Neuromyelitis optica spectrum disorders (NMOSD) is widely recognized as a central nervous system demyelinating disease associated with AQP4-IgG (T cell-dependent antibody), and its triggers are still unclear. In addition, the treatment of NMOSD currently relies on traditional immunosuppressive and modulating agents, and there is still no effective method to predict the efficacy of these therapeutics.
In this study, we performed high-throughput T cell receptor (TCR) sequencing on 151 pre-treatment AQP4-IgG+ NMOSD and 151 healthy individuals. Significant characteristics in TCR repertoire were observed between the patients and healthy individuals. The diversity of TCRβ repertoire and CDR3 length were significantly lower in NMOSD than in healthy individuals, and the shorter CDR3 length was caused by shorter insertion.
597 NMOSD disease-specific T-cell receptors (NMOSD-TCRs) were identified as disease-associated TCR clones, significantly enriched in NMOSD. Compared with randomly sampled CDR3 sequences, the CDR3 sequences of these NMOSD-TCRs have higher sequence similarity and a stronger affinity for the T-cell epitope of AQP4 than the randomly sampled CDR3 sequences. The characterization of NMOSD-TCRs and annotation of pathogen clones indicated that the occurrence of NMOSD may be associated with CMV virus infection, which was further corroborated by transcriptome and single-cell BCR analysis results from public databases.
In addition, we compared the abundance of NMOSD-TCRs in 28 paired AQP4-IgG+ patients pre- and post-treatment. The abundance of NMOSD-TCRs was significantly reduced after treatment in patients with good efficacy but not in those with poor efficacy. It suggests that NMOSD-TCRs may be associated with drug efficacy and potentially be used for drug efficacy prediction. 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.