title: Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.
abstract: BACKGROUND
  The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation.
  
  
  OBJECTIVE
  To elucidate mechanisms underlying different forms of HIES.
  
  
  METHODS
  A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively.
  
  
  RESULTS
  Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps.
  
  
  CONCLUSIONS
  In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.
authors: Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, Calif 90095-1752, USA.
authors: Shadi
authors: S
authors: Al Khatib
authors: Sevgi
authors: S
authors: Keles
authors: Maria
authors: M
authors: Garcia-Lloret
authors: Elif
authors: E
authors: Karakoc-Aydiner
authors: Ismail
authors: I
authors: Reisli
authors: Hasibe
authors: H
authors: Artac
authors: Yildiz
authors: Y
authors: Camcioglu
authors: Haluk
authors: H
authors: Cokugras
authors: Ayper
authors: A
authors: Somer
authors: Necil
authors: N
authors: Kutukculer
authors: Mustafa
authors: M
authors: Yilmaz
authors: Aydan
authors: A
authors: Ikinciogullari
authors: Olcay
authors: O
authors: Yegin
authors: Mutlu
authors: M
authors: Yüksek
authors: Ferah
authors: F
authors: Genel
authors: Ercan
authors: E
authors: Kucukosmanoglu
authors: Ali
authors: A
authors: Baki
authors: Nerin N
authors: NN
authors: Bahceciler
authors: Anupama
authors: A
authors: Rambhatla
authors: Derek W
authors: DW
authors: Nickerson
authors: Sean
authors: S
authors: McGhee
authors: Isil B
authors: IB
authors: Barlan
authors: Talal
authors: T
authors: Chatila
mesh_terms: D000293:Adolescent; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007223:Infant; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007375:Interleukin-1 / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology; D008297:Male; D009154:Mutation / Q000235:genetics; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000276:immunology / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: C508600:IL6 protein, human; D016898:Interferon-alpha; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018664:Interleukin-12; D007073:Immunoglobulin E; D007371:Interferon-gamma; D000098546:Interleukin-21