From the College of Life Sciences (M., X.J.), University of Chinese Academy of Sciences, Beijing; Department of Neurology (Z.S., L.Z., S.T., H.C., X.W., Q.D., Y.Z., W.L., M.F., H.Z.), West China Hospital, Sichuan University, Chengdu; and City University of Hong Kong (W.Z., S.L.), Shenzhen Research Institute, China.
Neurol Neuroimmunol Neuroinflamm. 2023 Jul 6;10(5). doi: 10.1212/NXI.0000000000200134. Print 2023 Sep.
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水通道蛋白 4 免疫球蛋白 G（T 细胞依赖性抗体）相关的中枢神经系统脱髓鞘疾病，但其发病机制仍不清楚。此外，尽管 NMOSD 的治疗目前可以依赖于传统的免疫抑制和调节药物，但缺乏预测这些治疗方法疗效的有效方法。
本研究对 151 例 AQP4-IgG NMOSD 患者和 151 例健康个体的外周血进行了高通量 T 细胞受体（TCR）测序。我们比较了 NMOSD 患者与健康个体的 TCR 谱，确定了在 NMOSD 中明显富集的 TCR 克隆。此外，我们对 28 例 AQP4-IgG NMOSD 患者进行了免疫抑制剂治疗，并进行了 6 个月的随访，以比较治疗前后 NMOSD 特异性 TCR（NMOSD-TCR）的变化。此外，我们分析了公共数据库中的转录组和单细胞 B 细胞受体（BCR）数据，并使用巨细胞病毒（CMV）的抗原表位进行了 T 细胞激活实验，以进一步探讨 AQP4-IgG NMOSD 的触发因素。
与健康对照组相比，AQP4-IgG NMOSD 患者的 TCRβ repertoire 多样性显著降低，CDR3 长度也较短。此外，我们鉴定了 597 个具有高序列相似性的 NMOSD-TCR，它们有可能用于 NMOSD 的诊断和预后。NMOSD-TCR 的特征描述和与病理学相关的克隆型注释表明，AQP4-IgG NMOSD 的发生可能与 CMV 感染有关，这一结论进一步得到了公共数据库转录组和单细胞 BCR 分析结果以及 T 细胞激活实验的证实。
我们的研究结果表明，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，并为治疗和监测该疾病提供了理论基础。
