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¹ Department of Immune Regulation and ² Department of Pediatrics and Developmental Biology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
³ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-0054, Japan
⁴ Department of Pediatrics, Tohoku University, Sendai 980-0872, Japan
⁵ Department of Pediatrics, Shinshu University, Matsumoto 390-8621, Japan
⁶ Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
⁷ Department of Pediatrics, Fujita Health University, Nagoya 470-1192, Japan

CORRESPONDENCE Yoshiyuki Minegishi: yminegishi.mbch{at}tmd.ac.jp

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.

© 2009 Minegishi et al.
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