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

Liu, L; Okada, S; Kong, XF; Kreins, AY; 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; María Cortés Grimaldo, R; Blancas-Galicia, L; Madrigal Beas, IM; Roesler, J; Magdorf, K; Engelhard, D; Thumerelle, C; Burgel, PR; Hoernes, M; Drexel, B; Seger, R; Kusuma, T; Jansson, AF; 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, FE; Lozano, CT; Kilic, SS; Oleastro, M; Etzioni, A; Traidl-Hoffmann, C; Renner, ED; Abel, L; Picard, C; Marodi, L; Boisson-Dupuis, S; Puel, A; Casanova, JL     «

Liu, L; Okada, S; Kong, XF; Kreins, AY; 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; María Cortés Grimaldo, R; Blancas-Galicia, L; Madrigal Beas, IM; Roesler, J; Magdorf, K; Engelhard, D; Thumerelle, C; Burgel, PR; Hoernes, M; Drexel, B; Seger, R; Kusuma, T; Jansson, AF; Sawall...     »

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-?. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-?/?, IFN-?, IFN-?, 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-?/?, IFN-?, 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.     «

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-?. Other loss-of-...     »