Background: Infectious mononucleosis caused by the Epstein-Barr virus has been associated with increased risk of multiple sclerosis. However, little is known about the characteristics of this association.Objective: To assess the significance of sex, age at and time since infectious mononucleosis, and attained age to the risk of developing multiple sclerosis after infectious mononucleosis.

The aetiology and pathogenesis of MS are unknown, but environmental agents, genetic susceptibility and stochastic events are likely to be involved. In order to evaluate the possibility that MS is linked to EBV infection, we here evaluate studies on MS- and EBV-epidemiology, prospective and retrospective analysis of EBV-serology, investigations of EBV DNA sequences in blood and tissues, specificity of antibodies in oligoclonal bands in MS patients and results from antiviral chemotherapy of MS patients. It could be demonstrated that EBV is complying with the epidemiological observations in MS and that all MS patients are seropositive to EBV in contrast to healthy controls. Importantly, despite difficulties in diagnosing child-MS, the vast majority of these patients are also EBV seropositive. In contrast to control groups, recent EBV infections have never been observed in children or adults with MS. Further prospective studies indicate a 2.8 times higher tendency for development of MS after infectious mononucleosis. In MS patients, unbiased analyses pull out EBV antigens as high-affinity targets for the antibodies in the oligoclonal bands. Humans are the exclusive natural host for EBV, a finding that may explain why MS is unique to humans. Together these unique observations strongly suggest a linkage between MS and EBV infection. Infection by EBV offers numerable mechanisms to perturb the immune system, including mimicry and superantigen induction, which may potentially participate in the disease mechanisms. In contrast, studies demonstrating higher IgG titres and occurrence of viral DNA in serum/plasma are likely to reflect a consequence of the disease. An explanation for a potential role of respiratory diseases in MS is discussed. It is concluded that the ultimate test to the hypothesis of MS and EBV is the development and application of an EBV vaccine, which is predicted to eradicate the disease.

During or after puberty, EBV is transmitted to a major proportion of the population in an MS high-prevalence area. Together with our previous documentation of an association between late infection with EBV and an increased risk of developing MS, these data support a role of EBV infection in MS.

SUMMARYAn increased frequency of antiviral CD8 + T cells is seen in chronic viral infections. During herpes virus infections the expanded CD8 + T cells are thought to control the reactivation of the latent infection. Because multiple sclerosis (MS), a presumed autoimmune disease of the central nervous system, has been associated with a late Epstein-Barr virus (EBV) infection, we wished to examine whether the CD8 + T cell response to EBV epitopes differed between MS patients and healthy controls. Here we report an increased frequency of CD8 + T cells responding to EBV epitopes from nuclear antigen 3 A (HLA-A2/CLG) and latent membrane protein 2 (HLA-B7/RPP) in MS patients. Noticeably, the altered CD8 + T cell response occurred to some but not all EBV epitopes and did not reach the high level seen during acute infection. The responses towards two immunodominant epitopes from human cytomegalovirus (HCMV) were similar in MS patients and normal controls. Together, our data demonstrate the presence of an increased frequency of CD8 + T cells reacting with two epitopes from EBV in patients with MS. The altered response to only two of the tested EBV epitopes would be consistent with the presence of cross-reactive epitopes.

Valacyclovir treatment did not reduce the formation of active lesions in patients with relapsing-remitting MS who had two or more relapses during the previous 2-year period. In a subgroup of patients with high levels of disease activity who had more than one active MRI-evident lesion during 4 weeks, valacyclovir treatment was associated with a reduced number of new active MRI-evident lesions and with an increase in the number of scans free of new active lesions. The results of the exploratory subgroup analysis provide support for further studies of antiherpes therapy for patients with MS and high levels of MRI-evident disease activity.