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Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model

MPS-Authors
/persons/resource/persons198205

Pan,  H.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons185153

Oliveira,  B.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182386

Saher,  G.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182126

Dere,  E
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182304

Mitjans,  M.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons215459

Seidel,  J.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons215463

Wesolowski,  J.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons215467

Wakhloo,  D.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182377

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

/persons/resource/persons202532

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

/persons/resource/persons182563

Begemann,  M.
Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182320

Nave,  K.-A.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182138

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

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Citation

Pan, H., Oliveira, B., Saher, G., Dere, E., Tapken, D., Mitjans, M., et al. (2019). Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model. Molecular Psychiatry, 24(10), 1489-1501. doi:10.1038/s41380-017-0011-3.


Cite as: http://hdl.handle.net/21.11116/0000-000A-691E-0
Abstract
Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1- AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE−/− and ApoE+/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE−/− mice, characterized by an open blood–brain barrier, but not in their ApoE+/+ littermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE−/− and ApoE+/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own.