Many studies have revealed a connection between SLE and EBV infection. Essentially all adult SLE patients are infected with EBV (99.5%) [24
]. However, the statistical significance of this finding is reduced by the large proportion of healthy adults infected as well (95%). In young people below the age of 20 years, the difference between SLE patients and healthy controls is more evident, as the prevalence of EBV infection in the control population is lower, with only 70% being infected, while essentially all pediatric SLE patients are infected with EBV (99.6%) [76
As demonstrated in , SLE and EBV-induced IM are known to have similar symptoms and clinical manifestations, indicating an association. Most interesting, presence of rheumafactor and autoantibodies against cellular components like DNA, histones, and ribonucleoproteins is found in IM patients as well as in SLE patients [78
]. EBV infection may somehow result in both diseases according to the genetic predisposition and the immune response against EBV in the individual.
SLE patients have been shown to have at least a 10-fold increased frequency of EBV-infected peripheral B cells compared to healthy controls. This increase is associated with increased disease activity in SLE patients and is independent of intake of immunosuppressive medication [31
]. In addition, an abnormally high viral load in the peripheral blood mononuclear cells (PBMCs) has been demonstrated in SLE patients compared to healthy controls in several studies [33
]. Kang et al. found, by the use of real-time quantitative PCR, a 40-fold increase of EBV load when comparing SLE patients to healthy controls [33
], and Moon et al. found at least a 15-fold increase of EBV load in SLE patients [34
]. Furthermore, Lu et al. found a significantly elevated level of EBV DNA in serum from 42% of the examined SLE patients compared to only 3% of the healthy controls [80
]. These findings suggest EBV active lytic cycle with profound viral replication in SLE patients. Thus, it may be indicated that reactivation of EBV is associated with the development of SLE.
Studies on normal immunocompetent carriers of EBV demonstrate that they usually show little or no mRNA expression by EBV. Gross et al. have demonstrated that SLE patients have abnormal expression of 4 viral mRNAs: BZLF-1, LMP-1, LMP-2
, and EBNA-1
in their PBMCs [31
]. The measured expression levels of mRNAs were often higher than in individuals with IM indicating very active virus. BZLF-1
is one of the early lytic genes, facilitating the initiation of the lytic replication of the virus, and expression of this mRNA in SLE patients clearly indicates reactivation of the virus. In addition, an abnormal latency state is indicated in the SLE patients by the increased expression of the three latent state mRNAs. The enhanced expression of LMP
mRNAs might result in improved survival of EBV-infected B cells, as the encoded antigens serve as survival signals that normally comes from the CD40 signal pathway and by antigen binding to the B-cell receptor [66
Also, Poole et al. measured the levels of EBV mRNA in PBMCs from SLE patients and healthy controls infected with EBV [81
]. They found a 3.2-fold increase in the BLLF-1
mRNA encoding gp350, which is essential for the binding and infection of new B cells. Also, the BCRF-1, EBNA-1
, and LMP-2
mRNAs were increased 1.7-fold in SLE patients compared to healthy controls. These results suggest that the EBV infection is active and harder to control in the SLE patients.
Serologic evidence of a connection between EBV infection and SLE development has been illustrated several times by examining the presence of antibodies to EBNA-1, EBV-VCA, and EBV-EA in sera from SLE patients. Studies on antibodies to EBNA-1 and EBV-VCA are contradictive. Most studies show no difference in the prevalence of IgG and IgM antibodies to either EBNA-1 or EBV-VCA between SLE patients and healthy controls [82
]. However, studies on pediatric SLE patients and one study on adults show that only two-thirds of healthy controls compared to all SLE patients are seropositive for these antibodies [24
]. Furthermore, an elevated amount of both EBNA-1 and EBV-VCA IgA antibodies has been detected in SLE patients [80
In addition, elevated titers of IgG antibodies to early lytic antigens including EBV-EA/D, EBV-EA/R, and the BALF-2
gene product have been found in approximately half of SLE patients compared to only 8–17% of healthy controls by several research groups [82
]. Most interesting, elevated levels of IgA antibodies to these antigens have also been found in SLE patients, characteristic of epithelial infection. Lau et al. demonstrated that 15% of SLE patients compared to none of the healthy controls were positive for EBV-EA IgA antibodies by immunofluorescence [90
], and Draborg et al. found a positive rate of IgA EBV-EA/D antibodies of 58% regarding SLE patients, whereas none of the serum samples from healthy controls showed IgA antibody binding to EBV-EA/D [65
]. Furthermore, when compiling the positivity for EBV-EA/D-reacting antibody isotypes (IgG, IgM, and IgA) for each individual, 65% of the SLE patients were positive for two or three isotypes. None of the healthy controls were positive for three isotypes, and only 10% were positive for two isotypes, whereas the majority (65%) had no antibodies against EBV-EA/D () [65
]. These results could not be explained by intake of immunosuppressive medication, indicating that the antibodies do not occur upon reactivation of EBV due to an iatrogenically suppressed immune system. Presumably, the results of high prevalence of IgA antibodies against EBV reflect the host's attempt to control reactivation or reinfection of EBV in epithelial cells. Additionally, the presence of multiple EBV-EA/D antibody isotypes indicates a more disseminated EBV infection in SLE patients than in healthy controls.
