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2018 ; 13
(7
): e0200546
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Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to
enhancing interleukin-17A production via Toll-like receptor 9
#MMPMID29995930
Salloum N
; Hussein HM
; Jammaz R
; Jiche S
; Uthman IW
; Abdelnoor AM
; Rahal EA
PLoS One
2018[]; 13
(7
): e0200546
PMID29995930
show ga
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.