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Gene expression analysis in primary cells derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139365 | GEO | 2020/08/12

REPOSITORIES: GEO

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Gene expression analysis in endothelial cells derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

Project description:Autosomal-dominant hyper-IgE syndrome (AD-HIES, Job’s syndrome) is a primary immunodeficiency caused by loss of function mutations in signal transducer and activator of transcription 3 (STAT3), a critical regulator of diverse cellular processes. In addition to immunological deficits, patients experience severe non-immunological features including skeletal, connective tissue and vascular abnormalities, poor post-infection healing, and subsequent pulmonary failure. The underlying mechanisms of these STAT3-dependent non-immunological features are not understood, preventing the development of targeted treatments. In this study, global gene expression was analysed in the patients umbilical vein endothelial cells in order to identify signaling pathway affected by the disease-causing STAT3 mutations with ultimate goal to better understand the disease mechanism and identify promising therapeutic targets.

2020-08-12 | GSE139188 | GEO

Analysis of gene expression in skin fibroblasts derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

Project description:Autosomal-dominant hyper-IgE syndrome (AD-HIES, Job’s syndrome) is a primary immunodeficiency caused by loss of function mutations in signal transducer and activator of transcription 3 (STAT3), a critical regulator of diverse cellular processes. In addition to immunological deficits, patients experience severe non-immunological features including skeletal, connective tissue and vascular abnormalities, poor post-infection healing, and subsequent pulmonary failure. The underlying mechanisms of these STAT3-dependent non-immunological features are not understood, preventing the development of targeted treatments. In this study, global gene expression was analysed in the patients skin fibroblasts in order to identify signaling pathway affected by the disease-causing STAT3 mutations with ultimate goal to better understand the disease mechanism and identify promising therapeutic targets.

2020-08-12 | GSE139202 | GEO

Generation of human induced pluripotent stem cell lines (NIHTVBi011-A, NIHTVBi012-A, NIHTVBi013-A) from autosomal dominant Hyper IgE syndrome (AD-HIES) patients carrying STAT3 mutation.

Project description:Autosomal dominant Hyper IgE syndrome (AD-HIES), a rare immune deficiency affecting fewer than one per million people, is caused by heterozygous deleterious mutations in STAT3. STAT3 signaling plays crucial roles in basic cellular functions affecting broad aspects of cellular homeostasis. Accordingly, in addition to immunological deficits, patients experience severe multisystem non-immunological features. Human induced pluripotent stem cells (hiPSC) are well established as in vivo disease models for various human pathologies. We describe the generation of iPSC from three AD-HIES patients. These iPSCs express pluripotency markers, differentiate into three germ layers, have normal karyotype and similar genome identity to parental cells.

| S-EPMC6957122 | biostudies-literature

Gene expression analysis in primary cells derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

Project description:Gene expression analysis in primary cells derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

| PRJNA579379 | ENA

Gene expression analysis in endothelial cells derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

Project description:Gene expression analysis in endothelial cells derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

| PRJNA578735 | ENA

Molecular Typing of Staphylococcus aureus Isolated from Patients with Autosomal Dominant Hyper IgE Syndrome.

Project description:Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immunodeficiency caused by a loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3). This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with Candida and Staphylococcus aureus. It has recently been recognized that the skin microbiome of patients with AD-HIES is altered with an overrepresentation of certain Gram-negative bacteria and Gram-positive staphylococci. However, these alterations have not been characterized at the species- and strain-level. Since S. aureus infections are influenced by strain-specific expression of virulence factors, information on colonizing strain characteristics may provide insights into host-pathogen interactions and help guide management strategies for treatment and prophylaxis. The aim of this study was to determine whether the immunodeficiency of AD-HIES selects for unique strains of colonizing S. aureus. Using multi-locus sequence typing (MLST), protein A (spa) typing, and PCR-based detection of toxin genes, we performed a detailed analysis of the S. aureus isolates (n = 13) found on the skin of twenty-one patients with AD-HIES. We found a low diversity of sequence types, and an abundance of strains that expressed methicillin resistance, Panton-Valentine leukocidin (PVL), and staphylococcal enterotoxins K and Q (SEK, SEQ). Our results indicate that patients with AD-HIES may often carry antibiotic-resistant strains that harbor key virulence factors.

| S-EPMC5488657 | biostudies-literature

Analysis of gene expression in skin fibroblasts derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

Project description:Analysis of gene expression in skin fibroblasts derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

| PRJNA578738 | ENA

Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance.

Project description:Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.

| S-EPMC8217968 | biostudies-literature

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome.

Project description:There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job's syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α-stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.

| S-EPMC7410079 | biostudies-literature

Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

Project description:Here we describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341.

2021-06-12 | GSE153886 | GEO

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