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¹ Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy
² Laboratory of Neuroimmunology, IRCCS Neurological Institute C. Mondino University of Pavia, 27100 Pavia, Italy
³ Department of Cellular & Molecular Neuroscience, Imperial College Faculty of Medicine, Charing Cross Hospital Campus, London W6 8RF, UK
⁴ Division of Infectious Diseases, San Raffaele Scientific Institute, 20127 Milano, Italy
⁵ Institute Pasteur-Cenci Bolognetti Foundation, Department of Experimental Medicine, University of Rome La Sapienza, 00161 Rome, Italy
⁶ Department of Neurology and Centro Neurologico Terapia Sperimentale (CENTERS), Ospedale S. Andrea, University of Rome La Sapienza, 00189 Rome, Italy

CORRESPONDENCE Francesca Aloisi: fos4{at}iss.it

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, has been associated with multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), but direct proof of its involvement in the disease is still missing. To test the idea that MS might result from perturbed EBV infection in the CNS, we investigated expression of EBV markers in postmortem brain tissue from MS cases with different clinical courses. Contrary to previous studies, we found evidence of EBV infection in a substantial proportion of brain-infiltrating B cells and plasma cells in nearly 100% of the MS cases examined (21 of 22), but not in other inflammatory neurological diseases. Ectopic B cell follicles forming in the cerebral meninges of some cases with secondary progressive MS were identified as major sites of EBV persistence. Expression of viral latent proteins was regularly observed in MS brains, whereas viral reactivation appeared restricted to ectopic B cell follicles and acute lesions. Activation of CD8⁺ T cells with signs of cytotoxicity toward plasma cells was also noted at sites of major accumulations of EBV-infected cells. Whether homing of EBV-infected B cells to the CNS is a primary event in MS development or the consequence of a still unknown disease-related process, we interpret these findings as evidence that EBV persistence and reactivation in the CNS play an important role in MS immunopathology.

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