title: Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Siegel
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Stone
authors.forename: Glenn
authors.initials: G
authors.lastname: Cruse
authors.forename: Monica G
authors.initials: MG
authors.lastname: Lawrence
authors.forename: Ana
authors.initials: A
authors.lastname: Olivera
authors.forename: Mi-yeon
authors.initials: MY
authors.lastname: Jung
authors.forename: John S
authors.initials: JS
authors.lastname: Barber
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Brien
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
authors.forename: Celeste G
authors.initials: CG
authors.lastname: Nelson
authors.forename: Laura B
authors.initials: LB
authors.lastname: Wisch
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Kong
authors.forename: Avanti
authors.initials: A
authors.lastname: Desai
authors.forename: Orly
authors.initials: O
authors.lastname: Farber
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
authors.forename: Juan
authors.initials: J
authors.lastname: Rivera
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015550:Cell Degranulation / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology; D005260:Female; D005512:Food Hypersensitivity / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism; D015994:Incidence; D007223:Infant; D007589:Job Syndrome / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D055815:Young Adult
chemical_list: D050796:STAT3 Transcription Factor; D007073:Immunoglobulin E
keywords: 2,4-Dinitrophenol; AD-HIES; Autosomal dominant hyper-IgE syndrome; BSB; Basophile stimulation buffer; DNP; ERK; Extracellular signal-regulated kinase; Job syndrome; NIH; National Institutes of Health; PE; Phycoerythrin; STAT3; Short hairpin RNA; Signal transducer and activator of transcription 3; degranulation; mast cell; shRNA; signal transducer and activator of transcription 3