Single-cell transcriptomics reveals cell type–specific immune regulation associated with anti-NMDA receptor encephalitis in humans

Jiang, Yuling; Dai, Shuhua; Lu, Jia; Qin, Lingzhi; Zhang, Milan; Liu, Huiqin; Wang, Xiaojuan; Pang, Rui; Zhang, Jiewen; Guo, Peng; Li, Wei

doi:10.3389/fimmu.2022.1075675

Cited by 5 publications

(3 citation statements)

References 72 publications

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“…The variability and diversity of antibodies induced by synthetic peptide are less pronounced, due to the small size of the peptide. In addition, the holoprotein immunization model is more dependent on T-cell involvement, whereas the synthetic peptide immunization model has been confirmed to involve B-cell-mediated pathology, which is consistent with clinical research (Liba et al, 2016 ; Scheibe et al, 2017 ; Wagnon et al, 2020 ; Jiang et al, 2022 ). Active immunization with the GluN1 356 − 385 peptide that targeted the amino-terminal domain of the GluN1 subunit (GluN1 356 − 385 ) has been reported in an adult model (Ding et al, 2021 ).…”

Section: Introductionsupporting

confidence: 77%

A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization

He,

Sun,

Zhu

et al. 2023

Front. Mol. Neurosci.

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IntroductionAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models.MethodsWe developed a model of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1356 − 385) against NMDARs in 3-week-old female C57BL/6J mice.ResultsImmunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed.ConclusionThe juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis.

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Section: Introductionsupporting

confidence: 77%

A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization

He,

Sun,

Zhu

et al. 2023

Front. Mol. Neurosci.

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“…T lymphocytes and B lymphocytes have been found in brain samples from patients with anti-NMDAR encephalitis ( 24 ). Single-cell sequencing confirmed the activation and differentiation of B lymphocytes and the amplification of plasma cells in anti-NMDAR encephalitis ( 25 ). Mild perivascular lymphocytic cuffing, microglial activation, and a decrease in NMDAR density have been observed in the hippocampus during a brain biopsy or autopsy ( 2 , 24 ).…”

Section: Anti-nmdar Encephalitis and Nmda Receptorsmentioning

confidence: 80%

Anti-NMDAR antibodies, the blood–brain barrier, and anti-NMDAR encephalitis

Gong,

Wang,

Zhu

et al. 2023

Front. Neurol.

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Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an antibody-related autoimmune encephalitis. It is characterized by the existence of antibodies against NMDAR, mainly against the GluN1 subunit, in cerebrospinal fluid (CSF). Recent research suggests that anti-NMDAR antibodies may reduce NMDAR levels in this disorder, compromising synaptic activity in the hippocampus. Although anti-NMDAR antibodies are used as diagnostic indicators, the origin of antibodies in the central nervous system (CNS) is unclear. The blood–brain barrier (BBB), which separates the brain from the peripheral circulatory system, is crucial for antibodies and immune cells to enter or exit the CNS. The findings of cytokines in this disorder support the involvement of the BBB. Here, we aim to review the function of NMDARs and the relationship between anti-NMDAR antibodies and anti-NMDAR encephalitis. We summarize the present knowledge of the composition of the BBB, especially by emphasizing the role of BBB components. Finally, we further provide a discussion on the impact of BBB dysfunction in anti-NMDAR encephalitis.

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“…However, its application in autoimmune encephalitis such as NMDAR-E is not yet widespread. To our knowledge, only three studies have reported the transcriptomic and immunological characteristics of B cell subsets in the CSF, peripheral blood (PB), and teratoma tissues of NMDAR-E patients [26][27][28] . To date, no studies have reported the transcriptomic and immunological characteristics of T cell subsets in CSF and PB of NMDAR-E patients.…”

mentioning

confidence: 99%

Single-cell analyses of CSF and PBMCs from anti-NMDAR encephalitis patients reveals distinct characteristics of T cell subpopulations

Yang

et al. 2023

Preprint

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BackgroundAnti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) is a rare and severe form of antibody-mediated autoimmune encephalitis. While the roles of B cells and NMDAR antibodies in NMDAR-E have been extensively studied, the contribution of T cell subsets to the development of the disease remains unclear.MethodsWe utilized single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) to examine a comprehensive collection of 45,088 individual immune cells sourced from both NMDAR-E patients and control subjects. Besides, we incorporated 14,536 immune cells obtained from a publicly available database. Additionally, cytometry analysis was conducted on samples from 60 NMDAR-E patients (with 89 samples) and 44 individuals in the control group. To investigate the influence of CD8+T cells on B cells, we performed in vitro co-culture experiments.ResultsWe observed the activation of effector memory CD8+T cells in the CSF and peripheral blood (PB) of NMDAR-E patients, accompanied by an expansion of TCR clones. These clonal CD8+T cells exhibited upregulated gene expression associated with cytotoxicity and cell trafficking. Furthermore, we detected elevated levels of KIR+CD8+T cells in the CSF and PB of NMDAR-E patients. Cell communication analysis revealed that these inhibitory KIR+CD8+T cells could interact with B cells through MHC-I molecules. Surprisingly, CD8+T cells isolated from the PB of NMDAR-E patients induced autologous B cell death, resulting in a higher rate of B cell apoptosis compared to the control group.ConclusionActivated CD8+T cells with TCR clones in NMDAR-E patients may contribute to the pathogenesis of NMDAR-E.

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Single-cell transcriptomics reveals cell type–specific immune regulation associated with anti-NMDA receptor encephalitis in humans

Cited by 5 publications

References 72 publications

A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization

A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization

Anti-NMDAR antibodies, the blood–brain barrier, and anti-NMDAR encephalitis

Single-cell analyses of CSF and PBMCs from anti-NMDAR encephalitis patients reveals distinct characteristics of T cell subpopulations

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