Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jul;41(5):864-880.
doi: 10.1007/s10875-021-01051-1. Epub 2021 May 1.

STAT3 Hyper-IgE Syndrome-an Update and Unanswered Questions

Christo Tsilifis  1   2 , Alexandra F Freeman  3 , Andrew R Gennery  4   5
Affiliations
Review

STAT3 Hyper-IgE Syndrome-an Update and Unanswered Questions

Christo Tsilifis et al. J Clin Immunol. 2021 Jul.

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.

Keywords: HIES; HSCT; Hyper-IgE; IgE; Job’s syndrome; STAT3; quality of life; vasculopathy.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Mechanisms for disruption of STAT3-related signaling in STAT3-HIES and its phenocopies. 1. ZNF341 positively regulates STAT3 transcription [27]. 2. IL-6 and IL-11 bind to their respective receptors and form a complex with GP130, then sequentially phosphorylate first a JAK, then STAT3. IL-6 signaling may be disrupted by mutations in IL6R, while IL-11 signaling may be disrupted by IL11R mutations, and both may be affected by mutated IL6ST or STAT3. 3. Mutations in the SH2 domain of STAT3 impact tyrosine phosphorylation, while mutations in the DBD domain impact on STAT3 dimers binding to DNA [108]. 4. STAT3 activates ERBIN and disrupts TGFβ-SMAD2/3 signaling by sequestering phospho-SMAD2/3 in the cytoplasm and preventing transcriptional action of TGFβ [84]. This may be disrupted by mutations in STAT3 or ERBB2IP. Key: STAT3, signal transducer and activator of transcription 3; ERBIN, ERBB2-interacting protein; ZNF341, zinc finger protein 341; GP130, glycoprotein 130
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448(7157):1058–1062. - PubMed
    1. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 Mutations in the hyper-IgE syndrome. N Engl J Med [Internet]. 2007;357(16):1608–19. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMoa073687. Accessed Jan 2021. - DOI - PubMed
    1. Gernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM, et al. Autosomal dominant hyper-IgE syndrome in the USIDNET Registry. J Allergy Clin Immunol Pract [Internet]. 2018;6(3):996–1001. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2213219817306001. Accessed Jan 2021. - PMC - PubMed
    1. Villarino AV, Kanno Y, Shea JJO. Mechanism of JAK/STAT signaling in immunity disease". J Immunol. 2016;194(1):21–27. - PMC - PubMed
    1. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–170. - PMC - PubMed

Publication types

Substances

LinkOut - more resources