Viruses and multiple sclerosis

Abstract

Multiple sclerosis (MS) is a heterogeneous disease that develops as an interplay between the immune system and environmental stimuli in genetically susceptible individuals. There is increasing evidence that viruses may play a role in MS pathogenesis acting as these environmental triggers. However, it is not known if any single virus is causal, or rather several viruses can act as triggers in disease development. Here, we review the association of different viruses to MS with an emphasis on two herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). These two agents have generated the most impact during recent years as possible co-factors in MS disease development. The strongest argument for association of EBV with MS comes from the link between symptomatic infectious mononucleosis and MS and from seroepidemiological studies. In contrast to EBV, HHV-6 has been found significantly more often in MS plaques than in MS normal appearing white matter or non-MS brains and HHV-6 re-activation has been reported during MS clinical relapses. In this review we also suggest new strategies, including the development of new infectious animal models of MS and antiviral MS clinical trials, to elucidate roles of different viruses in the pathogenesis of this disease. Furthermore, we introduce the idea of using unbiased sequence-independent pathogen discovery methodologies, such as next generation sequencing, to study MS brain tissue or body fluids for detection of known viral sequences or potential novel viral agents.

Fig. 1

As a response to viral infection B cells can process and present viral peptides to T cells leading to activation of T cells and maturation of B cells into antibody producing plasma cells. These plasma cells can produce clonal IgG molecules that are present in serum during the active infection of the periphery. If virus invades the CNS, B cells can activate and maturate into plasma cells and produce antibodies in a mannar similar to in the periphery (1). The viral antigens might resemble myelin antigens and induce T cell as well as B cell responses including cross-reactive antibodies to viral as well as autoantigens through molecular mimicry mechanisms (2). Chronic viral infection can also cause local tissue damage leading to presentation of autoantigens, which are then recognized by autoreactive T or B cells (3). This leads to production of novel clones of T cells and plasma cells that recognize only autoantigens but not viral antigens that may have initiated the process. Any of these events occurring in the CNS could produce antibodies that are not seen in peripheral blood and therefore would be present in CSF as oligoclonal bands.