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anti-NMDAR1, autoantibodies, encephalitis
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.
