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

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

doi:10.1186/s12974-023-02844-4

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

J Neuroinflammation. 2023 Jul 13;20(1):164. doi: 10.1186/s12974-023-02844-4.

Authors

Yaqing Shu^#¹, Fuhua Peng^#¹, Bingchu Zhao², Chunxin Liu³, Qihui Li¹, Huilu Li¹, Yuge Wang¹, Yanjun Jiang^{4

5

6}, Tingting Lu¹, Qin Wang⁷, Jian Sun⁸, Huiyu Feng⁹, Zhengqi Lu¹, Xiaodong Liu^{10

11

12}, Jie Wang^{13

14

15}, Wei Qiu¹⁶

Affiliations

¹ Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
² Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan, 430071, China.
³ Department of Emergency, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
⁴ Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁵ Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁶ Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁷ Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
⁸ Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original BacteriaCollege of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
⁹ Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
¹⁰ Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. xdliu@cuhk.edu.hk.
¹¹ Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China. xdliu@cuhk.edu.hk.
¹² Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. xdliu@cuhk.edu.hk.
¹³ Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan, 430071, China. jie.wang@wipm.ac.cn.
¹⁴ Institute of Neuroscience and Brain Diseases; Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China. jie.wang@wipm.ac.cn.
¹⁵ University of Chinese Academy of Sciences, Beijing, 100049, China. jie.wang@wipm.ac.cn.
¹⁶ Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China. qiuwei@mail.sysu.edu.cn.

^# Contributed equally.

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^NODFlk2^-/- 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: Anakinra; Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis; Blood–brain barrier (BBB); Humanized mouse model; Il-1β; Peripheral blood mononuclear cells (PBMC).

MeSH terms

Animals
Anti-N-Methyl-D-Aspartate Receptor Encephalitis*
Autoantibodies
Blood-Brain Barrier
Disease Models, Animal
Endothelial Cells
Leukocytes, Mononuclear
Mice
Mice, Inbred NOD
Receptors, N-Methyl-D-Aspartate

Substances

Autoantibodies
Receptors, N-Methyl-D-Aspartate

Abstract

MeSH terms

Substances

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