Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation
Open accessAbstract
Background Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied. Objective Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease. Methods We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking. Results Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired FcεRI-mediated proximal and distal signaling, as well as reduced degranulation. Conclusion This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others.
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Studies in mut-Stat3 mice bearing two copies of the V463del STAT3 mutation demonstrated defective mast cell degranulation and reduced endothelial cell permeability.
“Studies in the mut-Stat3 bearing two copies of the V463del STAT3 mutation frequently found in Job’s syndrome patients demonstrated both defective mast cell degranulation and reduced endothelial cell permeability”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Siegel et al., 2013
The Methods (mut-Stat3 mice; page unavailable) describe mice carrying two copies of a transgene encoding the V463 deletion. The Results (page unavailable) report a reduced anaphylactic response and infer impaired in vivo mast cell degranulation. The paper does not report reduced endothelial cell permeability; its mouse anaphylaxis assay measured body temperature, not permeability. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHuman mast cell function in Job's syndrome patients was affected somewhat by reduced STAT3 signaling.
“human mast cell function in Job’s syndrome patients was affected somewhat by the reduced STAT3 signaling”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Siegel et al., 2013
Clinical food allergy and anaphylaxis are decreased in patients with Job's or AD-HIES despite a significant burden of eczematous skin disease and increased IgE.
“clinical food allergy and anaphylaxis are decreased in patients with Job’s or AD-HIES, despite a significant burden of eczematous skin disease and increased levels of IgE”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Siegel et al., 2013
AD-HIES patients demonstrate reduced numbers of memory CD8+ T cells and fewer memory CD4+ T cells relative to healthy controls.
“AD-HIES patients demonstrate reduced numbers of memory CD8+ T cells, as well as fewer memory CD4+ T cells, relative to healthy controls”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Siegel et al., 2013
The Results discuss reduced memory B-cell frequency and impaired T follicular helper-cell generation in AD-HIES, but do not report numbers of memory CD8+ or memory CD4+ T cells. Searches for those subsets and for reduced T-cell memory populations yielded no supporting passage in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“, 2013), contributing to their impaired ability to manage chronic infections (Siegel et al., 2013).”
BackgroundInfluentialGenetics of allergy and allergic sensitization: common variants, rare mutations
Bønnelykke, K., Sparks, R., Waage, J., & Milner, J. D. (2015) · Current Opinion in Immunology · doi:10.1016/j.coi.2015.08.002 · Cited by 73 · see citing works
Self-citation
- Authors
- Siegel, A. M., Stone, K. D., Cruse, G., Lawrence, M. G., Olivera, A., Jung, M.-Y., Barber, J. S., Freeman, A. F., Holland, S. M., O'Brien, M., Jones, N., Wisch, L. B., Kong, H. H., Desai, A., Farber, O., Gilfillan, A. M., Rivera, J., & Milner, J. D.
- Affiliations
- National Institute of Allergy and Infectious Diseases (US)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- National Institutes of Health (US)
- Corresponding author
- Milner, Joshua D.
- ORCID
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 132
- Issue
- 6
- Pages
- 1388-1396.e3
- ISSN
- 0091-6749 (ISSN-L)
- PMC
- PMC3881191
- OpenAlex
- W2158823847
- Cited by
- 131
- References
- 0
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 4 · 2022: 10 · 2021: 7 · 2020: 13 · 2019: 8 · 2018: 21 · 2017: 10 · 2016: 12 · 2015: 9 · 2014: 11
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Allergy and Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Laboratoire d'Excellence Inflamex
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (ZIAAI001183, T32AI007610)
- NIH Clinical Center
- NHLBI Division of Intramural Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Immunology and Allergy › Food Allergy and Anaphylaxis Research
- Keywords
- STAT3 mutations, autosomal dominant hyper-IgE syndrome, mast cell degranulation, food allergy, anaphylaxis, atopic dermatitis, IgE, basophil activation, FcεRI signaling, transgenic mouse model
- MeSH terms
- Adolescent, Adult, Aged, Animals, Cells, Cultured, Child, Child, Preschool, Dermatitis, Atopic, Female, Food Hypersensitivity, Humans, Immunoglobulin E, Infant, Job Syndrome, Male, Mast Cells, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Mutation, Signal Transduction, Cell Degranulation, Incidence, Transgenes, STAT3 Transcription Factor, Mice, Young Adult
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