Neuromyelitis optica spectrum disorders (NMOSD) is widely recognized as a CNS demyelinating disease associated with AQP4-IgG (T cell–dependent antibody), and its trigger is still unclear. In addition, although the treatment of NMOSD currently can rely on traditional immunosuppressive and modulating agents, effective methods to predict the efficacy of these therapeutics are lacking.

In this study, high-throughput T-cell receptor (TCR) sequencing was performed on peripheral blood from 151 pretreatment patients with AQP4-IgG⁺ NMOSD and 151 healthy individuals. We compared the TCR repertoire of those with NMOSD with that of healthy individuals and identified TCR clones that were significantly enriched in NMOSD. In addition, we treated 28 patients with AQP4-IgG⁺ NMOSD with immunosuppressants and followed up for 6 months to compare changes in NMOSD-specific TCRs (NMOSD-TCRs) before and after treatment. Moreover, we analyzed transcriptome and single-cell B-cell receptor (BCR) data from public databases and performed T-cell activation experiments using antigenic epitopes of cytomegalovirus (CMV) to further explore the triggers of AQP4-IgG⁺ NMOSD.

Compared with healthy controls, patients with AQP4-IgG⁺ NMOSD had significantly reduced diversity and shorter CDR3 length of TCRβ repertoire. Furthermore, we identified 597 NMOSD-TCRs with a high sequence similarity that have the potential to be used in the diagnosis and prognosis of NMOSD. The characterization of NMOSD-TCRs and pathology-associated clonotype annotation indicated that the occurrence of AQP4-IgG⁺ NMOSD may be associated with CMV infection, which was further corroborated by transcriptome and single-cell BCR analysis results from public databases and T-cell activation experiments.

Our findings suggest that the occurrence of AQP4-IgG⁺ NMOSD may be associated with CMV infection. In conclusion, our study provides new clues to uncover the causative factors of AQP4-IgG⁺ NMOSD and provides a theoretical foundation for treating and monitoring the disease.

视神经脊髓炎谱系疾病 (NMOSD) 被广泛认为是一种与 AQP4-IgG（T 细胞依赖性抗体）相关的中枢神经系统脱髓鞘疾病，但其触发因素仍不清楚。此外，虽然目前NMOSD的治疗可以依靠传统的免疫抑制剂和调节剂，但缺乏有效的方法来预测这些疗法的疗效。

^{在这项研究中，对 151 名 AQP4-IgG +} NMOSD 预处理患者和 151 名健康个体的外周血进行了高通量 T 细胞受体 (TCR) 测序。我们将 NMOSD 患者的 TCR 库与健康个体的 TCR 库进行了比较，并鉴定了 NMOSD 显着富集的 TCR 克隆。此外，我们使用免疫抑制剂治疗了28例AQP4-IgG ⁺ NMOSD患者，并随访6个月，比较治疗前后NMOSD特异性TCR（NMOSD-TCR）的变化。^{此外，我们分析了来自公共数据库的转录组和单细胞 B 细胞受体 (BCR) 数据，并使用巨细胞病毒 (CMV) 抗原表位进行 T 细胞激活实验，以进一步探索 AQP4-IgG +}的触发因素NMOSD。

与健康对照相比，AQP4-IgG ⁺ NMOSD 患者的 TCRβ 库多样性显着降低，CDR3 长度更短。此外，我们还鉴定了 597 个具有高度序列相似性的 NMOSD-TCR，有可能用于 NMOSD 的诊断和预后。NMOSD-TCR的表征和病理相关克隆型注释表明AQP4-IgG ⁺ NMOSD的发生可能与CMV感染有关，公共数据库的转录组和单细胞BCR分析结果以及T细胞激活实验进一步证实了这一点。

^{我们的研究结果提示AQP4-IgG +} NMOSD的发生可能与CMV感染有关。总之，我们的研究为揭示AQP4-IgG ⁺ NMOSD的致病因素提供了新的线索，并为该疾病的治疗和监测提供了理论基础。