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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2023

Open Access 01-12-2023 | Anti-NMDA Receptor Encephalitis | Research

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

Authors: Yaqing Shu, Fuhua Peng, Bingchu Zhao, Chunxin Liu, Qihui Li, Huilu Li, Yuge Wang, Yanjun Jiang, Tingting Lu, Qin Wang, Jian Sun, Huiyu Feng, Zhengqi Lu, Xiaodong Liu, Jie Wang, Wei Qiu

Published in: Journal of Neuroinflammation | Issue 1/2023

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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−/−SirpαNODFlk2−/− 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.
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Metadata
Title
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
Authors
Yaqing Shu
Fuhua Peng
Bingchu Zhao
Chunxin Liu
Qihui Li
Huilu Li
Yuge Wang
Yanjun Jiang
Tingting Lu
Qin Wang
Jian Sun
Huiyu Feng
Zhengqi Lu
Xiaodong Liu
Jie Wang
Wei Qiu
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-023-02844-4

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