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STAT3 Hyper-IgE Syndrome-an Update and Unanswered Questions

Lookup NU author(s): Dr Christo Tsilifis, Professor Andrew Gennery

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

Author(s): Tsilifis C, Freeman AF, Gennery AR

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Immunology

Year: 2021

Pages: epub ahead of print

Online publication date: 01/05/2021

Acceptance date: 20/04/2015

Date deposited: 04/05/2021

ISSN (print): 0271-9142

ISSN (electronic): 1573-2592

Publisher: Springer

URL: https://doi.org/10.1007/s10875-021-01051-1

DOI: 10.1007/s10875-021-01051-1

PubMed id: 33932191


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