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Journal Article

Autoantibodies against NMDA receptor 1 modify rather than cause encephalitis

MPS-Authors
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Wilke,  Justus B. H.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Hindermann,  Martin
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons202532

Berghoff,  Stefan A.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons268841

Zihsler,  Svenja
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons214271

Arinrad,  Sahab
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182377

Ronnenberg,  Anja
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons268844

Barnkothe,  Nadine
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons268847

Steixner-Kumar,  Agnes A.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons268850

Röglin,  Stefan
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Nave,  Klaus
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182138

Ehrenreich,  Hannelore
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

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3363633.pdf
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Citation

Wilke, J. B. H., Hindermann, M., Berghoff, S. A., Zihsler, S., Arinrad, S., Ronnenberg, A., et al. (2021). Autoantibodies against NMDA receptor 1 modify rather than cause encephalitis. Molecular Psychiatry, In Press. doi:10.1038/s41380-021-01238-3.


Cite as: http://hdl.handle.net/21.11116/0000-0009-D713-F
Abstract
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.