Spontaneous Gastrointestinal Perforations in STAT3-Deficient Hyper-IgE Syndrome

Bhattacharya, Sumona; Williamson, Hastings; Urban, Amanda; Heller, Theo; Freeman, Alexandra F.

doi:10.1007/s10875-020-00836-0

Cited by 6 publications

(4 citation statements)

References 13 publications

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“…Recent reports include other epithelial sites being affected, including intestinal perforation (both spontaneous and associated with infection, including extra-gastrointestinal infection) [79,80]. Proposed mechanisms include gut dysbiosis from antibiotic therapy, defective IL-6 signaling supported by reports of perforation with IL-6 blockade with tocilizumab [81], and dysregulated TGF-β signaling supported by murine models of TGF-β knockout [82].…”

Section: Connective Tissue Abnormalities and Poor Wound Healing In Stat3-hiesmentioning

confidence: 99%

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

2021

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The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Since the prototypical HIES description 55 years ago, areas of significant progress have included description of key disease-causing genes and differentiation into clinically distinct entities. The first two patients reported had what is now understood to be HIES from dominant-negative mutations in signal transduction and activator of transcription 3 (STAT3-HIES), conferring a broad immune defect across both innate and acquired arms, as well as defects in skeletal, connective tissue, and vascular function, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infection, scoliosis and minimal trauma fractures, and vascular tortuosity and aneurysm. Due to the constitutionally expressed nature of STAT3, initial reports at treatment with allogeneic stem cell transplantation were not positive and treatment has hinged on aggressive antimicrobial prophylaxis and treatment to prevent the development of end-organ disease such as pneumatocele. Research into the pathophysiology of STAT3-HIES has driven understanding of the interface of several signaling pathways, including the JAK-STAT pathways, interleukins 6 and 17, and the role of Th17 lymphocytes, and has been expanded by identification of phenocopies such as mutations in IL6ST and ZNF341. In this review we summarize the published literature on STAT3-HIES, present the diverse clinical manifestations of this syndrome with current management strategies, and update on the uncertain role of stem cell transplantation for this disease. We outline key unanswered questions for further study.

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Section: Connective Tissue Abnormalities and Poor Wound Healing In Stat3-hiesmentioning

confidence: 99%

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

2021

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“…However, adverse events due to tocilizumab have been reported by recent data, the most common of which are infection and abnormal laboratory findings including neutropenia, thrombocytopenia, dyslipidemia, and transaminase (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) elevations [ 35 ]. In addotion, gastrointestinal perforation is an uncommon but serious side-effect in tocilizumab therapy due to the impaired IL-6 signaling, which also plays a role in maintaining intestinal health [ 35 , 36 ]. In this study, P1 and P3 manifested recurrent fever, elevated inflammatory indices and no joint swelling or arthralgia and showed good responses to tocilizumab.…”

Section: Discussionmentioning

confidence: 99%

Tocilizumab effectively reduces flares of hyperimmunoglobulin D syndrome in children: Three cases in China

Li,

Chen,

Tang

et al. 2024

Molecular Genetics and Metabolism Reports

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“…We included 6 patients from 5 unrelated Spanish families with heterozygous DN STAT3 mutations located in the DNA binding and Src homology 2 (SH2) domains, all of them previously described to cause AD-HIES (Fig. S1) [3,[28][29][30]. Patients with STAT1 GOF mutations (N658H, M202I, and P326S) were included as controls.…”

Section: Increased Stat1 Levels and Cytokine-induced Phosphorylation ...mentioning

confidence: 99%

Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations

et al. 2022

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Purpose STAT1 gain-of-function (GOF) and dominant-negative (DN) STAT3 syndromes share clinical manifestations including infectious and inflammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors shows promising results in treating STAT1 GOF-associated symptoms while management of DN STAT3 patients has been largely supportive. We here assessed the impact of ruxolitinib on the JAK-STAT1/3 pathway in DN STAT3 patients' cells. Methods Using flow cytometry, immunoblot, qPCR, and ELISA techniques, we examined the levels of basal STAT1 and phosphorylated STAT1 (pSTAT1) of cells obtained from DN STAT3, STAT1 GOF patients, and healthy donors following stimulation with type I/II interferons (IFNs) or interleukin (IL)-6. We also describe the impact of ruxolitinib on cytokineinduced STAT1 signaling in these patients. Results DN STAT3 and STAT1 GOF resulted in a similar phenotype characterized by increased STAT1 and pSTAT1 levels in response to IFNα (CD3 + cells) and IFNγ (CD14 + monocytes). STAT1-downstream gene expression and C-X-C motif chemokine 10 secretion were higher in most DN STAT3 patients upon stimulation compared to healthy controls. Ex vivo treatment with the JAK1/2-inhibitor ruxolitinib reduced cytokine responsiveness and normalized STAT1 phosphorylation in DN STAT3 and STAT1 GOF patient' cells. In addition, ex vivo treatment was effective in modulating STAT1 downstream signaling in DN STAT3 patients. Conclusion In the absence of effective targeted treatment options for AD-HIES at present, modulation of the JAK/STAT1 pathway with JAK inhibitors may be further explored particularly in those AD-HIES patients with autoimmune and/or autoinflammatory manifestations.

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Spontaneous Gastrointestinal Perforations in STAT3-Deficient Hyper-IgE Syndrome

Cited by 6 publications

References 13 publications

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

Tocilizumab effectively reduces flares of hyperimmunoglobulin D syndrome in children: Three cases in China

Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations

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