephalitis patients to mice precipitated seizures, thereby confirming that antibodies are directly pathogenic for seizures. Although different repertoires of anti-NMDA receptor antibodies could contribute to the distinct clinical manifestations in encephalitis patients, the role of specific antibodies in the expression of seizure, motor, and cognitive phenotypes remains unclear. Using three different patient-derived monoclonal antibodies with distinct epitopes within the N-terminal domain (NTD) of the NMDA receptor, we characterized the seizure burden, motor activity and anxiety-related behavior in mice. We found that continuous administration of 5F5, 2G6 or 3C11 antibodies for 2 weeks precipitated seizures, as measured with continuous EEG using cortical screw electrodes. The seizure burden was comparable in all three antibody-treated groups. The seizures were accompanied by increased hippocampal C-C chemokine ligand 2 (CCL2) mRNA expression 3 days after antibody infusion had stopped. Antibodies did not affect the motor performance or anxiety scores in mice. These findings suggest that neuronal antibodies targeting different epitopes within the NMDA receptor may result in a similar seizure phenotype.