Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of experimental medicine, 2011-08, Vol.208 (8), p.1635-1648

Ort / Verlag

United States: The Rockefeller University Press

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, 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-α/β, IFN-γ, 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.