Early multiple sclerosis activity associated with TBX21⁺CD21^loCXCR3⁺ B cell expansion resembling EBV-induced phenotypes

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Abstract

Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) onset and plays a poorly understood etiologic role. To investigate possible viral pathogenesis, we analyzed single-cell expression in peripheral B cells from people with early MS collected longitudinally during the Immune Tolerance Network STAyCIS Trial. Expression profiles were compared with single-cell RNA-Seq (scRNA-Seq) from in vitro EBV models, autoimmune disorders, chronic infectious diseases, and healthy controls. Analyses focused on CD19+CD20+CD21loCD11c+T-bet+ atypical B cells (ABCs). ABCs were significantly enriched in early MS PBMCs versus healthy controls by scRNA-Seq and flow cytometry, establishing ABC expansion as a clinical feature. EBV-associated ABC expression, including CXCR3, programmed cell death ligand 1 (PD-L1), and PD-L2, was enriched in early MS; however, direct EBV infection of ABCs was not detected. Early MS ABCs exhibited significantly upregulated inflammatory cytokine mRNAs (CXCL8, IL18, VEGFA). Further, de novo EBV-infected B cells secreted IL-8 and VEGF. MS activity stratification revealed rare, distinctive inflammatory ABCs significantly underrepresented in individuals with no evidence of activity long-term versus people with additional relapsing-remitting MS activity at the primary endpoint. Moreover, CXCR3+ ABCs increased after baseline diagnosis and were significantly enriched in people with disease exacerbation during the study. Thus, ABC expansion and inflammatory responses correlate to early MS activity, possibly as a bystander response to EBV.

Authors

Elliott D. SoRelle, Ellora Haukenfrers, Gillian Q. Horn, Vaibhav Jain, James Giarraputo, Karen Abramson, Emily Hocke, Laura A. Cooney, Kristina M. Harris, Scott S. Zamvil, Simon G. Gregory, Micah A. Luftig