title: Involvement of TLR7 MyD88-dependent signaling pathway in the pathogenesis of adult-onset Still's disease.
abstract: BACKGROUND
  The objective of this study was to investigate the potential role of the Toll-like receptor 7 (TLR7) signaling pathway in the pathogenesis of adult-onset Still's disease (AOSD).
  
  
  METHODS
  Frequencies of TLR7-expressing precursor of myeloid dendritic cells (pre-mDCs) and mDCs in 28 AOSD patients, 28 patients with systemic lupus erythematosus (SLE) and 12 healthy controls (HC) were determined by flow cytometry analysis. Transcript and protein levels of TLR7 signaling molecules in peripheral blood mononuclear cells (PBMCs) were evaluated by quantitative PCR and western blotting respectively. Serum cytokines levels were measured by ELISA.
  
  
  RESULTS
  Significantly higher median frequencies of TLR7-expressing pre-mDCs and mDCs were observed in AOSD patients (65.5% and 14.9%, respectively) and in SLE patients (60.3% and 14.4%, respectively) than in HC (42.8% and 8.8%, respectively; both P <0.001). Transcript and protein levels of TLR7-signaling molecules, including MyD88, TRAF6, IRAK4 and IFN-α, were upregulated in AOSD patients and SLE patients compared with those in HC. Disease activity scores were positively correlated with the frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules in both AOSD and SLE patients. TLR7 ligand (imiquimod) stimulation of PBMCs resulted in significantly enhanced levels of interleukin (IL)-1β, IL-6, IL-18 and IFN-α in AOSD and SLE patients. Frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules significantly decreased after effective therapy.
  
  
  CONCLUSIONS
  Elevated levels of TLR7 signaling molecules and their positive correlation with disease activity in AOSD patients suggest involvement of the TLR7 signaling pathway in the pathogenesis of this disease. The overexpression of TLR7 MyD88-dependent signaling molecules may be a common pathogenic mechanism for both AOSD and SLE.
authors.forename: Der-Yuan
authors.initials: DY
authors.lastname: Chen
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Lin
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Chen
authors.forename: Joung-Liang
authors.initials: JL
authors.lastname: Lan
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hung
authors.forename: Hsin-Hua
authors.initials: HH
authors.lastname: Chen
authors.forename: Kuo-Lung
authors.initials: KL
authors.lastname: Lai
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Hsieh
mesh_terms: D000328:Adult; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D016706:Still's Disease, Adult-Onset / Q000097:blood / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis / Q000276:immunology*
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7