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Liu, L.* ; Okada, S.* ; Kong, X.F.* ; Kreins, A.Y.* ; Cypowyj, S.* ; Abhyankar, A.* ; Toubiana, J.* ; Itan, Y.* ; Audry, M.* ; Nitschke, P.* ; Masson, C.* ; Toth, B.* ; Flatot, J.* ; Migaud, M.* ; Chrabieh, M.* ; Kochetkov, T.* ; Bolze, A.* ; Borghesi, A.* ; Toulon, A.* ; Hiller, J. ; Eyerich, S. ; Eyerich, K. ; Gulácsy, V.* ; Chernyshova, L.* ; Chernyshov, V.* ; Bondarenko, A.* ; Grimaldo, R.M.* ; Blancas-Galicia, L.* ; Beas, I.M.* ; Roesler, J.* ; Magdorf, K.* ; Engelhard, D.* ; Thumerelle, C.* ; Burgel, P.R.* ; Hoernes, M.* ; Drexel, B.* ; Seger, R.* ; Kusuma, T.* ; Jansson, A.F.* ; Sawalle-Belohradsky, J.* ; Belohradsky, B.* ; Jouanguy, E.* ; Bustamante, J.* ; Bué, M.* ; Karin, N.* ; Wildbaum, G.* ; Bodemer, C.* ; Lortholary, O.* ; Fischer, A.* ; Blanche, S.* ; Al-Muhsen, S.* ; Reichenbach, J.* ; Kobayashi, M.* ; Rosales, F.E.* ; Lozano, C.T.* ; Kilic, S.S.* ; Oleastro, M.* ; Etzioni, A.* ; Traidl-Hoffmann, C. ; Renner, E.D.* ; Abel, L.* ; Picard, C.* ; Maródi, L.* ; Boisson-Dupuis, S.* ; Puel, A.* ; Casanova, J.L.*

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

J. Exp. Med. 208, 1635-1648 (2011)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords hyper-ige syndrome; sequencing-based discovery; cd4(+) t-cells; th17 cells; inborn-errors; ifn-gamma; th17-associated cytokines; deficiency; disease; il-27
ISSN (print) / ISBN 0022-1007
e-ISSN 1540-9538
Journal Journal of Experimental Medicine
Quellenangaben Volume: 208, Issue: 8, Pages: 1635-1648 Article Number: , Supplement: ,
Publisher Rockefeller University Press
Publishing Place New York, NJ
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
Institute of Epidemiology (EPI)