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

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.

• Authors: Hong Pan, Bárbara Oliveira, Gesine Saher, Ekrem Dere, Daniel Tapken, Marina Mitjans, Jan Seidel, Janina Wesolowski, Debia Wakhloo, Christina Klein-Schmidt, Anja Ronnenberg, Kerstin Schwabe, Ralf Trippe, Kerstin Mätz-Rensing, Stefan Berghoff, Yazeed Al-Krinawe, Henrik Martens, Martin Begemann, Winfried Stöcker, Franz-Josef Kaup, Reinhard Mischke, Susann Boretius, Klaus-Armin Nave, Joachim K Krauss, Michael Hollmann, Fred Lühder, Hannelore Ehrenreich
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 24 Issue 10 Pg. 1489-1501 (10 2019) ISSN: 1476-5578 [Electronic] England
• PMID: 29426955 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• GRIN1 protein, human
• Immunoglobulin G
• NMDA receptor A1
• Nerve Tissue Proteins
• Receptors, N-Methyl-D-Aspartate

Topics

• Adult
• Animals
• Anti-N-Methyl-D-Aspartate Receptor Encephalitis (immunology)
• Autoantibodies (immunology)
• Blood-Brain Barrier
• Brain (immunology)
• Cats
• Dogs
• Female
• Humans
• Immunoglobulin G (genetics, immunology)
• Male
• Mental Disorders (immunology)
• Mice
• Nerve Tissue Proteins (immunology, metabolism)
• Neurons (immunology)
• Primates
• Rats
• Receptors, N-Methyl-D-Aspartate (immunology, metabolism)
• Seroepidemiologic Studies