Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome - 20/08/11
, Sevgi Keles, MD b, , Maria Garcia-Lloret, MD a, Elif Karakoc-Aydiner, MD b, Ismail Reisli, MD c, Hasibe Artac, MD c, Yildiz Camcioglu, MD d, Haluk Cokugras, MD d, Ayper Somer, MD e, Necil Kutukculer, MD f, Mustafa Yilmaz, MD g, Aydan Ikinciogullari, MD h, Olcay Yegin, MD i, Mutlu Yüksek, MD j, Ferah Genel, MD k, Ercan Kucukosmanoglu, MD l, Ali Baki, MD m, Nerin N. Bahceciler, MD b, Anupama Rambhatla a, Derek W. Nickerson, BS a, Sean McGhee, MD a, Isil B. Barlan, MD b, ⁎ 
, Talal Chatila, MD, MSc a, ⁎ Reprint requests: Talal A. Chatila, MD, MSc, Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, MDCC 12-430, 10833 Le Conte Avenue, Los Angeles, CA 90095-1752.Isil B. Barlan, MD, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.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 TH17 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-⍺ was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. TH17 and TH1 cell differentiation was assessed by measuring the production of IL-17 and IFN-γ, 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 TH17 responses, but whereas STAT3 mutations abrogated early steps in TH17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps.
Conclusion |
In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired TH17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.
Le texte complet de cet article est disponible en PDF.Key words : Hyper IgE syndrome, STAT3, TH17, IL-6, IL-21, RORγt
Abbreviations used : AD, AR, HIES, JAK, RORγt, SH2, STAT, TYK2
Plan
| Supported by National Institutes of Health grant 5R01AI065617 (T.C.). |
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| Disclosure of potential conflict of interest: T. Chatila, M. Garcia-Lloret, and S. McGhee have received research support from the National Institutes of Health. The rest of the authors have declared that they have no conflict of interest. |
Vol 124 - N° 2
P. 342 - août 2009 Retour au numéro
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