title: Reduced toll-like receptor 9 expression on peripheral CD14+ monocytes of chronic hepatitis B patients and its restoration by effective therapy.
abstract: BACKGROUND
  Chronic hepatitis B (CHB) patients display Toll-like receptor 9 (TLR9)-dependent defective immune responses. We aimed to study TLR9 expression on CHB patients and its alteration during therapy.
  
  
  METHODS
  We compared TLR9 expression on fresh peripheral CD14+ monocytes from a cohort of 97 CHB patients and 35 HBsAg-negative, anti-HCV-negative controls, during pegylated interferon or entecavir therapy. TLR9 expression on liver tissue was also investigated.
  
  
  RESULTS
  Compared with controls, peripheral CD14+ monocytes of CHB patients displayed reduced expression of TLR9 mean fluorescence intensity (MFI; 9.90 ±3.64 versus 7.95 ±3.61; P=0.007) independent of age, gender and alanine aminotransferase (ALT; -2.09, 95% CI -3.568, -0.613; P=0.006). Furthermore, age, gender, ALT, HBeAg status, quantitative HBsAg (qHBsAg) or HBV DNA did not predict the TLR9 expression (P=0.863). Hepatic TLR9 messenger RNA (mRNA) was significantly reduced in 54 patients compared with 3 controls (0.45 ±0.32 versus 1-fold). Using response-guided therapy by qHBsAg levels and pretreatment TLR9 MFI as a reference, TLR9 MFI restored to a mean of 1.7- to 2.7-fold in pegylated interferon responders and reduced to a mean of 0.6- to 0.7-fold in non-responders starting from treatment week 12. Among 10 entecavir-treated patients, TLR9 MFI gradually restored to a mean of 1.2- to 2.1-fold starting from treatment week 48.
  
  
  CONCLUSIONS
  CHB patients display reduced TLR9 expression on peripheral CD14+ monocytes, which is independent of host and viral markers, and on liver tissue. Responders to pegylated interferon and those under entecavir demonstrate restoration of TLR9 expression. On-treatment TLR9 expression on peripheral monocytes might predict response to pegylated interferon therapy.
authors.affiliation: Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Huang
authors.forename: Cheng-Kai
authors.initials: CK
authors.lastname: Hsu
authors.forename: Shih-Chang
authors.initials: SC
authors.lastname: Lin
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.forename: Jui-Ting
authors.initials: JT
authors.lastname: Hu
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Chang
authors.forename: Cher-Wei
authors.initials: CW
authors.lastname: Liang
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Ping-Ning
authors.initials: PN
authors.lastname: Hsu
authors.forename: Sien-Sing
authors.initials: SS
authors.lastname: Yang
authors.forename: Jia-Horng
authors.initials: JH
authors.lastname: Kao
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D004279:DNA, Viral; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019694:Hepatitis B, Chronic / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D011446:Prospective Studies; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D016898:Interferon-alpha; D018950:Lipopolysaccharide Receptors; D051217:Toll-Like Receptor 9; C413685:entecavir; D006147:Guanine