Epstein-Barr virus reactivation is associated with altered immune cell profiles in peripheral blood and cerebrospinal fluid of treatment-naive multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, with autoimmune and neurodegenerative components, recently linked with Epstein-Barr virus (EBV) infection. To investigate immunological alterations associated with EBV reactivation (EBV-R) in MS we analyzed immune cell profiles in matched peripheral blood (PB) and cerebrospinal fluid (CSF) samples from treatment-naive MS patients, in relation to plasma EBV serology markers. In our Hellenic MS cohort, 12 of 33 patients (39 %) exhibited serological evidence of EBV-R (VCA IgG+ with VCA IgA+, VCA IgM+, or EA(D) IgG+), and 7 of these 12 also tested positive for plasma BZLF1 mRNA, indicative of lytic infection. EBV-R patients showed reduced CD19+ B cells in PB and equal proportions in CSF compared to patients with latent EBV infection. Conversely, EBV-R patients showed increased cytotoxic CD56 NK cells and CD14 monocytes in PB, while cytotoxic CD56 NK cells remained absent in the CSF, regardless of EBV status. Proportions of regulatory CD56 NK cells were reduced in both PB and CSF during EBV-R. Our results reveal that MS patients with serological evidence of EBV-R show altered immune responses, with reduced B cell proportions in the PB in the presence of expanded cytotoxic NK cells, and unaffected B cell proportions in CSF in the absence of cytotoxic NK cell surveillance.