Epstein-Barr virus promotes interferon-alpha production by plasmacytoid dendritic cells.
OBJECTIVE
Epstein-Barr virus (EBV) infection has been linked to systemic lupus erythematosus (SLE), as demonstrated by the presence of increased seroprevalence and elevated viral loads, but the mechanism of this linkage has not been elucidated. Increased interferon-alpha (IFNalpha) levels and signatures, which are associated with innate immune responses, have been found in patients with SLE. Plasmacytoid dendritic cells (PDCs) are innate immune cells that mediate viral immunity by producing large quantities of IFNalpha, but the role they play during infection with EBV remains unclear. To address this issue, we investigated the ability of EBV to promote IFNalpha production by PDCs in healthy subjects.


METHODS
Human PDCs were sorted and cultured in the presence of EBV, EBV-encoded RNA, and EBV double-stranded DNA. IFNalpha production by PDCs was measured by enzyme-linked immunosorbent assay, with the activation of these cells measured by flow cytometry.


RESULTS
We found that EBV DNA and RNA promoted IFNalpha production by human PDCs through engagement of Toll-like receptor 9 (TLR-9) and TLR-7, respectively, with the initial viral recognition by PDCs mediated by binding to class II major histocompatibility complex (MHC) molecules.


CONCLUSIONS
These data demonstrate that class II MHC-specific engagement by virus, with subsequent viral nucleic acid recognition, mediates IFNalpha production by PDCs. Our results suggest that elevated levels of IFNalpha found in SLE patients may be a result of aberrantly controlled chronic viral infection.
Quan
Timothy E
TE
Department of Internal Medicine, Section of Rheumatology, Yale University, New Haven, Connecticut 06520, USA. tim.quan@yale.edu
Roman
Robert M
RM
Rudenga
Benjamin J
BJ
Holers
V Michael
VM
Craft
Joseph E
JE
D034961:Antigens, Nuclear / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000821:virology; D008285:Major Histocompatibility Complex / Q000276:immunology; D018709:Statistics, Nonparametric; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology
D034961:Antigens, Nuclear; D016898:Interferon-alpha; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9