Epstein-Barr Virus: Environmental Trigger of Multiple Sclerosis?

Abstract

Autoimmune diseases affect approximately 5% of the population in the United States and are the third most common disease category after cancer and heart disease. At least 15 diseases are known to be the direct result of an autoimmune response, while circumstantial evidence implicates autoimmunity in more than 80 conditions. Multiple sclerosis (MS), autoimmune skin and thyroid diseases, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) are among the most prevalent disorders in this category. Diseases of autoimmune origin are generally believed to arise from unfortunate combinations of genetic susceptibility and environmental insults. HLA-DR and -DQ alleles within the HLA class II region on chromosome 6 are by far the strongest risk-conferring genes for most of the aforementioned entities. Viral and bacterial infections are logical candidates as environmental triggers. However, for the numerous agents that have been linked with specific autoimmune diseases based on serology, pathology, or virus isolation, none of the postulated associations has been conclusive. The difficulty in identifying a causative single microorganism might indicate that Koch's paradigm, “one organism, one disease,” does not apply to such complex diseases and suggests that several different agents can induce or exacerbate autoimmune diseases and that these are most likely ubiquitous pathogens of a high prevalence in the population (37, 69). Epstein-Barr virus (EBV) has been a leading candidate trigger for several autoimmune diseases since the initial description of raised EBV-specific antibody titers in patients with SLE in 1971 (23). EBV is a biologically plausible candidate since it is ubiquitous in nature, establishes a lifelong dormant infection with continuous virus production due to reactivation, and modulates the human immune system. In its immune-modifying function, EBV rescues infected B cells via latent antigen expression and assists their differentiation into memory B cells, in which it persists. In addition, the virus continuously stimulates strong T-cell responses via chronic antigen presence, and this immune control is crucial to prevent EBV-associated malignancies. Recent studies indicate that EBV-specific cellular and humoral immune responses and the regulation of viral persistence in EBV-infected memory B cells are altered in patients with autoimmune diseases (3, 29, 38, 52, 54, 79, 80). In MS patients, longitudinal analyses of serum samples collected more than 10 years before the onset of clinical symptoms consistently showed that the risk of developing the disease increased significantly with the level of EBV antibody titers, and the strongest association was found for immunoglobulin G (IgG) antibodies binding to a EBV latent antigen, nuclear antigen 1 (EBNA1) (3, 21, 46). The mechanisms responsible for the association of EBV infection and the evolution of MS have so far not been clarified. In this review, we will discuss new evidence and hypotheses for a potential linkage between host-EBV interactions and the initiation as well as maintenance of autoimmune diseases. Since the existing literature suggests that different mechanisms lead to EBV association with the various autoimmune diseases, we will focus our discussion primarily on MS and refer to SLE and RA only when similarities or differences between these diseases and MS have been clearly defined.