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

Slides:

Advertisements

Similar presentations

Karin R. Engelhardt, PhD, Michael E

Advertisements

Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome Karin R. Engelhardt,

Plasmacytoid dendritic cell depletion in DOCK8 deficiency: Rescue of severe herpetic infections with IFN-α 2b therapy Sevgi Keles, MD, Haifa H. Jabara,

Homozygous N-terminal missense mutation in TRNT1 leads to progressive B-cell immunodeficiency in adulthood Glynis Frans, MPharm, Leen Moens, PhD, Heidi.

Challenges of genetic counseling in patients with autosomal dominant diseases, such as the hyper-IgE syndrome (STAT3-HIES) Benedikt D. Spielberger, Cristina.

Russell S. Traister, MD, PhD, Crystal E. Uvalle, BS, Gregory A

BCG-osis and tuberculosis in a child with chronic granulomatous disease Jacinta Bustamante, MD, PhD, Guzide Aksu, MD, Guillaume Vogt, PhD, Ludovic de.

Laurent L'homme, PhD, David Dombrowicz, PhD

Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome Karin R. Engelhardt,

Designing hypoallergenic derivatives for allergy treatment by means of in silico mutation and screening Theresa Thalhamer, PhD, Heidi Dobias, MSc, Tatjana.

Immunologic defects in 22q11.2 deletion syndrome

Karin R. Engelhardt, PhD, Michael E

Penicillium marneffei infection and impaired IFN-γ immunity in humans with autosomal- dominant gain-of-phosphorylation STAT1 mutations Pamela P.W. Lee,

Pentraxin 3 deletion aggravates allergic inflammation through a TH17-dominant phenotype and enhanced CD4 T-cell survival Jyoti Balhara, MSc, Lianyu Shan,

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation Almut Meyer-Bahlburg,

Chronic mucocutaneous candidiasis associated with an SH2 domain gain-of-function mutation that enhances STAT1 phosphorylation Ali Sobh, MD, Janet Chou,

IL-4 confers resistance to IL-27–mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling Zhihong.

Dorothy M. Ryan, MD, Stephen J. Fowler, MD, Robert M. Niven, MD

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis Stéphanie.

Differences in innate immune function between allergic and nonallergic children: New insights into immune ontogeny Meri K. Tulic, BSc, PhD, Megan Hodder,

Flow cytometric measurement of STAT1 and STAT3 phosphorylation in CD4+ and CD8+ T cells—clinical applications in primary immunodeficiency diagnostics

CD19 controls Toll-like receptor 9 responses in human B cells

Aaruni Khanolkar, MBBS, PhD, Dawn A. Kirschmann, PhD, Edward A

Distinct mutations at the same positions of STAT3 cause either loss or gain of function Prabha Chandrasekaran, PhD, Ofer Zimmerman, MD, Michelle Paulson,

Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-γ receptor deficiency Bianca Tesi, MD, Elena Sieni, MD, Conceição Neves, MD, Francesca.

Diagnostic approach to the hyper-IgE syndromes: Immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis Lena.

Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells Sofi Johansson, MSc, Göran Wennergren, MD, PhD, Nils Åberg,

The innate antiviral response upregulates IL-13 receptor α2 in bronchial fibroblasts Gemma Campbell-Harding, PhD, Hannah Sawkins, BSc, Nicole Bedke, PhD,

Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3–positive regulatory versus TH2 effector cells to.

Yuichi Teraki, MD, Aika Sakurai, MD, Seiichi Izaki, MD

Miriam Wittmann, MD, Jana Zeitvogel, Dong Wang, MD, Thomas Werfel, MD

The Wiskott-Aldrich syndrome

Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD,

Jerome A. Sigua, MD, Becky Buelow, MD, Dorothy S

Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor–dependent innate antiviral immune responses Douglas R. McDonald, MD, PhD,

Hematopoietic stem cell transplantation outcomes for 11 patients with dedicator of cytokinesis 8 deficiency Waleed Al-Herz, MD, Julia I. Chu, MD, Jet.

Peter M. Wolfgram, MD, David B. Allen, MD

IL-2–inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells Arun K. Kannan, MS, Nisebita.

Inhibition of human B-cell development into plasmablasts by histone deacetylase inhibitor valproic acid Anne-Kathrin Kienzler, MSc, Marta Rizzi, MD,

Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes TH17 cell differentiation Sevgi Keles,

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription.

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations Giovanna.

A peptide derived from the Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP) restores WAS protein level and actin cytoskeleton reorganization.

Elucidating the effects of disease-causing mutations on STAT3 function in autosomal- dominant hyper-IgE syndrome Simon J. Pelham, MSc, Helen C. Lenthall,

Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes.

Jon Genuneit, MD, MSc Journal of Allergy and Clinical Immunology

Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species László Maródi, MD, PhD, Sophie Cypowyj, PhD, Beáta Tóth, PhD,

Macrophage polarization: Reaching across the aisle?

T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production Ayako Matsuki, MD, Hiroaki Takatori, MD,

Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease Aurélie.

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

The mannose receptor negatively modulates the Toll-like receptor 4–aryl hydrocarbon receptor–indoleamine 2,3-dioxygenase axis in dendritic cells affecting.

Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation Fayhan J. Alroqi, MD,

Sabah El-Ghaiesh, MSc, Joseph P

Weiguo Chen, PhD, Gurjit K. Khurana Hershey, MD, PhD

Autophagy: Nobel Prize 2016 and allergy and asthma research

Amplification of Toll-like receptor–mediated signaling through spleen tyrosine kinase in human B-cell activation Shigeru Iwata, MD, PhD, Kunihiro Yamaoka,

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Cytokine responses in cord blood predict the severity of later respiratory syncytial virus infection Hanna Juntti, MD, Pamela Österlund, PhD, Jorma Kokkonen,

TH9 immunodeficiency in patients with hyper-IgE syndrome

Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients Mustafa Yavuz Köker, MD, PhD, Yıldız Camcıoğlu,

The mannose receptor negatively modulates the Toll-like receptor 4–aryl hydrocarbon receptor–indoleamine 2,3-dioxygenase axis in dendritic cells affecting.

Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell–mediated allergic inflammation Yong-Jun Liu, MD, PhD Journal.

Reply Journal of Allergy and Clinical Immunology

CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X- linked–like syndrome, and defective IL-10 expression from CD4 lymphocytes

Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis Jennifer K. Mulligan, PhD, Whitney Nagel,

Natural history of cow’s milk allergy

Primary prevention of asthma and allergy

Combined immunodeficiency in a patient with c-Rel deficiency

Thymic stromal lymphopoietin links keratinocytes and dendritic cell–derived IL-23 in patients with psoriasis Elisabetta Volpe, PhD, Lucia Pattarini,

Presentation transcript:

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 342-348.e5 (August 2009) DOI: 10.1016/j.jaci.2009.05.004 Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2009 124, 342-348.e5DOI: (10.1016/j.jaci.2009.05.004) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2009 124, 342-348.e5DOI: (10.1016/j.jaci.2009.05.004) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2009 124, 342-348.e5DOI: (10.1016/j.jaci.2009.05.004) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2009 124, 342-348.e5DOI: (10.1016/j.jaci.2009.05.004) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2009 124, 342-348.e5DOI: (10.1016/j.jaci.2009.05.004) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2009 124, 342-348.e5DOI: (10.1016/j.jaci.2009.05.004) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions