Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T_H17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome

详细信息    查看全文

• 作者：Ellen D. Renner ; Stacey Rylaarsdam ; Stephanie Aň ; over-Sombke ; Anita L. Rack ; Janine Reichenbach ; John C. Carey ; Qili Zhu ; Annette F. Jansson ; Julia Barboza ; Lena F. Schimke ; Mark F. Leppert ; Melissa M. Getz ; Reinhard A. Seger ; Harry R. Hill ; Bernd H. Belohradsky ; Troy R. Torgerson ; Hans D. Ochs
• 关键词：Hyper-IgE syndrome ; HIES ; autosomal-dominant hyper-IgE syndrome ; Job syndrome ; IgE ; STAT3 mutations ; STAT3 phosphorylation ; T_H17 cells
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2008
• 出版时间：July 2008
• 年：2008
• 卷：122
• 期：1
• 页码：181-187
• 全文大小：561 K

文摘

Background

Hyper-IgE syndrome (HIES) is a rare, autosomal-dominant immunodeficiency characterized by eczema, Staphylococcus aureus skin abscesses, pneumonia with pneumatocele formation, Candida infections, and skeletal/connective tissue abnormalities. Recently it was shown that heterozygous signal transducer and activator of transcription 3 (STAT3) mutations cause autosomal-dominant HIES.

Objective

To determine the spectrum and functional consequences of heterozygous STAT3 mutations in a cohort of patients with HIES.

Methods

We sequenced the STAT3 gene in 38 patients with HIES (National Institutes of Health score >40 points) from 35 families, quantified T_H17 cells in peripheral blood, and evaluated tyrosine phosphorylation of STAT3.

Results

Most STAT3 mutations in our cohort were in the DNA-binding domain (DBD; 22/35 families) or Src homology 2 (SH2) domain (10/35) and were missense mutations. We identified 2 intronic mutations resulting in exon skipping and in-frame deletions within the DBD. In addition, we identified 2 mutations located in the transactivation domain downstream of the SH2 domain: a 10–amino acid deletion and an amino acid substitution. In 1 patient, we were unable to identify a STAT3 mutation. T_H17 cells were absent or low in the peripheral blood of all patients who were evaluated (n = 17). IL-6–induced STAT3-phosphorylation was consistently reduced in patients with SH2 domain mutations but comparable to normal controls in patients with mutations in the DBD.

Conclusion

Heterozygous STAT3 mutations were identified in 34 of 35 unrelated HIES families. Patients had impaired T_H17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation.