Reactivation of Human Herpesvirus 6 and Epstein-Barr Virus in relapsing remitting multiple sclerosis: association with disabilities, disease progression, and inflammatory processes.

Background: Multiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS). Reactivation of Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) is observed in MS. Objectives: This study investigates immunoglobulins (Ig)G, IgM, and IgA directed against EBV nuclear antigen EBNA-366-406, HHV-6 and EBV deoxyuridine- triphosphatase (dUTPase), and different immune profiles in 58 patients with relapsing remitting MS (RRMS) compared to 60 healthy controls. Methods: We employed enzyme-linked immunosorbent assays (ELISA) to measure the immunoglobulins to viral antigens. Multiplex immunoassays were used to measure cytokines, chemokines and growth factor levels that were used to compute immune profiles, including M1 macrophage, T helper (Th)-1, Th-17, and overall immune activation. We assessed disabilities using the Expanded Disability Status Scale (EDSS) and disease progression using the Multiple Sclerosis Severity Score (MSSS). Results: IgG/IgA/IgM directed to the three viral antigens were significantly higher in RRMS than in controls. RRMS was significantly discriminated from controls by using IgG and IgM against HHV-6 dUTPase, yielding an accuracy of 91.5% (sensitivity=87.3% and specificity=95.2%). Neural network analysis showed that using IgG to EBV- dUTPase, IgM to EBV-dUTPase, and immune profiles yielded an area under the ROC curve of 1 and a predictive accuracy of 97.1%. There were strong associations between IgG/IgM responses to HHV-6 and EBV-dUTPases and the EDSS/MSSS scores and aberrations in M1, Th-17, profiles, and overall immune activation. Conclusions: HHV-6 and EBV reactivation play a key role in RRMS and these effects are mediated by activation of cytokine profiles.