Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.

Background: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)–3 and impaired T_H17 differentiation. Objective: To elucidate mechanisms underlying different forms of HIES. Methods: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-α was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T_H17 and T_H1 cell differentiation was assessed by measuring the production of IL-17 and IFN-γ, respectively. Results: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T_H17 responses, but whereas STAT3 mutations abrogated early steps in T_H17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. Conclusion: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T_H17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome. [Copyright &y& Elsevier]