Autoantibodies against NMDA receptor 1 modify rather than cause encephalitis

Area of Science:

• Neuroimmunology
• Neurology
• Pathogenesis of Autoimmune Encephalitis

Background:

• The exact cause and development of anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis and the role of autoantibodies (AB) are not fully understood.
• While NMDAR1-AB can antagonize NMDAR function through receptor internalization, there is no definitive evidence that they alone trigger brain inflammation.

Purpose of the Study:

• To investigate the hypothesis that NMDAR encephalitis arises from a primary brain inflammation that coincides with the presence of NMDAR1-AB, potentially shaping the clinical presentation.
• To test if immunization with NMDAR1 peptides, combined with induced sterile encephalitis (diphtheria toxin-mediated ablation of pyramidal neurons in DTA mice), modifies the encephalitis phenotype.
• To attempt replication of a previous study claiming NMDAR1-N368/G369 region immunization induces brain inflammation.

Main Methods:

• Mice were immunized with a cocktail of four NMDAR1 peptides.
• Sterile encephalitis was induced in DTA mice via diphtheria toxin-mediated ablation of pyramidal neurons.
• Behavioral, neurological, and neuropathological assessments were conducted, including attempts to replicate prior immunization protocols.

Main Results:

• DTA mice exhibited hyperactivity, learning/memory deficits, network dysfunction, blood-brain barrier impairment, inflammation, neuronal death, microgliosis, astrogliosis, and regional atrophy.
• The presence of NMDAR1-AB exacerbated the hyperactivity (psychosis-like) phenotype in DTA mice, but other outcomes were similar to control-immunized DTA mice.
• Non-DTA mice, with or without NMDAR1-AB, showed no signs of encephalitis. Replication attempts of the NMDAR1-N368/G369 immunization protocol failed in two independent cohorts.

Conclusions:

• NMDAR1-AB can contribute to the behavioral aspects of an existing encephalitis.
• The induction of encephalitis solely by NMDAR1-AB remains unproven.
• The study failed to replicate findings that immunization against specific NMDAR1 peptides induces brain inflammation.