Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced TH17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome

Abstract

Background Hyper-IgE Syndrome (HIES) is a rare, autosomal dominant (AD) 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 STAT3 mutations cause AD-HIES. Objective To determine the spectrum and functional consequences of heterozygous STAT3 mutations in a cohort of HIES patients. Methods We sequenced the STAT3 gene in 38 HIES patients (NIH-score >40 points) from 35 families, quantified TH17 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 SH2 domain (10/35), and were missense mutations. We identified two intronic mutations resulting in exon skipping and in-frame deletions within the DBD. In addition, we identified two mutations located in the transactivation domain downstream of the SH2 domain: A ten amino acid deletion and an amino acid substitution. In one patient, we were unable to identify a STAT3 mutation. TH17 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 34/35 unrelated HIES families. Patients had impaired TH17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation. Clinical implication Mutations in STAT3 and decreased TH17 cells identify individuals with AD-HIES, thereby allowing timely diagnosis and early treatment of these patients. Capsule summary Results from this patient cohort expand the spectrum of heterozygous STAT3 mutations in AD-HIES, and demonstrate impaired development of TH17 cells in all and reduced STAT3-phosphorylation in patients with SH2-domain mutations.

A novel mutation in the linker domain of the signal transducer and activator of transcription 3 gene, p.Lys531Glu, in hyper-IgE syndrome

“…TSLP is known to initiate typical IgE-and T H 2 cell-dependent allergic diseases through its effects on dendritic cells, whereas its ability to potently stimulate MCs might contribute to the T cell-and IgE-independent allergic inflammation. 4,5 In agreement with a previous study, 6 here we show that primary human BSM cells from nonasthmatic donors (commercially 5 with or without antibody to TNF or isotype control (10 mg/mL each). Data are representative of 4 experiments.…”

“…Lastly, we performed flow cytometric analyses to demonstrate the functional deficit of the STAT3 protein, as recently described. 4 As a result, we observed that the patient had impaired generation of IL-17-secreting CD4 1 T cells (T H 17 cells) on stimulation compared with control levels (Fig 1, B). Collectively, all these findings indicate that this de novo heterozygous missense mutation, K531E, in the linker domain of STAT3 was the diseasecausing mutation in the patient.…”

“…2,3 Most STAT3 mutations were located in the DNA-binding domain or Src homology 2 domain, whereas missense mutations were also found in the transactivation domain downstream of the Src homology 2 domain. [2][3][4] Here we report the first STAT3 mutation in the linker domain of the protein in a boy with HIES.A 5-year-old Korean boy was admitted because of fever, cough, and otorrhea for a week. His parents were not consanguineous.…”

“…It was reported that STAT3 mutations were not always found in patients with HIES. 3,4 In addition, homozygous mutations in the tyrosine kinase 2 gene are the genetic defect in a subgroup of patients with HIES. 6 The K531E mutation described in this report is the first mutation in the linker domain of STAT3, further expanding the genetic heterogeneity of HIES.…”

“…6 The K531E mutation described in this report is the first mutation in the linker domain of STAT3, further expanding the genetic heterogeneity of HIES. According to recent studies, 4,7,8 patients with HIES with STAT3 mutations showed absent or markedly decreased levels of T H 17 cells in their peripheral blood. By comparison, patients with HIES or HIES-like symptoms (without recurrent candidiasis/staphylococcal abscess or lung infection) without STAT3 mutations were shown to have higher levels of T H 17 cells than those with mutations, albeit still significantly lower than levels seen in control individuals.…”