Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Luyan Liu; Satoshi Okada; Xiao-Fei Kong; Alexandra Y. Kreins; Sophie Cypowyj; Avinash Abhyankar; Julie Toubiana; Yuval Itan; Magali Audry; Patrick Nitschke; Cecile Masson; Beata Toth; Jerome Flatot; Melanie Migaud; Maya Chrabieh; Tatiana Kochetkov; Alexandre Bolze; Alessandro Borghesi; Antoine Toulon; Julia Hiller; Stefanie Eyerich; Kilian Eyerich; Vera Gulacsy; Ludmyla Chernyshova; Viktor Chernyshov; Anastasia Bondarenko; Rosa Maria Cortes Grimaldo; Lizbeth Blancas-Galicia; Ileana Maria Madrigal Beas; Joachim Roesler; Klaus Magdorf; Dan Engelhard; Caroline Thumerelle; Pierre-Regis Burgel; Miriam Hoernes; Barbara Drexel; Reinhard Seger; Theresia Kusuma; Annette F. Jansson; Julie Sawalle-Belohradsky; Bernd Belohradsky; Emmanuelle Jouanguy; Jacinta Bustamante; Melanie Bue; Nathan Karin; Gizi Wildbaum; Christine Bodemer; Olivier Lortholary; Alain Fischer; Stephane Blanche; Saleh Al-Muhsen; Janine Reichenbach; Masao Kobayashi; Francisco Espinosa Rosales; Carlos Torres Lozano; Sara Sebnem Kilic; Matias Oleastro; Amos Etzioni; Claudia Traidl-Hoffmann; Ellen D. Renner; Laurent Abel; Capucine Picard; Laszlo Marodi; Stephanie Boisson-Dupuis; Anne Puel; Jean-Laurent Casanova

doi:10.1084/jem.20110958

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Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

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Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Luyan Liu, Satoshi Okada, Xiao-Fei Kong, Alexandra Y. Kreins, Sophie Cypowyj, Avinash Abhyankar, Julie Toubiana, Yuval Itan, Magali Audry, Patrick Nitschke, …

The Journal of experimental medicine, Vol.208(8), pp.1635-1648

01/08/2011

DOI: https://doi.org/10.1084/jem.20110958

PMCID: 3149226

PMID: 21727188

Abstract

Immunology

Life Sciences & Biomedicine

Medicine, Research & Experimental

Research & Experimental Medicine

Science & Technology

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-gamma. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-alpha/beta, IFN-gamma, IFN-lambda, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-alpha/beta, IFN-gamma, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

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Title: Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis
Creators - without role: Luyan Liu - Inserm
Satoshi Okada - Rockefeller University
Xiao-Fei Kong - Rockefeller University
Alexandra Y. Kreins - Rockefeller University
Sophie Cypowyj - Rockefeller University
Avinash Abhyankar - Rockefeller University
Julie Toubiana - Délégation Paris 5
Yuval Itan - Rockefeller University
Magali Audry - Rockefeller University
Patrick Nitschke - Délégation Paris 5
Cecile Masson - Délégation Paris 5
Beata Toth - University of Debrecen
Jerome Flatot - Inserm
Melanie Migaud - Inserm
Maya Chrabieh - Inserm
Tatiana Kochetkov - Rockefeller University
Alexandre Bolze - Inserm
Alessandro Borghesi - Inserm
Antoine Toulon - Délégation Paris 5
Julia Hiller - Helmholtz Zentrum München
Stefanie Eyerich - Helmholtz Zentrum München
Kilian Eyerich - Helmholtz Zentrum München
Vera Gulacsy - University of Debrecen
Ludmyla Chernyshova - Shupyk National Healthcare University of Ukraine
Viktor Chernyshov - College Station Medical Center
Anastasia Bondarenko - College Station Medical Center
Rosa Maria Cortes Grimaldo - UMAE HE CMNO IMMS, Allergy & Immunol Dept, Guadalajara 44500, Jalisco, Mexico
Lizbeth Blancas-Galicia - Natl Inst Pediat, Mexico City 04530, DF, Mexico
Ileana Maria Madrigal Beas - UMAE HE CMNO IMMS, Allergy & Immunol Dept, Guadalajara 44500, Jalisco, Mexico
Joachim Roesler - University Hospital Carl Gustav Carus
Klaus Magdorf - Charité - Universitätsmedizin Berlin
Dan Engelhard - Hadassah Academic College
Caroline Thumerelle - Hôpital Jeanne de Flandre
Pierre-Regis Burgel - Hôpital Cochin
Miriam Hoernes - University Children's Hospital Zurich
Barbara Drexel - University Children's Hospital Zurich
Reinhard Seger - University Children's Hospital Zurich
Theresia Kusuma - Ludwig-Maximilians-Universität München
Annette F. Jansson - Ludwig-Maximilians-Universität München
Julie Sawalle-Belohradsky - Ludwig-Maximilians-Universität München
Bernd Belohradsky - Ludwig-Maximilians-Universität München
Emmanuelle Jouanguy - Rockefeller University
Jacinta Bustamante - Inserm
Melanie Bue - Centre Hospitalier Régional Universitaire de Brest
Nathan Karin - Technion – Israel Institute of Technology
Gizi Wildbaum - Technion – Israel Institute of Technology
Christine Bodemer - University of Debrecen
Olivier Lortholary - University of Debrecen
Alain Fischer - University of Debrecen
Stephane Blanche - University of Debrecen
Saleh Al-Muhsen - Technion – Israel Institute of Technology
Janine Reichenbach - University Children's Hospital Zurich
Masao Kobayashi - Hiroshima University
Francisco Espinosa Rosales - Natl Inst Pediat, Mexico City 04530, DF, Mexico
Carlos Torres Lozano - UMAE HE CMNO IMMS, Allergy & Immunol Dept, Guadalajara 44500, Jalisco, Mexico
Sara Sebnem Kilic - Uludağ University
Matias Oleastro - Garrahan Hospital
Amos Etzioni - Technion – Israel Institute of Technology
Claudia Traidl-Hoffmann - Helmholtz Zentrum München
Ellen D. Renner - Ludwig-Maximilians-Universität München
Laurent Abel - Inserm
Capucine Picard - Délégation Paris 5
Laszlo Marodi - University of Debrecen
Stephanie Boisson-Dupuis - Inserm
Anne Puel - Inserm
Jean-Laurent Casanova - Délégation Paris 5
Publication Details: The Journal of experimental medicine, Vol.208(8), pp.1635-1648
Publisher: Rockefeller Univ Press
Number of pages: 14
Grant note: Gebert Ruf Stiftung RE2799/3-1 / DFG; German Research Foundation (DFG) 5UL1RR024143-04 / Rockefeller University St. Giles Foundation 4.2.1./B-09/1/KONV-2010-0007; 4.2.2-08/1-2008-0015 / TAMOP Candidoser Association Shanghai Educational Development Foundation UL1RR024143 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) Choh-Hao Li Memorial Fund Institut National de la Sante et de la Recherche Medicale, University Paris Descartes; Institut National de la Sante et de la Recherche Medicale (Inserm) Az. 10.07.1.159 / Fritz-Thyssen research foundation 680/658 / LMU Munich FoFoLe grant AXA Research Fund
Identifiers: 9948572708331
Academic Unit: King Saud University
Language: English
Resource Type: Journal article