Altered immune landscape of cervical lymph nodes reveals Epstein-Barr virus signature in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and Epstein-Barr virus (EBV) infection is a prerequisite for developing the disease. However, the pathogenic mechanisms that lead to MS remain to be determined. Here, we characterized the immune landscape of deep cervical lymph nodes (dcLNs) in newly diagnosed untreated patients with MS (pwMS) using fine-needle aspirations. By combining single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing, we observed increased memory B cells and reduced germinal center B cells with decreased clonality in pwMS. Double-negative memory B cells were increased in pwMS that transcriptionally resembled B cells with a lytic EBV infection. Moreover, EBV-targeting memory CD8 T cells were detected in a subset of pwMS. We also detected increased EBV DNA in dcLNs and elevated viral loads in patient saliva. These findings suggest that EBV-driven B cell dysregulation is a critical mechanism in MS pathogenesis.