title: Hyper-IgE syndrome is not associated with defects in several candidate toll-like receptor pathway genes.
abstract: The genetic basis of hyper-IgE syndrome (HIES), also known as Job syndrome, a primary immunodeficiency associated with recurrent skin and pulmonary infections, is unknown. We hypothesized that HIES is due to a defect in the Toll-like receptor signaling pathway. We used a whole blood cytokine assay to compare inflammatory responses to stimulation with specific Toll-like receptor (TLR) pathway agonists in four individuals with HIES and nine healthy controls. Production of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-12 was not impaired in response to stimulation with lipopolysaccharide, peptidoglycan, zymosan, lipoteichoic acid, Staphylococcus aureus, Escherichia coli, or Streptococcus pneumoniae. Interferon (IFN)-gamma was reduced in HIES subjects in response to each of these stimuli. We sequenced several candidate genes from the TLR pathway in HIES individuals to determine whether any mutations were associated with this syndrome. No novel mutations or polymorphisms were found in the coding regions of TLR1, TLR2, TLR6, MyD88, or TRAF6. In summary, although HIES individuals had an IFN-gamma secretion defect, they also produced normal levels of several TLR-regulated proinflammatory cytokines. No unique mutations or polymorphisms were observed in several candidate genes from the TLR pathway. Our studies do not support a role for a defective TLR response in HIES individuals.
authors.affiliation: University of Washington School of Medicine, Seattle, WA 98103-8904, USA. thawn@u.washington.edu
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
authors.forename: Adrian
authors.initials: A
authors.lastname: Ozinsky
authors.forename: Luke M
authors.initials: LM
authors.lastname: Williams
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rodrigues
authors.forename: April
authors.initials: A
authors.lastname: Clark
authors.forename: Uyenvy
authors.initials: U
authors.lastname: Pham
authors.forename: Harry R
authors.initials: HR
authors.lastname: Hill
authors.forename: Hans
authors.initials: H
authors.lastname: Ochs
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000943:Antigens, Differentiation / Q000235:genetics; D001419:Bacteria / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D007378:Interleukins / Q000378:metabolism; D007589:Job Syndrome / Q000097:blood / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88; D010457:Peptidoglycan / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics; D013682:Teichoic Acids / Q000494:pharmacology; D051194:Toll-Like Receptor 1 / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051216:Toll-Like Receptor 6 / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D007378:Interleukins; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D010457:Peptidoglycan; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D048029:TNF Receptor-Associated Factor 6; D013682:Teichoic Acids; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D007371:Interferon-gamma; D015054:Zymosan