Cerebrospinal fluid exosomal Epstein-Barr virus microRNAs in multiple sclerosis and effects of disease modifying therapies

Abstract

Epstein-Barr virus (EBV) may be crucial for development of multiple sclerosis (MS). EBV encodes 44 microRNAs (miRNAs) that are found in exosomes. We investigated EBV miRNAs in cerebrospinal fluid (CSF) exosomes in 50 newly diagnosed people with relapsing-remitting MS (pwRRMS), 24 with clinically isolated syndromes (CIS), 45 symptomatic controls (SC), 15 anti-CD20 antibody-treated 24 natalizumab (NTZ)-treated pwRRMS. miRNAs were measured by quantitative PCR. Plasma anti-EBNA1 antibody and various CSF biomarkers were measured by immunoassays. ebv-miR-BART13-5p and ebv-miR-BART19-3p were reliably measured. ebv-miR-BART19-3p was lower in pwRRMS and correlated with disease severity. In NTZ-treated pwRRMS, ebv-miR-BART19-3p was higher, correlated with treatment duration, and was associated with soluble B-cell maturation antigen, CD27, and zonula occludens-1. No differences were observed in anti-CD20 antibody-treated pwRRMS. These findings may reflect the presence of more exosome recipient cells in pwRRMS, resulting in fewer exosomes as they become internalized in recipient cells along with their EBV miRNA cargo.