Potential Association Identified Between Cytomegalovirus Infections and AQP4-IgG-Seropositive NMOSD

Recently published in Neurology Neuroimmunology Neuroinflammation, findings from a study demonstrated that cytomegalovirus (CMV) infection may be a potential trigger for the occurrence of aquaporin-4 immunoglobulin seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD).1 These results provide indications to the potential of NMOSD T-cell receptors (TCRs) as markers for predicting the efficacy of immunosuppression among patients with the disease.

Among a total of 302 patients, those with AQP4-IgG+ NMOSD (n = 151) had significantly reduced diversity and shorter complementarity determining region 3 (CDR3) of TCRβ repertoire compared with the healthy controls (n = 151). Additionally, in the analysis researchers identified 597 NMOSD-TCRs with a high sequence similarity that may have some potential to be utilized in the diagnosis and prognosis of patients living with 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 B-cell receptor (BCR) analysis results from public databases and T-cell activation experiments,” cosenior author Hongyu Zhou, PhD, professor of neurology, West China Hospital, Sichuan University, Chengdu in China, and colleagues wrote.¹

All told, high throughput TCR sequencing was conducted on peripheral blood from pretreated patients with AQP4-IgG+ NMOSD and healthy individuals who were recruited from West China Hospital between October 2014 and March 2017. Following that, TCR repertoire of those with NMOSD was compared with that of healthy individuals, which showed that TCR clones were significantly enriched in NMOSD.

Additionally, patients with AQP4-IgG+ NMOSD (n = 28) treated with immunosuppressants were followed up for 6 months to compare the changes in NMOSD-specific TCRs pre- and posttreatment. Moreover, transcriptome and single-cell BCR data from public databases were analyzed and T-cell activation experiments were performed using antigenic epitopes of CMV to further assess the triggers of AQP4-IgG+ NMOSD.

According to the findings, TCRβ diversity was limited with fewer unique clones and a higher proportion of nonfunctional TCR clones in patients with NMOSD compared with healthy individuals. Notably, the shorter CDR3 sequences in NMOSD-TCRs as observed by the researchers suggested that there may be an increase self recognition risk that can possibly lead to autoimmune disease.

All told, based on the clonotype analysis and antigenic epitope predictions, the results demonstrated that NMOSD may be associated with viral infections. In addition, the transcriptome data showed enrichment in viral infection and innate immunity pathways among patients with NMOSD. Patients with NMOSD experienced elevated interferon related and viral infection related gene expression along with a specific antibody clonotype (AQP4-IgG1) that had a higher affinity for AQP4, explaining the potential link of NMOSD and CMV infection.

The change in the TCR characteristics posttreatment among patients with NMOSD suggested that NMOSD-TCRs may serve as prognosis predictors, especially for those who have good treatment responses. Authors hypothesized that CMV induces clonal expansion of self-reactive T cells and this contributes to the pathogenesis of NMOSD by activating innate immune signaling pathways, which then leads to neural demyelination. In addition, the crossreactive antigenic epitopes between C perfringens and CMV, both of which seemingly interact with AQP4, may underline the involvement of multiple pathogens in NMOSD as influenced by their various genetic background across different populations.

“To verify that CMV infection is associated with NMOSD, we performed antigen peptide stimulation experiments in vitro and initially indicated that CMV antigen peptides could activate antigen specific CD4+ T cells from the periphery of patients with NMOSD, which was not found in healthy individuals. It is suggested that CMV may be involved in NMOSD pathogenesis through the activation of self-reactive T cells,” Zhou et al noted.¹

As for the limitations, authors noted that the pathology clonotype annotation of NMOSD-TCRs might be influenced by the antigen preference of the database. Also, they noted that further research is needed to confirm the possibility that NMOSD is associated with CMV infection. In addition, authors recommended further antigen crossreactivity experiments and validation in animal models to confirm whether CMV activates self-reactive T cells through molecular mimetic mechanisms and thus participates in the pathogenesis of NMOSD.

REFERENCES
1. Miao Y, Shi Z, Zhang W, et al. Immune Repertoire Profiling Reveals Its Clinical Application Potential and Triggers for Neuromyelitis Optica Spectrum Disorders. Neurol Neuroimmunol Neuroinflamm. 2023;10(5):e200134. Published 2023 Jul 6. doi:10.1212/NXI.0000000000200134