PMID- 34331009 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20230206 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 26 IP - 12 DP - 2021 Dec TI - Autoantibodies against NMDA receptor 1 modify rather than cause encephalitis. PG - 7746-7759 LID - 10.1038/s41380-021-01238-3 [doi] AB - The etiology and pathogenesis of "anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis" and the role of autoantibodies (AB) in this condition are still obscure. While NMDAR1-AB exert NMDAR-antagonistic properties by receptor internalization, no firm evidence exists to date that NMDAR1-AB by themselves induce brain inflammation/encephalitis. NMDAR1-AB of all immunoglobulin classes are highly frequent across mammals with multiple possible inducers and boosters. We hypothesized that "NMDAR encephalitis" results from any primary brain inflammation coinciding with the presence of NMDAR1-AB, which may shape the encephalitis phenotype. Thus, we tested whether following immunization with a "cocktail" of 4 NMDAR1 peptides, induction of a spatially and temporally defined sterile encephalitis by diphtheria toxin-mediated ablation of pyramidal neurons ("DTA" mice) would modify/aggravate the ensuing phenotype. In addition, we tried to replicate a recent report claiming that immunizing just against the NMDAR1-N368/G369 region induced brain inflammation. Mice after DTA induction revealed a syndrome comprising hyperactivity, hippocampal learning/memory deficits, prefrontal cortical network dysfunction, lasting blood brain-barrier impairment, brain inflammation, mainly in hippocampal and cortical regions with pyramidal neuronal death, microgliosis, astrogliosis, modest immune cell infiltration, regional atrophy, and relative increases in parvalbumin-positive interneurons. The presence of NMDAR1-AB enhanced the hyperactivity (psychosis-like) phenotype, whereas all other readouts were identical to control-immunized DTA mice. Non-DTA mice with or without NMDAR1-AB were free of any encephalitic signs. Replication of the reported NMDAR1-N368/G369-immunizing protocol in two large independent cohorts of wild-type mice completely failed. To conclude, while NMDAR1-AB can contribute to the behavioral phenotype of an underlying encephalitis, induction of an encephalitis by NMDAR1-AB themselves remains to be proven. CI - (c) 2021. The Author(s). FAU - Wilke, Justus B H AU - Wilke JBH AUID- ORCID: 0000-0003-1368-159X AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Hindermann, Martin AU - Hindermann M AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Berghoff, Stefan A AU - Berghoff SA AD - Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Zihsler, Svenja AU - Zihsler S AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Arinrad, Sahab AU - Arinrad S AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Ronnenberg, Anja AU - Ronnenberg A AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Barnkothe, Nadine AU - Barnkothe N AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Steixner-Kumar, Agnes A AU - Steixner-Kumar AA AUID- ORCID: 0000-0001-7913-2716 AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Roglin, Stefan AU - Roglin S AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Stocker, Winfried AU - Stocker W AD - Institute for Experimental Immunology, affiliated to Euroimmun, Lubeck, Germany. FAU - Hollmann, Michael AU - Hollmann M AD - Department of Biochemistry I-Receptor Biochemistry, Ruhr University, Bochum, Germany. FAU - Nave, Klaus-Armin AU - Nave KA AUID- ORCID: 0000-0001-8724-9666 AD - Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Gottingen, Germany. FAU - Luhder, Fred AU - Luhder F AD - Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Gottingen, Gottingen, Germany. FAU - Ehrenreich, Hannelore AU - Ehrenreich H AUID- ORCID: 0000-0001-8371-5711 AD - Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. ehrenreich@em.mpg.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210730 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Autoantibodies) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Animals MH - Autoantibodies MH - Blood-Brain Barrier MH - *Encephalitis MH - Mice MH - Pyramidal Cells MH - *Receptors, N-Methyl-D-Aspartate PMC - PMC8872987 COIS- WS is a member of the board and holds stocks in Euroimmun AG. All other authors declare no competing financial or other interests. EDAT- 2021/08/01 06:00 MHDA- 2022/03/15 06:00 PMCR- 2021/07/30 CRDT- 2021/07/31 07:23 PHST- 2021/04/28 00:00 [received] PHST- 2021/07/09 00:00 [accepted] PHST- 2021/07/06 00:00 [revised] PHST- 2021/08/01 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/07/31 07:23 [entrez] PHST- 2021/07/30 00:00 [pmc-release] AID - 10.1038/s41380-021-01238-3 [pii] AID - 1238 [pii] AID - 10.1038/s41380-021-01238-3 [doi] PST - ppublish SO - Mol Psychiatry. 2021 Dec;26(12):7746-7759. doi: 10.1038/s41380-021-01238-3. Epub 2021 Jul 30.