Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis
Daniela F Angelini, Barbara Serafini, Eleonora Piras, Martina Severa, Eliana M Coccia, Barbara Rosicarelli, Serena Ruggieri, Claudio Gasperini, Fabio Buttari, Diego Centonze, Rosella Mechelli, Marco Salvetti, Giovanna Borsellino, Francesca Aloisi, Luca Battistini, Daniela F Angelini, Barbara Serafini, Eleonora Piras, Martina Severa, Eliana M Coccia, Barbara Rosicarelli, Serena Ruggieri, Claudio Gasperini, Fabio Buttari, Diego Centonze, Rosella Mechelli, Marco Salvetti, Giovanna Borsellino, Francesca Aloisi, Luca Battistini
Abstract
It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.
Conflict of interest statement
Marco Salvetti, MD, received lecture fees from Biogen-Dompé and research support from Bayer-Schering, Biogen-Dompé, Merck-Serono, Sanofi-Aventis. Claudio Gasperini, MD, has served as a consultant for Merck Serono and Biogen Idec, and has received speaker honoraria from Teva, Merck Serono, Bayer Shering and Biogec Idec. Diego Centonze, MD, is an Advisory Board member of Merck-Serono, Teva and Bayer Shering and received funding for travelling and speaker honoraria or consultation fees from Merck Serono, Teva, Novartis, Bayer Shering, Sanofi-Aventis and Biogen Idec. He is also an external expert consultant of the European Medicine Agency (EMA) and the principal investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Shering, Sanofi Aventis and Biogen Idec. The other authors have no competing interests to report. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials.
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