Transfer of patient’s peripheral blood mononuclear cells (PBMCs) disrupts blood–brain barrier and induces anti-NMDAR encephalitis: a study of novel humanized PBMC mouse model

Abstract

Abstract Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood–brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients. Methods In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients’ peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2 −/− Il2rg −/− Sirpα NOD Flk2 −/− mice. Results We found that engraftment of patients’ PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1β as a hub gene implicated in pathological changes. We further demonstrated that Il-1β was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors. Conclusions Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient’s lymphocytes.

Keywords

• Humanized mouse model
• Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis
• Peripheral blood mononuclear cells (PBMC)
• Blood–brain barrier (BBB)
• Il-1β
• Anakinra