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Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome  Shadi Al Khatib, MD, Sevgi Keles, MD, Maria.

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Presentation on theme: "Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome  Shadi Al Khatib, MD, Sevgi Keles, MD, Maria."— Presentation transcript:

1 Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome  Shadi Al Khatib, MD, Sevgi Keles, MD, Maria Garcia-Lloret, MD, Elif Karakoc-Aydiner, MD, Ismail Reisli, MD, Hasibe Artac, MD, Yildiz Camcioglu, MD, Haluk Cokugras, MD, Ayper Somer, MD, Necil Kutukculer, MD, Mustafa Yilmaz, MD, Aydan Ikinciogullari, MD, Olcay Yegin, MD, Mutlu Yüksek, MD, Ferah Genel, MD, Ercan Kucukosmanoglu, MD, Ali Baki, MD, Nerin N. Bahceciler, MD, Anupama Rambhatla, Derek W. Nickerson, BS, Sean McGhee, MD, Isil B. Barlan, MD, Talal Chatila, MD, MSc  Journal of Allergy and Clinical Immunology  Volume 124, Issue 2, Pages e5 (August 2009) DOI: /j.jaci Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Characteristics of the HIES cohort for age (A), HIES score (B), serum IgE levels (C), blood eosinophilia (D) and disease complications (E) in HIES patients with normal STAT3 sequence (HIES-STAT3wt) versus those with STAT3 mutations (HIES-STAT3mut). Abscesses include those in the skin and viscera; skeletal involvement includes fractures, retained primary teeth, and hyperextensibility; severe infections are those requiring hospitalization; CNS involvement includes infections, infarcts, vessel occlusion, and ischemic injury. ∗P = .02 for eosinophil counts (Student 2-tailed t test) and †P = .005 for pneumatocele formation (Fisher exact test) in the HIES-STAT3wt versus the HIES-STAT3mut group. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Defective IL-6–induced STAT3 phosphorylation in T cells of subjects with HIES with, but not without, STAT3 mutations. A, Representative intracellular staining profile of phospho-tyrosine (pY) 705STAT3 in T cells of a control subject, a subject with HIES with a normal STAT3 sequence (HIES-STAT3wt) and subjects with HIES with DNA binding and SH2 domain mutations (HIES-STAT3R382Q and HIES-STAT3Y668F, respectively), after stimulation with IL-6 for 15 minutes. B, ∗P < .01 for patients with HIES with STAT3 mutations (HIES-STAT3mut) versus HIES-STAT3wt or unrelated controls (n = 4 for each group). MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Defective IL-21–induced STAT3 phosphorylation in T cells of patients with HIES with STAT3 mutations. A, Representative intracellular staining profile of phospho-tyrosine (pY) 705STAT3 in T cells of a control subject, a subject with HIES with a normal STAT3 sequence (HIES-STAT3wt), and subjects with HIES with DNA binding and SH2 domain mutations (HIES-STAT3R382Q and HIES-STAT3Y657C, respectively), after stimulation with IL-21 for 15 minutes. B, ∗P < .001 for unrelated and parent controls (n = 6 and 17, respectively) versus patients with HIES with STAT3 mutations (HIES-STAT3mut; n = 5), and for HIES-STAT3wt (n = 15) versus HIES-STAT3mut. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Impaired TH17 differentiation is a common attribute of different forms of HIES. A, Real-time PCR analysis of RORγt mRNA levels in peripheral blood T-cell blasts of parent control subjects (n = 7), HIES without STAT3 mutations (HIES-STAT3wt; n = 7), and subjects with HIES with STAT3 mutations (HIES-STAT3mut; n = 3); ∗P = .01 and ∗∗P = .001 for parent controls versus HIES-STAT3mut and HIES-STAT3wt subjects, respectively. B, IL-17 production by peripheral blood T cells of HIES and control subjects after TH17 differentiation; ∗∗∗P = .001 for controls (n = 17) versus HIES-STAT3mut (n = 6) and HIES-STAT3wt (n = 12), respectively. C, IFN-γ production after TH1 differentiation is not impaired in HIES groups. RORγt mRNA expression (D) and IL-17 production (E) in TH0 and TH17 cells derived from naive T cells of control, HIES-STAT3mut, and HIES-STAT3wt subjects; ∗P < .05 for TH17 HIES-STAT3wt versus TH17 HIES-STAT3mut (D), and ∗∗P < .01 for TH17 HIES-STAT3wt versus TH17 control or TH17 HIES-STAT3mut (E). Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 STAT3 mutations in the HIES cohort. A
STAT3 mutations in the HIES cohort. A. Schematic representation of the STAT3 domains: N, N-terminal, CC, coiled-coil, DNA DNA binding, LK, linker, SH2, SH2 domain, Y, phosphotyrosyl tail segment, and TA, transactivation domain. Mutations are schematically represented by the following symbols: Δ, □, R382Q/W; §, IVS14+1delG; ●, Y657C; ○, S668F; and †, Y705C. B. Sequencing chromatograms of the individual mutations. ∗Novel mutation. Arrow indicates deletion site. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 IFN-α-induced pSTAT1 phosphorylation is similarly induced in T cells of control subjects and patients with HIES with or without STAT3 mutations. A. Representative intracellular staining profiles of pY705STAT1 in T cells after stimulation with IFN-α for 15 minutes. B. Box and whisker graphs (same number of subjects for the respective group as in Fig 3). MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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