An EBV-associated atypical B cell signature in clinically isolated syndrome is implicated in progression of multiple sclerosis

Abstract

ABSTRACTExpansion and pathogenicity of CD19+/CD20+/CD11c+/T-bet+atypical B cells (ABCs) are hallmarks of numerous autoimmune disorders and chronic infections. In many such cases Epstein-Barr virus (EBV) is another associated or etiologic factor, though EBV involvement in these diseases remains poorly understood. Notably, the expansion of pro-inflammatory ABCs and a putative causal role for EBV have been identified independently in multiple sclerosis (MS). A common precipitating event in MS onset is Clinically Isolated Syndrome (CIS), a neuroinflammatory demyelinating condition of which 60-80% of cases progress to relapsing-remitting MS (RRMS). Here we report single-cell gene and surface protein expression (scRNA/CITE-seq) in peripheral B cells collected longitudinally from patients with CIS during the Immune Tolerance Network STAyCIS Trial. We focus on the transcriptomic signatures of ABCs from this cohort, publicly available scRNA-seq datasets from six other autoimmune and chronic infectious diseases, andin vitroEBV infection. Conservation of an expanded ABC expression profile across diseases establishes ABC dysregulation as a feature of CIS. Critically, we also observed transcriptomic features that distinguished CIS andde novoEBV-infected ABCs from those found in healthy controls and other disease contexts. Outcome stratification of CIS samples revealed a rare yet distinctive pro-inflammatory ABC subset that was significantly underrepresented in long-term non-progressor (LTNP) versus cases with RRMS activity (∼5-fold difference). Collectively, this study provides evidence for altered ABC regulation – possibly arising from niche-specific responses to EBV infection – preceding MS onset.SUMMARYSingle-cell transcriptomics establishes an EBV-associated signature in T-bet+atypical B cells in CIS and a pro-inflammatory phenotype underrepresented in patients with no disease progression.