title: Human blood dendritic cells from allergic subjects have impaired capacity to produce interferon-alpha via Toll-like receptor 9.
abstract: BACKGROUND
  High-affinity IgE receptor (Fc epsilon RI) expression on blood dendritic cells reportedly correlates with serum IgE levels. Our studies demonstrate that plasmacytoid dendritic cells (pDCs) secrete pro-inflammatory cytokines (IL-6, TNF-alpha) following Fc epsilon RI stimulation - a mode of activation that simultaneously reduces expression of Toll-like receptor 9 (TLR9). Whether or not TLR9 and/or Fc epsilon RI levels and their function on dendritic cells relate to allergic status is unknown.
  
  
  OBJECTIVE
  The aim of this study is to compare the innate (TLR9-mediated) immune response of human pDCs to TLR9 and Fc epsilon RI alpha receptor expression in allergic and non-allergic subjects.
  
  
  METHODS
  Basophil-depleted mononuclear cell fractions containing pDCs were prepared from peripheral blood of allergic and non-allergic subjects. Intracellular TLR9 and surface Fc epsilon RI alpha expression in blood dendritic cell antigen-2-positive cells were determined by flow cytometry. Activating anti-IgE antibody, anti-Fc epsilon RI alpha antibody, and TLR9 agonist were used to stimulate cell suspensions, with cytokine levels determined by ELISA.
  
  
  RESULTS
  No difference in the frequency of pDCs was detected among allergic (n=9) vs. non-allergic (n=11) subjects (P=0.261). While there was also no difference in the baseline expression of TLR9, pDCs from allergic subjects produced sixfold less IFN-alpha when stimulated with CpG (P=0.002). Conversely, there was higher Fc epsilon RI alpha expression (P=0.01) on the pDCs of allergic subjects.
  
  
  CONCLUSIONS
  Impaired TLR9-dependent immune responses in human pDCs are associated with allergic status and inversely correlated with Fc epsilon RI alpha expression. This impaired innate immune response among dendritic cells of allergic subjects may lead to more targeted therapeutic approaches and could provide a better understanding of the mechanisms underlying conventional and CpG-based immunotherapy.
authors.affiliation: Department of Medicine, Johns Hopkins Asthma and Allergy Center, Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224, USA. Jodytversky@yahoo.com
authors.forename: J R
authors.initials: JR
authors.lastname: Tversky
authors.forename: T V
authors.initials: TV
authors.lastname: Le
authors.forename: A P
authors.initials: AP
authors.lastname: Bieneman
authors.forename: K L
authors.initials: KL
authors.lastname: Chichester
authors.forename: R G
authors.initials: RG
authors.lastname: Hamilton
authors.forename: J T
authors.initials: JT
authors.lastname: Schroeder
mesh_terms: D000328:Adult; D001249:Asthma / Q000276:immunology / Q000503:physiopathology; D018899:CpG Islands / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005512:Food Hypersensitivity / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology* / Q000503:physiopathology*; D016898:Interferon-alpha / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017455:Receptors, IgE / Q000378:metabolism; D012221:Rhinitis, Allergic, Perennial / Q000276:immunology / Q000503:physiopathology; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology / Q000503:physiopathology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D016898:Interferon-alpha; D017455:Receptors, IgE; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9