Abstract
Infection with the Epstein-Barr virus (EBV) has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have previously reported that DNA from this virus enhances production of the pro-autoimmune interleukin 17A (IL-17A) in mice. In this study we assessed the effect of EBV DNA on regulatory T cell programming and examined whether it mediated its effects via Toll-like receptor 9 (TLR9) in mice; moreover, we evaluated whether EBV DNA in humans had similar effects to those seen in mice. For this purpose, we assessed the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects and matched controls. A modulatory effect for the viral DNA was observed for regulatory T cell markers with an inhibitory effect observed for CTLA4 expression in the EBV DNA-treated mice. To examine whether TLR9 mediated the detection of EBV DNA and enhancement of IL-17A production, mouse peripheral blood mononuclear cells were treated with the DNA in the presence or absence of the TLR9 inhibitor ODN 2088. Subsequently, IL-17A production from these cells was assessed. Treatment with the TLR9 inhibitor resulted in a significant decrease in IL-17A production indicating that TLR9 is involved in this pathway. In human subjects, examining the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects showed a propensity for linearity that was not observed in controls. Our data thus indicates that EBV DNA itself acts as a modulator of the Th17 compartment as well as that of regulatory T cell mechanisms. The involvement of TLR9 in the EBV DNA-triggered induction of IL-17A suggests therapeutic targeting of this endosomal receptor in EBV positive subjects with an autoimmune flare-up or possibly for prophylactic purposes.
Highlights
The Epstein-Barr virus (EBV), known as Human herpes virus 4, is a member of the herpes family of viruses; its genome consists of a linear double-stranded DNA
We have previously reported an increase in the levels of interleukin 17A (IL-17A), a pro-inflammatory cytokine, in mice injected with EBV DNA [13]
RORγT is a transcription factor that regulates the expression of IL-17A among other genes in T-helper 17 (Th17) cells [32] and that plays an essential role in Th17 cell differentiation [33, 34]
Summary
The Epstein-Barr virus (EBV), known as Human herpes virus 4, is a member of the herpes family of viruses; its genome consists of a linear double-stranded DNA. More than 90% of adults are infected by this virus, EBV is highly prevalent worldwide [1]. EBV DNA and pro-autoimmune mechanisms members of the Herpesviridae, EBV establishes latency in the infected host with potential recurrence of viral replication and shedding. EBV infection occurs through person-to-person transmission [2]. The majority of EBV infections are transmitted orally via saliva, but it could be transmitted sexually and through blood transfusions. A primary infection with EBV during childhood is mostly asymptomatic. If the acquisition of EBV infection occurs in adolescence, which typically happens in developed countries [3], it usually causes infectious mononucleosis (IM)
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