Author:
Shu Yaqing,Peng Fuhua,Zhao Bingchu,Liu Chunxin,Li Qihui,Li Huilu,Wang Yuge,Jiang Yanjun,Lu Tingting,Wang Qin,Sun Jian,Feng Huiyu,Lu Zhengqi,Liu Xiaodong,Wang Jie,Qiu Wei
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−/−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.
Funder
National Natural Science Foundation of China
Guangdong Basic and Applied Basic Research Fund
Key project of Guangdong Basic and Applied Basic Research Fund
Guangzhou Municipal School (Hospital) Joint Funding
Municipal Key Laboratory Construction Project
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology,Immunology,General Neuroscience
Cited by
1 articles.
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