TY - JOUR
T1 - Inborn errors of human STAT1
T2 - Allelic heterogeneity governs the diversity of immunological and infectious phenotypes
AU - Boisson-Dupuis, Stephanie
AU - Kong, Xiao Fei
AU - Okada, Satoshi
AU - Cypowyj, Sophie
AU - Puel, Anne
AU - Abel, Laurent
AU - Casanova, Jean Laurent
N1 - Funding Information:
We thank Yelena Nemirovskaya and Eric Anderson for secretarial assistance, Shen-Ying Zhang for the HSE figure, Emmanuelle Jouanguy and Amandine Crequer for critical reading and all the Laboratory of Human Genetics of Infectious Diseases for helpful discussions. The Laboratory of Human Genetics of Infectious Diseases is supported partly by grants from the St. Giles Foundation , the Jeffrey Modell Foundation , The Rockefeller University Center for Clinical and Translational Science grant number 5UL1RR024143 , the National Institute of Allergy and Infectious Diseases grant numbers 5R01AI089970-02 and 1R37AI095983-01 , The Rockefeller University , the Agence Nationale de la Recherche (ANR) , and the European Research Council (ERC) . X.F.K. was supported by a Choh-Hao Li Memorial Fund Scholar Award and the Shanghai Educational Development Foundation , and S.C. is supported by the AXA Research Fund .
PY - 2012/8
Y1 - 2012/8
N2 - The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human . STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human . STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.
AB - The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human . STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human . STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.
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U2 - 10.1016/j.coi.2012.04.011
DO - 10.1016/j.coi.2012.04.011
M3 - Review article
C2 - 22651901
AN - SCOPUS:84865308028
SN - 0952-7915
VL - 24
SP - 364
EP - 378
JO - Current Opinion in Immunology
JF - Current Opinion in Immunology
IS - 4
ER -