Table 2 EBV-EA/D antibodies in SLE patients and healthy controls .
The constant attempts of the host's immune system to control the virus apparently lead to attack on cells expressing EBV-EA/D, resulting in killing of infected cells before assembly of mature EBV particles. This results in release of EBV-EA/D (presumably bound to dsDNA) and intracellular antigens (including those involved in EBV replication and protein synthesis). Since this occurs both in B cells and epithelial cells, the antibody response involves both IgG and IgA to EBV-EA/D and autoantigens (e.g., dsDNA and ribonucleoproteins), depending on the individuals infection distribution and immune system.
Actually, IgA deficiency has been shown to be a risk factor for development of SLE as it results in frequent infections, and approximately 6% of SLE patients have been shown to suffer from IgA deficiency [91
]. It could be speculated that defects in controlling EBV infection result in SLE development in different ways. Presumably, some individuals develop SLE due to lack of production of IgA antibodies to counteract an epithelial EBV reactivation. Other individuals are not able to control EBV infection as a result of other immune defects and therefore attempt to control EBV with production of IgA antibodies against EBV lytic cycle antigens (especially EBV-EA/D).
An additional mechanism by which EBV can contribute to development of SLE is molecular mimicry. EBNA-1 has been shown to cross-react with SLE-associated autoantigens resulting in cross-reactive antibodies followed by epitope spreading, which eventually can result in development of SLE [93
The reduced EBV-specific T-cell reactivity observed in SLE patients is possibly a consequence of defective EBV-specific T cells, which indicate poor control of EBV infection. Actually, the defective control of the virus has been demonstrated to involve an impaired EBV-specific T-cell response in SLE patients [33
]. Studies conducted by Berner et al. on EBV-specific T cells in SLE patients showed a tendency of an increased frequency of CD8+
T cells toward a specific epitope of the lytic cycle BMLF1 protein. These results were obtained by analysis of PBMCs using MHC I tetramers. Using an ELISPOT assay, the EBV-reactive CD8+
T cells were found to be incapable of producing IFN-γ
upon stimulation [96
]. This indicates that the EBV-specific CD8+
T cells of SLE patients may have a defect in their ability to become activated upon stimulation and will thereby produce poor effector responses. In addition, Kang et al. found a tendency of SLE patients to have a decreased amount of EBV-specific CD8+
cytotoxic T cells producing IFN-γ
, when samples of whole blood were stimulated with EBV [33
]. Simultaneously, they showed a significantly increased frequency of EBV-specific CD4+
T cells producing IFN-γ
in SLE patients when stimulated [33
]. These results suggest that the impaired EBV-specific T-cell response in SLE patients comprises a defect in EBV-specific CD8+
T-cell cytotoxicity and a compensatory increased frequency of EBV-specific CD4+
The above-mentioned associations between active and uncontrolled EBV infection and SLE indicate that EBV and possibly also other viruses have a pathogenic role in the development of SLE. Other viruses besides EBV have been suggested to be associated with SLE including cytomegalovirus [97
], parvovirus B19 [98
], hepatitis B [98
], and human endogenous retroviruses [99
]. Overall, infections are presumably involved in SLE induction, and SLE patients have an increased susceptibility to many kinds of infections [100
]. These findings are related to the intrinsic immune defects found in SLE patients.