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International Immunology Advance Access originally published online on December 15, 2008
International Immunology 2009 21(2):105-112; doi:10.1093/intimm/dxn134
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

review-article

Defects in Jak–STAT-mediated cytokine signals cause hyper-IgE syndrome: lessons from a primary immunodeficiency

Yoshiyuki Minegishi and Hajime Karasuyama

Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, 1-5-45, Bunkyo-ku, Yushima, Tokyo 113-8519, Japan

Correspondence to: Y. Minegishi; E-mail: yminegishi.mbch{at}tmd.ac.jp

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular bacteria and fungi, which frequently occur in the skin and lung. Atopic manifestations in HIES include extremely high serum IgE levels, eczema and eosinophilia. Most of the extracellular bacterial infections are associated with disproportionally milder inflammation than normal, which was originally described as having a ‘cold abscess’. Non-immunological abnormalities are also observed in most patients with HIES, including a distinctive facial appearance, scoliosis, hyper-extensive joints and retained primary teeth. Recent studies have demonstrated that hypomorphic mutations in signal transducer and activator of transcription 3 result in the classical multisystem form of HIES, whereas a null mutation in tyrosine kinase 2 causes the autosomal recessive form of HIES that is associated with viral and mycobacterial infections. Analyses of cytokine responses in both types of HIES have revealed defects in signal transduction for multiple cytokines including IL-6 and IL-23, leading to impaired Th17 function. These results suggest that the defect in multiple cytokine signals is the molecular basis of the immunological and non-immunological abnormalities in HIES and that the susceptibility to infections with extracellular bacteria and fungi in HIES might be associated with the defect in Th17 cell differentiation.

Keywords: primary immunodeficiency, STAT3, Tyk2

Transmitting editor: H. Kikutani

Received 9 November 2008, accepted 20 November 2008.


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Y. Minegishi, M. Saito, M. Nagasawa, H. Takada, T. Hara, S. Tsuchiya, K. Agematsu, M. Yamada, N. Kawamura, T. Ariga, et al.
Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome
J. Exp. Med., June 8, 2009; 206(6): 1291 - 1301.
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