Epstein-Barr Virus and Autoimmunity

The Role of a Latent Viral Infection in Multiple Sclerosis and Systemic Lupus Erythematosus Pathogenesis

Costanza Casiraghi; Marc S Horwitz


Future Virology. 2013;8(2):173-182. 

In This Article

EBV & Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease and affects 2–4 million people worldwide.[51] Women make up 90% of all SLE patients. The disease is characterized by the development of autoantibodies against different components of the cell's nucleus, such as DNA, histones and chromatin. Deposition of immune complexes (antibody and cognate antigen complexes) starts an immune response in the target organ, leading to tissue inflammation and damage.[6] Skin, kidneys, lungs, brain and heart are the most affected organs.

Genetic predisposition and environmental factors have both been shown to be important contributors to SLE. However, the trigger that leads to the production of autoantibodies and immune dysregulation is currently unknown.[6,52] Different viruses have been indicated as environmental triggers of SLE,[53,54] and EBV is one of the pathogens closely associated with SLE development.[55,56]

Association Between SLE & EBV in Epidemiological Studies

EBV prevalence in SLE patients has been measured in different studies to investigate whether an association is present between EBV exposure and the development of the disease. Since EBV seropositivity in the adult population is approximately 85–95%, pediatric cohorts, which generally have a lower EBV prevalence, can be more informative, as it has been proven for MS. One of the first studies showed that 99% of pediatric SLE patients were EBV-seropositive. In contrast, only 70% of children among the controls had been infected by EBV.[57] There was no difference in seropositivity between cases and controls when other herpesviruses were tested. Subsequent serologic results, testing seropositivity for EBV and other herpesviruses on both children and adults, confirmed these early results.[58,59] These results are similar to those obtained in MS cohorts, but data on the association between a history of mononucleosis and SLE development are not as strong as the ones obtained from MS patients. In fact, it has been shown that mononucleosis is not associated with risk of SLE.[60]

EBV Replication Control & Reactivation in SLE Patients

EBV could probably trigger SLE through increased replication or more frequent reactivation in SLE patients. The number of EBV-positive B cells typically declines with age in healthy individuals, however, this is not the case in SLE patients.[61] Intriguingly, when SLE flares up, it is correlated with increases in the frequency of EBV-positive B cells. Furthermore, the levels of EBV-infected B cells in SLE patients were similar to the levels typically found in immunosuppressed patients, indicating that EBV infection is abnormally regulated in SLE patients or that SLE flares have an effect on EBV replication.[62] It should be noted that this was true for SLE patients in this study that were not taking any immunosuppressive drugs. Two additional studies detected 15–40-fold higher EBV viral loads in SLE patients than healthy individuals.[51,63] These findings were recently reconfirmed.[64] In this study, Larsen et al. also showed that increases in the EBV viral load always occurred one week or more after the onset of a SLE relapse.[64] It is possible that, if EBV-infected B cells are also autoreactive, increases in the percentages of these EBV-infected B cells in the blood of SLE patients could contribute to enhanced autoantibody production.

EBV Humoral Responses & Molecular Mimicry in SLE Patients

Anti-Sm autoantibodies (where Sm stands for Smith antigen, a set of nuclear proteins) are found in SLE patients and used as a diagnostic criterion.[65] Analysis of serum samples from SLE patients detected cross-reactivity between a Sm peptide and an EBV EBNA-1 peptide.[66,67] Interestingly, immunization of rabbits with the EBNA-1 peptide was enough to initiate an anti-Sm antibody response in the immunized animals.[67] This discovery made EBV and the EBNA-1 protein possible candidates for environmental triggers for SLE. Similar results were obtained when the Ro antigen, another nuclear antigen, was analyzed.[68–70] Anti-Ro antibodies are produced by SLE patients at an early stage of the disease. The initial epitope recognized by the anti-Ro antibody response cross-reacts with the EBNA-1 peptide.[70] Mice immunized with the EBNA-1 viral peptide progressively develop antibodies specific for multiple Ro epitopes and other autoantigens, developing symptoms of SLE, such as renal dysfunction.[68] Interestingly, the antibody response against EBNA-1 is usually directed towards the large alanine–glycine repeat in healthy individuals infected by EBV. On the other hand, EBNA-1-specific antibodies in SLE patients are directed against other EBNA-1 epitopes that are cross-reactive with Ro and Sm.[69] These cross-reactive antibodies are also found in mononucleosis patients.[70] However, anti-EBNA-1/autoantigen cross-reactive antibodies disappear after mononucleosis resolution in healthy individuals, but persist in SLE patients.[70]

Additionally, there are reports that demonstrate that mononucleosis can induce the onset of SLE symptoms.[71–73] It is possible to speculate that, after EBV infection, individuals that later develop SLE do so because they are not able to control the production of autoantibodies that both increase in number and expand in their specificities to autoantigens over time, until ultimately the symptoms of SLE progress to manifest disease.

EBV T-cell Responses in SLE Patients

As discussed above, SLE patients showed increased levels of EBV reactivation. This could be due to an impaired ability of the EBV-specific T-cell response to control viral latency in SLE patients. Early studies found that T cells from SLE patients were not as efficient as T cells from healthy controls in controlling EBV infection of autologous B cells.[74] Additionally, the decreased ability of EBV-specific CD8+ T cells to produce IFN-γ was detected in SLE patients, suggesting that impaired control of EBV replication could be due to impaired EBV-specific CD8+ immunity.[63,75]

More recent work showed that the frequency of polyfunctional EBV-specific CD8+ T cells producing IFN-γ, TNF-α, IL-2 and MIP-1β after antigen stimulation was decreased, and EBV-specific CD8+ T cells were less efficient in the exocytosis of cytotoxic granules in SLE patients. This impairment is likely due to the increased expression of PD-1 on EBV-specific CD8+ T cells and can be reversed through PD-1 blockade.[64] Overall, it seems that SLE patients have functional impairments in their EBV-specific CD8+ T-cell response and this may account for a deficient control of EBV reactivation in SLE patients.