title: Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome.
abstract: Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular pathogens, typically Staphylococcus aureus, which preferentially affect the skin and lung. Previous studies reported the defective differentiation of T helper 17 (Th17) cells in HIES patients caused by hypomorphic STAT3 mutations. However, the apparent contradiction between the systemic Th17 deficiency and the skin/lung-restricted susceptibility to staphylococcal infections remains puzzling. We present a possible molecular explanation for this enigmatic contradiction. HIES T cells showed impaired production of Th17 cytokines but normal production of classical proinflammatory cytokines including interleukin 1beta. Normal human keratinocytes and bronchial epithelial cells were deeply dependent on the synergistic action of Th17 cytokines and classical proinflammatory cytokines for their production of antistaphylococcal factors, including neutrophil-recruiting chemokines and antimicrobial peptides. In contrast, other cell types were efficiently stimulated with the classical proinflammatory cytokines alone to produce such factors. Accordingly, keratinocytes and bronchial epithelial cells, unlike other cell types, failed to produce antistaphylococcal factors in response to HIES T cell-derived cytokines. These results appear to explain, at least in part, why HIES patients suffer from recurrent staphylococcal infections confined to the skin and lung in contrast to more systemic infections in neutrophil-deficient patients.
authors.affiliation: Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan. yminegishi.mbch@tmd.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Minegishi
authors.forename: Masako
authors.initials: M
authors.lastname: Saito
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamada
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kawamura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ariga
authors.forename: Ikuya
authors.initials: I
authors.lastname: Tsuge
authors.forename: Hajime
authors.initials: H
authors.lastname: Karasuyama
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000946:Antigens, Fungal / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D007589:Job Syndrome / Q000276:immunology / Q000382:microbiology; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology; D008171:Lung Diseases / Q000276:immunology / Q000382:microbiology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology*; D013207:Staphylococcal Skin Infections / Q000276:immunology / Q000382:microbiology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D023083:beta-Defensins / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D000946:Antigens, Fungal; D018925:Chemokines; D016207:Cytokines; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D016209:Interleukin-8; D017472:Receptors, Interleukin-1; D050796:STAT3 Transcription Factor; D023083:beta-Defensins