Epstein-Barr virus and Multiple Sclerosis: in-depth analysis of the virus-specific antibody response at the time of diagnosis and during therapy

Introduction: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) of unknown etiology. Seroepidemiological observations had associated MS to Epstein-Barr virus (EBV), a human !-herpesvirus with a widespread distribution in the human population. The first part of this study aimed to investigate this association by doing an in-depth analysis of the virus specific antibody response in a large cohort of MS patients and neurological controls. The second goal of the research was to verify the use of EBV-specific antibodies as biomarker for the response to treatment with disease modifying therapy. Methods: Serum and cerebrospinal fluid (CSF) concentrations, intrathecal synthesis, oligoclonal pattern and affinity distribution of EBV-specific IgG were determined in 100 multiple sclerosis relapsing-remitting (RRMS) patients and 200 age/sex matched controls with other inflammatory neurological disorders (OIND) and other non-inflammatory neurological disorders (NIND) at the time of diagnosis. Temporal fluctuations of EBV-specific IgG were measured in 20 RRMS patients treated with TYSABRI® for the first 15 months of therapy. Results: Levels of anti-EBNA-1 and anti-VCA IgG were different among RRMS, OIND and NIND in CSF (p<0.0001 and p<0.01, respectively) and serum (p<0.001 and p<0.05, respectively) samples. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by Antibody Index, was underrepresented in RRMS (6% and 2% respectively), in OIND (7% and 5%, respectively) and in NIND (2% and 1%, respectively). EBV-specific IgG oligoclonal bands (OCB) were detected in 24% RRMS patients and absent in controls. High-affinity antibodies were more frequent in RRMS than in NIND for CSF anti-EBNA-1 IgG (p<0.05) and for serum anti-VCA IgG (p<0.01) and in RRMS and OIND than in NIND for CSF anti-VCA IgG (p<0.05). After treatment with 5M of NaSCN, EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed. During 15 months of TYSABRI® therapy, temporal fluctuations of EBV-specific antibodies were not affected by drug treatment. This lack of statistical significance was also reflected in the comparison between patients who responded to treatment and patients who otherwise had relapsed during this period. Interpretation: Taken together these results do not support the potential role of an EBV persistent brain chronic infection in MS and suggest that an EBV-specific intrathecal oligoclonal IgG production can occur in a subset of MS patients as part of humoral polyreactivity driven by chronic brain inflammation. Moreover, our data argue against the use of EBV-specific antibodies as biomarker for monitoring therapeutic response to TYSABRI®.