Downregulation of TLR7/9 leads to deficient production of IFN-α from plasmacytoid dendritic cells in chronic hepatitis B.
OBJECTIVE
To investigate whether Toll-like receptor (TLR) 7 and TLR9-mediated interferon α (IFN-α) production in plasmacytoid dendritic cells (pDCs) is compromised in patients with chronic hepatitis B virus (HBV) infection.


METHODS
Peripheral blood mononuclear cells (PBMCs) were prepared from 32 chronic HBV patients and 13 healthy volunteers, and treated with loxoribine or cytidine phosphate guanosine (CpG) oligodeoxynucleotides (ODN). Interferon α in the supernatant was measured by sandwich ELISA. PDC frequency and the expression levels of TLR7 and TLR9 in pDCs were quantified by flow cytometry. The serum viral load of HBV was quantified using a highly sensitive real-time PCR kit.


RESULTS
Compared to cells from healthy control group, PBMCs and pDCs from the HBV group showed significantly decreased production of IFN-α in response to ligand for TLR7 (loxoribine) and TLR9 (CpG ODN, P < 0.05). Mechanistically, the number of pDCs in peripheral blood, and the expression of pDC-associated TLR7 and TLR9 were significantly lower in HBV group than in the healthy control group (P < 0.05). In addition, the number of pDCs and the expression of TLR9 on pDCs were correlated inversely with the serum load of HBV.


CONCLUSIONS
Impaired IFN-α production from pDC may contribute to the immunopathogenesis of chronic HBV infection, which may be the result of a reduced amount of pDCs as well as decreased expression of TLR7 and TLR9 on pDCs.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310031, China. xuning@zjut.edu.cn
Ning
N
Xu
Hang-Ping
HP
Yao
Guo-Cai
GC
Lv
Zhi
Z
Chen
D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019694:Hepatitis B, Chronic / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000819:agonists; D019562:Viral Load
C526902:CpG ODN 2216; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D006151:Guanosine; C068562:loxoribine