Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease of the central nervous system (CNS) that, despite overlapping phenotypic features with multiple sclerosis (MS), manifests with more severe clinical outcomes. The defining pathogenic driver of NMOSD is the aquaporin-4 (AQP4) autoantibody, which induces astrocytic injury via complement-dependent cytotoxicity (CDC). MS is predominantly managed with disease-modifying therapies (DMTs) such as interferon-beta (IFN-β) to reduce relapse rates. However, these therapies are often ineffective or even detrimental in NMOSD. Our findings demonstrate that while IFN-β mitigates experimental autoimmune encephalomyelitis (EAE), it exacerbates NMOSD-like astrocytopathy. Deleting IFNAR1 counteracts this effect by selectively enhancing astrocyte activation without altering other CNS cells. Subsequently, we characterized multiple MS therapeutics that paradoxically worsen NMOSD-like pathology, whereas agents promoting astrocytic activation confer protection. Collectively, we establish a framework for astrocyte-centered drug screening and underscore the therapeutic potential of targeting astrocytes in NMOSD, connecting fundamental disease mechanisms to clinical applications.
Qing Fu,Xuhuai Fu,Jinzhou Feng,Jing Wang,Jinyu Jiang,Shijia Ding,Daobin Han,Manxia Wang
Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system demyelinating disease that typically causes severe visual impairment and paralysis, and the aquaporin-4 antibodies (AQP4-IgG) serve as its specific diagnostic marker. In patients presenting with typical NMOSD symptoms, a positive AQP4-IgG result is sufficient to confirm the diagnosis. However, current clinical methods for detecting AQP4-IgG suffer from limited sensitivity, time-consuming procedures, and labor-intensive workflows, underscoring the urgent need for more efficient and reliable diagnostic approaches. To address these limitations, we report a novel electrochemical biosensor leveraging a hierarchical ZIF-67@PDA@PtCu nanozyme for ultrasensitive and rapid AQP4-IgG detection. ZIF-67@PDA@PtCu, a composite material consisting of a ZIF-67 core coated with polydopamine (PDA) and further decorated with PtCu nanoparticles, was utilized as a signal amplification component. The PtCu alloy nanoflowers demonstrated exceptional catalytic activity, which was further amplified by the sturdy ZIF-67 framework that enabled the integration of additional functional materials. In parallel, PDA enhanced the synergy between the unsaturated edge sites of the metal-organic framework and the outstanding catalytic properties of the PtCu alloy, thereby boosting the overall performance of the system. The integration of graphene oxide (GO) and gold nanoparticles (AuNPs) enhanced electrical conductivity. This configuration enabled efficient electrochemical (EC) signal generation, facilitating the detection of AQP4-IgG with high stability, a broad detection range of 0.1–80 U mL −1 , and an impressively low detection limit of 0.05 U mL −1 . Our findings offer a novel approach for the early diagnosis of NMOSD and provide valuable insights into the detection of other antibody-dependent neuroimmune disorders.
Yang Hong,Wu Yi-Fan,Ding Jie,Liu Wei,Zhu De-Sheng,Shen Xia-Feng,Guan Yang-Tai
Background: N6-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. But its role in neuromyelitis optica spectrum disorders (NMOSD) is not known.Aims: To explore the mechanism of m6A in NMOSD patients.Methods: This study assessed the m6A methylation levels in blood from two groups: NMOSD patients and healthy controls. Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) and RNA-seq were performed to assess differences in m6A methylation between NMOSD patients and healthy controls. Ultra-high performance liquid chromatography coupled with triple quadruple mass spectrometry (UPLC-QQQ-MS) method was performed to check m6A level. Differential m6A methylation genes were validated by MeRIP-qPCR.Results: Compared with that in the control group, the total m6A level was decreased in the NMOSD group. Genes with upregulated methylation were primarily enriched in processes associated with RNA splicing, mRNA processing, and innate immune response, while genes with downregulated methylation were enriched in processes associated with the regulation of transcription, DNA-templating, and the positive regulation of I-kappa B kinase/NF-kappa B signalling.Conclusion: These findings demonstrate that differential m6A methylation may act on functional genes to regulate immune homeostasis in NMOSD.
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