1. Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan
2. Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
3. Department of Pediatrics, Fujita Health University, Aichi 470-1192, Japan
4. Department of Pediatrics, Kyushu University, Fukuoka 812-8582, Japan
5. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
6. Pediatric Immunology, Mother and Child Health Institute, Belgrade 110 70, Serbia
7. Laboratory for Forensic Genetics, Institute of Forensic Medicine, University of Belgrade, Belgrade 110 70, Serbia
8. Pediatric Immunology Department, SB Ankara Diskapi Children's Hospital, Ankara 06110, Turkey

Correspondence to: Yoshiyuki Minegishi¹ Correspondence and requests for materials should be addressed to Y.M. (Email: yminegishi.mbch@tmd.ac.jp).

Abstract

Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities¹. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.

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