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

被引：601

作者：

Liu, Luyan ^{[1
,2
]}

Okada, Satoshi ^{[3
]}

Kong, Xiao-Fei ^{[3
]}

Kreins, Alexandra Y. ^{[3
]}

Cypowyj, Sophie ^{[3
]}

Abhyankar, Avinash ^{[3
]}

Toubiana, Julie ^{[4
]}

Itan, Yuval ^{[3
]}

Audry, Magali ^{[3
]}

Nitschke, Patrick ^{[5
]}

Masson, Cecile ^{[5
]}

Toth, Beata ^{[10
]}

Flatot, Jerome ^{[1
,2
]}

Migaud, Melanie ^{[1
,2
]}

Chrabieh, Maya ^{[1
,2
]}

Kochetkov, Tatiana ^{[3
]}

Bolze, Alexandre ^{[1
,2
,3
]}

Borghesi, Alessandro ^{[1
,2
]}

Toulon, Antoine ^{[6
]}

Hiller, Julia ^{[11
]}

Eyerich, Stefanie ^{[11
]}

Eyerich, Kilian ^{[11
,12
]}

Gulacsy, Vera ^{[10
]}

Chernyshova, Ludmyla ^{[13
]}

Chernyshov, Viktor ^{[14
]}

Bondarenko, Anastasia ^{[13
]}

Cortes Grimaldo, Rosa Maria ^{[15
]}

Blancas-Galicia, Lizbeth ^{[16
]}

Madrigal Beas, Ileana Maria ^{[15
]}

Roesler, Joachim ^{[17
]}

Magdorf, Klaus ^{[18
]}

Engelhard, Dan ^{[19
]}

Thumerelle, Caroline ^{[20
]}

Burgel, Pierre-Regis ^{[21
]}

Hoernes, Miriam ^{[22
]}

Drexel, Barbara ^{[22
]}

Seger, Reinhard ^{[22
]}

Kusuma, Theresia ^{[23
]}

Jansson, Annette F. ^{[23
]}

Sawalle-Belohradsky, Julie ^{[23
]}

Belohradsky, Bernd ^{[23
]}

Jouanguy, Emmanuelle ^{[1
,2
,3
]}

Bustamante, Jacinta ^{[1
,2
]}

Bue, Melanie ^{[24
]}

Karin, Nathan ^{[25
]}

Wildbaum, Gizi ^{[25
]}

Bodemer, Christine ^{[6
]}

Lortholary, Olivier ^{[7
]}

Fischer, Alain ^{[8
]}

Blanche, Stephane ^{[8
]}

机构：

[1] Necker Med Sch, INSERM, U980, Lab Human Genet Infect Dis,Necker Branch, F-75015 Paris, France

[2] Univ Paris 05, F-75015 Paris, France

[3] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA

[4] Hop Necker Enfants Malad, AP HP, Dept Pediat, F-75015 Paris, France

[5] Hop Necker Enfants Malad, AP HP, Bioinformat Unit, F-75015 Paris, France

[6] Hop Necker Enfants Malad, AP HP, Dept Dermatol, F-75015 Paris, France

[7] Hop Necker Enfants Malad, AP HP, Dept Infect Dis, F-75015 Paris, France

[8] Hop Necker Enfants Malad, AP HP, Pediat Hematol Immunol Unit, F-75015 Paris, France

[9] Hop Necker Enfants Malad, AP HP, Ctr Immunodeficiency, F-75015 Paris, France

[10] Univ Debrecen, Med & Hlth Sci Ctr, Dept Infect & Pediat Immunol, H-4032 Debrecen, Hungary

[11] Helmholtz Ctr TUM, Ctr Allergy & Environm, D-80802 Munich, Germany

[12] Tech Univ Munich, Dept Dermatol, D-80802 Munich, Germany

[13] Natl Med Acad Postgrad Educ, Dept Pediat Infect Dis & Clin Immunol, UA-01024 Kiev, Ukraine

[14] Natl Acad Med Sci, Inst Pediat Obstet & Gynecol, Immunol Lab, UA-01024 Kiev, Ukraine

[15] UMAE HE CMNO IMMS, Allergy & Immunol Dept, Guadalajara 44500, Jalisco, Mexico

[16] Natl Inst Pediat, Mexico City 04530, DF, Mexico

[17] Univ Hosp Carl Gustav Carus, Dept Pediat, D-01307 Dresden, Germany

[18] Charite Med Sch Berlin, Dept Pediat Pneumol & Immunol, D-11117 Berlin, Germany

[19] Hadassah Univ Hosp, Dept Pediat, IL-91120 Jerusalem, Israel

[20] Hosp Jeanne de Flandres, Pneumol & Allergol Unit, F-59037 Lille, France

[21] Hop Cochin, AP HP, Pneumol & UPRES EA 2511, F-75014 Paris, France

[22] Univ Zurich, Childrens Hosp, Div Immunol Hematol & BMT, Childrens Res Ctr, CH-8032 Zurich, Switzerland

[23] Univ Munich, Univ Childrens Hosp, Dr von Haunersches Kinderspital, D-80337 Munich, Germany

[24] Univ Hosp Ctr Brest, F-29609 Brest, France

[25] Technion Israel Inst Technol, Rappaport Fac Med, IL-31096 Haifa, Israel

[26] King Saud Univ, Coll Med, PrinceNaif Ctr Immunol Res, Dept Pediat, Riyadh 11461, Saudi Arabia

[27] Hiroshima Univ, Grad Sch Biomed Sci, Dept Pediat, Hiroshima 7398511, Japan

[28] Uludag Univ, Sch Med, Dept Pediat, TR-16059 Bursa, Turkey

[29] Natl Childrens Hosp Prof Dr Juan P Garrahan, RA-12049 Buenos Aires, DF, Argentina

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2011年 / 208卷 / 08期

关键词：

HYPER-IGE SYNDROME; SEQUENCING-BASED DISCOVERY; CD4(+) T-CELLS; TH17; CELLS; INBORN-ERRORS; IFN-GAMMA; TH17-ASSOCIATED CYTOKINES; DEFICIENCY; DISEASE; IL-27;

D O I：

10.1084/jem.20110958

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：1635 / 1648

页数：14

共 71 条

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