Woellner, C; (2014) Genetic and functional characterisation of the autosomal dominant form of Hyper IgE Syndrome. Doctoral thesis , UCL (University College London).

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Abstract

Background: Autosomal dominant Hyper IgE Syndrome (AD-HIES) is a rare primary immunodeficiency characterized by high serum IgE levels, eosinophilia, and skin and lung infections. Additional features of AD-HIES include characteristic facial appearance, scoliosis, retained primary teeth, and joint hyperextensibility. Recently, AD-HIES has been associated with heterozygous dominant negative mutations in the signal transducer and activator of transcription 3 (STAT3) which plays a key role in the signal transduction of a broad range of cytokines, and is crucial for IL-6-mediated regulation of Th17 cells. Objective: We aimed to characterize patients with the clinical diagnosis of ADHIES, to identify STAT3 mutations, and to assess the frequency and functional consequences of these mutations. Furthermore, we studied STAT3-dependent signalling pathways in patients with an AD-HIES phenotype but no STAT3 mutation. Methods: We sequenced STAT3 in 153 patients with a strong clinical suspicion of AD-HIES and further components of the IL-6 signalling pathway in patients found to be STAT3 wild type. The impact of the mutations on immune cell function was assessed by measurement of cytokine release by immune cells, T cell phenotyping and STAT1 phosphorylation assays. Results: About 60% of the AD-HIES patients revealed mutations in STAT3. All mutations found were heterozygous, clustered mainly in the DNA-binding or the SH2 domain and exerted dominant-negative effects. Functional analysis of mutations affecting different domains of STAT3 revealed that some mutations might have a less severe impact on functionality of STAT3, About 40% of our cohort of patients presenting with AD-HIES phenotype harboured wild type STAT3 and may carry mutations in other genes of either the same or closely related signalling pathways. Nevertheless, we ruled out mutations affecting the IL-6 pathway iIn five Sardinian patients with wild type STAT3. Impact of findings: The results lead to a better characterization of heterozygous STAT3 mutations and of the pathogenesis of AD-HIES.

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