The role of the Epstein-Barr virus in the pathogenesis of some autoimmune disorders — Similarities and differences

Abstract

After a brief summary on the properties of the Epstein-Barr virus (EBV), the course and latency stages of the infection, the characteristics of infectious mononucleosis (IM), and other disorders caused by this virus, as well as the course of the serological responses to EBV, the current paper focuses on the role of EBV in two autoimmune disorders: multiple sclerosis (MS), and systemic lupus erythematosus (SLE). Diverse evidence suggests that infection by EBV during late childhood or young adulthood may have a role in the pathogenesis of MS. These include the similarity between the geographical distribution of IM and MS, the high risk of contracting MS by individuals who have recovered from IM, the elevation of the titers of IgG antibodies against EBV nuclear antigens occurring years before the initial manifestations of MS, and the extremely rare occurrence of MS in individuals seronegative for EBV. However, the data on the mechanism underlying the relationship between EBV and MS are controversial. Moreover, many observations indicate that EBV contributes also to the pathomechanism of SLE. However, this contribution differs from the relationship between EBV and MS, as shown by the lack of any increase in the risk of SLE after IM. In SLE, EBV serology is quantitatively and qualitatively different from the normal response -that is, EBV viral load is higher and a strong cross-reaction can be detected between certain EBV antigens and autoantigens of pathological importance. These observations, along with the findings pointing to a possible role of EBV in rheumatoid arthritis and myasthenia gravis indicate that infection by EBV may be one of the environmental factors, which can facilitate the development of some autoimmune disorders in genetically susceptible individuals.

Epstein-Barr Virus-Specific Humoral Immune Responses in Health and Disease

“…Antigen mimicry, induced by aberrant EBV exposure or defective immune control, plays a central role in each disease and has been addressed in a number of recent reviews (Ballandraud et al 2004;Pender 2011;Lossius et al 2012;James and Robertson 2012;Füst 2013;Igoe and Scofield 2013). All affected individuals, including the juvenile cases, are EBV seropositive (i.e.…”

“…General consensus seems exist for a role of EBV as inflammatory trigger, possibly through the release of EBER molecules into the circulation, providing general innate and adaptive activation signals (Iwakiri 2014) and EBNA1-DNA complexes as a rich source of antigen sequences that may induce cross-reactive antibodies, depending on the host MHC-II background (Yadav et al 2011). The release of complex and structured multi-epitope EBNA1-DNA complexes presented on APC during the cytokine-rich convalescent phase of mononucleosis together with innate signalling triggered by released EBER-protein/exosome complexes may trigger autoantibody formation by crossing the tolerance threshold and extending the restricted repertoire to include autoreactive clones, a phenomenon called epitope spreading (Füst 2013;Cornaby et al 2014). Evidence for such B-cell repertoire disturbance during mononucleosis has been presented and requires further analysis (Mockridge et al 2004).…”

Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus

“…The difference is more evident in juvenile patients, suggesting that EBV could be an environmental factor influencing the development of SLE [53]. Because EBV infects B cells, it is possible that the process of viral DNA integration into the host and latent gene expression could alter B cell activation pathways and induce autoimmunity [54]. Indeed, expression of latent membrane protein (LMP) 1 can enhance autoimmune phenotypes in susceptible mice [55], and LMP2A directly alters B cell activation via disruption of signaling microdomains [56, 57].…”

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

“…Earlier, we summarized [4] findings indicating differences in the relationship of EBV with the two autoimmune diseases, MS and SLE. The incidence of MS [38], but not of SLE [39], is markedly higher in those who had had infectious mononucleosis previously.…”

“…Most studies addressed the EBV association of the former two [2][3][4]. Perhaps the strongest evidence for the association of the EBV infection and MS is the observation that patients with a high Epstein-Barr nuclear antigen 1 (EBNA-1) immunoglobulin (Ig)G titre face a several-fold higher chance of developing MS subsequently, compared to those with a low titre.…”