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<p>Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE) is a devastating autoimmune disease associated with the presence of autoantibodies targeting NMDAR1 in the cerebrospinal fluid (CSF) and serum of patients. Besides the critical roles of anti-NMDAR1 autoantibodies, studies have implicated other factors such as brain inflammation in NMDARE. To comprehensively uncover the molecular mechanisms underlying NMDARE, here we performed multi-omics analyses based on human forebrain organoids (hFOs). The transcriptomic and metabolomic analyses showed that hFOs exposed to either monoclonal anti-NMDAR1 IgG antibodies or purified patient CSF-derived IgG antibodies alone led to NMDAR hypofunction that caused a reduction of glutamate content and neuroactivities. Interestingly, hFOs exposed to either patient CSF or IgG-depleted patient CSF led to neuronal hyperexcitability rather than hypo neuroactivities. The following proteomic analysis and electrophysiological assays identified that the activated interleukin (IL)-17 signaling pathway in patient CSF accounted for the neuronal hyperexcitability. Neutralizing IL-17 alleviated the neuronal hyperexcitability in hFOs and seizure-like behaviors in mice exposed to CSF from NMDARE patients. Together, this study indicated that the anti-NMDAR1 antibodies and IL-17 signaling pathway shape NMDARE. Inactivating the IL-17 signaling pathway could be a potential therapeutic strategy for NMDARE treatment.</p>

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The anti-NMDAR1 antibodies and IL-17 signaling pathway shape NMDAR encephalitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Zhenhong Xu,
  • Hongye Yan,
  • Bo Wang,
  • Juan Wan,
  • Huimin Wang,
  • Ye Xia,
  • Yong U. Liu,
  • Xuejing Wang,
  • Heng Wu,
  • Jiamei Jiang,
  • Lin Zeng,
  • Beisha Tang,
  • Qingtuan Meng

摘要

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE) is a devastating autoimmune disease associated with the presence of autoantibodies targeting NMDAR1 in the cerebrospinal fluid (CSF) and serum of patients. Besides the critical roles of anti-NMDAR1 autoantibodies, studies have implicated other factors such as brain inflammation in NMDARE. To comprehensively uncover the molecular mechanisms underlying NMDARE, here we performed multi-omics analyses based on human forebrain organoids (hFOs). The transcriptomic and metabolomic analyses showed that hFOs exposed to either monoclonal anti-NMDAR1 IgG antibodies or purified patient CSF-derived IgG antibodies alone led to NMDAR hypofunction that caused a reduction of glutamate content and neuroactivities. Interestingly, hFOs exposed to either patient CSF or IgG-depleted patient CSF led to neuronal hyperexcitability rather than hypo neuroactivities. The following proteomic analysis and electrophysiological assays identified that the activated interleukin (IL)-17 signaling pathway in patient CSF accounted for the neuronal hyperexcitability. Neutralizing IL-17 alleviated the neuronal hyperexcitability in hFOs and seizure-like behaviors in mice exposed to CSF from NMDARE patients. Together, this study indicated that the anti-NMDAR1 antibodies and IL-17 signaling pathway shape NMDARE. Inactivating the IL-17 signaling pathway could be a potential therapeutic strategy for NMDARE treatment.