Drew Levy

Introduction. Autoimmune Encephalitis is a disease in which autoantibodies are created against neuronal and synaptic antigens¹. A variety of antigens are associated with the disease, but this report will focus on the N-Methyl-D-Aspartate receptor (NMDAR). The pathogenesis of this disease involves three main steps: auto-antibody attack of the NMDAR GluN1 subunit², cross-linking of receptors³, and internalization of receptors⁴. The decrease in the number of NMDARs produces the clinical neuropsychiatric symptoms associated with the disease: hallucinations, mania, delusions, anxiety, and insomnia¹. Recently, research has revealed that EphB2, a tyrosine kinase transmembrane receptor found in the post-synaptic membrane in proximity to NMDARs, can protect NMDARs from internalization in the presence of NMDAR autoantibodies⁵. This finding suggests a new, potential therapeutic target for treating this disease and other neurological and psychiatric diseases. Methods. In the experimental group, C57 mice were infused with human cerebrospinal fluid (CSF) from patients who had NMDAR autoimmune encephalitis; this CSF contained NMDAR autoantibodies. A control group was infused with human CSF from patients who did not have autoimmune encephalitis or autoantibodies. A subset of mice in each CSF group were infused with 100 ng of ephrin-B2 (agonist of the EphB2 receptor) over a 14 day period. There were four study groups: patient CSF only, patient CSF + ephrin-B2, control CSF only, control CSF + ephrin-B2⁵. Results. Mice receiving patient CSF and ephrin-B2 did not show a significant decrease in NMDAR density compared to the control groups whereas mice receiving only patient CSF showed a significant decrease in NMDAR density compared to the control groups. Additionally, mice receiving patient CSF and ephrin-B2 showed only a mild change in memory at day 10 and no memory deficits at day 18. They also showed no depressive-like behavior. Mice receiving only patient CSF displayed memory deficits and depressive behavior⁵. Conclusions. EphB2 appears to play a protective role in preventing autoantibody-mediated NMDAR internalization. This finding was supported by quantification of NMDAR density and observed behavior in an experimental mouse model. While the disease can be treated with immunosuppressive and immunomodulatory medications⁶, this finding suggests a new therapeutic target for treating not only this disease, but other neurological and psychiatric diseases that involve similar disease mechanisms.

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