Immunoregulatory programs in anti-N-methyl-D-aspartate receptor encephalitis identified by single-cell multi-omics analysis

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-01-08 DOI:10.1002/ctm2.70173

Xinhui Li, Yicong Xu, Weixing Zhang, Zihao Chen, Dongjie Peng, Wenxu Ren, Zhongjie Tang, Huilu Li, Jin Xu, Yaqing Shu

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引用次数: 0

Abstract

Background

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a prevalent type of autoimmune encephalitis caused by antibodies targeting the NMDAR's GluN1 subunit. While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immunological mechanisms underlying anti-NMDARE remain elusive. This study aimed to characterize immune cell interactions and dysregulation in anti-NMDARE by leveraging single-cell multi-omics sequencing technologies.

Methods

Peripheral blood mononuclear cells (PBMCs) from patients in the acute phase of anti-NMDARE and healthy controls were sequenced using single-cell joint profiling of transcriptome and chromatin accessibility. Differential gene expression analysis, transcription factor activity profiling, and cell-cell communication modeling were performed to elucidate the immune mechanisms underlying the disease. In parallel, single-cell B cell receptor sequencing (scBCR-seq) and repertoire analysis were conducted to assess antigen-driven clonal expansion within the B cell population.

Results

The study revealed a significant clonal expansion of B cells, particularly plasma cells, in anti-NMDARE patients. The novel finding of type I interferon (IFN-I) pathway activation suggests a regulatory mechanism that may drive this expansion and enhance antibody secretion. Additionally, activation of Toll-like receptor 2 (TLR2) in myeloid cells was noted, which may connect to tumor necrosis factor-alpha (TNF-α) secretion. This cytokine may contribute to the activation of B and T cells, thereby perpetuating immune dysregulation.

Conclusions

This study presents a comprehensive single-cell multi-omics characterization of immune dysregulation in anti-NMDARE, highlighting the expansion of B cell and the activation of the IFN-I and TLR2 pathways. These findings provide deeper insights into the molecular mechanism driving the pathogenesis of anti-NMDARE and offer promising targets for future therapeutic intervention.

Key points

Significant B cell clonal expansion, particularly in plasma cells, driven by antigen recognition.
IFN-I pathway activation in plasma cells boosts their antibody production and potentially exacerbates immune dysregulation.
TLR2 pathway activation in myeloid cells contributes to TNF-α secretion and could influence adaptive immune responses.

Abstract Image

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单细胞多组学分析鉴定抗n -甲基- d -天冬氨酸受体脑炎的免疫调节程序。

背景：抗n -甲基- d -天冬氨酸受体脑炎（anti-NMDARE）是一种常见的自身免疫性脑炎，由靶向NMDAR的GluN1亚基的抗体引起。虽然在阐明自身免疫性疾病的病理生理方面取得了重大进展，但抗nmdare的免疫学机制仍然难以捉摸。本研究旨在利用单细胞多组学测序技术表征抗nmdare免疫细胞相互作用和失调。方法：采用单细胞联合转录组和染色质可及性分析对抗nmdare急性期患者和健康对照的外周血单个核细胞（PBMCs）进行测序。通过差异基因表达分析、转录因子活性分析和细胞间通讯模型来阐明该疾病的免疫机制。同时，进行了单细胞B细胞受体测序（scBCR-seq）和库分析，以评估B细胞群体中抗原驱动的克隆扩增。结果：研究显示抗nmdare患者的B细胞，特别是浆细胞有显著的克隆扩增。I型干扰素（IFN-I）通路激活的新发现提示了一种可能驱动这种扩展并增强抗体分泌的调节机制。此外，髓细胞中toll样受体2 （TLR2）的激活可能与肿瘤坏死因子α (TNF-α)的分泌有关。这种细胞因子可能有助于B细胞和T细胞的激活，从而使免疫失调永久化。结论：本研究对抗nmdare免疫失调进行了全面的单细胞多组学表征，强调了B细胞的扩增和IFN-I和TLR2通路的激活。这些发现为探究抗nmdare的分子机制提供了更深入的见解，并为未来的治疗干预提供了有希望的靶点。重点：在抗原识别驱动下，显著的B细胞克隆扩增，特别是在浆细胞中。血浆细胞中IFN-I通路的激活促进了它们的抗体产生，并可能加剧免疫失调。髓细胞中TLR2通路的激活有助于TNF-α的分泌，并可能影响适应性免疫反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.