Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome

Yoshiyuki Minegishi, Masako Saito, Masayuki Nagasawa, Hidetoshi Takada, Toshiro Hara, Shigeru Tsuchiya, Kazunaga Agematsu, Masafumi Yamada, Nobuaki Kawamura, Tadashi Ariga, Ikuya Tsuge, Hajime Karasuyama

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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 1β. 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.

Original languageEnglish
Pages (from-to)1291-1301
Number of pages11
JournalJournal of Experimental Medicine
Volume206
Issue number6
DOIs
Publication statusPublished - Jun 8 2009

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Minegishi, Y., Saito, M., Nagasawa, M., Takada, H., Hara, T., Tsuchiya, S., Agematsu, K., Yamada, M., Kawamura, N., Ariga, T., Tsuge, I., & Karasuyama, H. (2009). Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. Journal of Experimental Medicine, 206(6), 1291-1301. https://doi.org/10.1084/jem.20082767