Chronic mucocutaneous candidiasis and connective tissue
disorder in humans with impaired JNK1-dependent responses to
IL-17A/F and TGF-beta

J 2019

Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-beta

LI, J., M. RITELLI, C. S. MA, G. RAO, T. HABIB et. al.

Basic information

Original name

Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-beta

Authors

LI, J. (840 United States of America), M. RITELLI (380 Italy), C. S. MA (36 Australia), G. RAO (36 Australia), T. HABIB (634 Qatar), E. CORVILAIN (250 France), S. BOUGARN (634 Qatar), S. CYPOWYJ (840 United States of America), Lucie GRODECKÁ (203 Czech Republic), R. LEVY (250 France), V. BEZIAT (250 France), L. SHANG (840 United States of America), K. PAYNE (36 Australia), D. T. AVERY (36 Australia), M. MIGAUD (250 France), S. BOUCHERIT (250 France), S. BOUGHORBEL (250 France), A. GUENNOUN (250 France), M. CHRABIEH (250 France), F. RAPAPORT (840 United States of America), B. BIGIO (840 United States of America), Y. ITAN (840 United States of America), B. BOISSON (250 France), V. CORMIER-DAIRE (250 France), D. SYX (56 Belgium), F. MALFAIT (56 Belgium), N. ZOPPI (380 Italy), L. ABEL (250 France), Tomáš FREIBERGER (203 Czech Republic, guarantor, belonging to the institution), H. C. DIETZ (840 United States of America), N. MARR (634 Qatar), S. G. TANGYE (36 Australia), M. COLOMBI (380 Italy), J. L. CASANOVA (250 France), A. PUEL (250 France) and C. FIESCHI

Edition

SCIENCE IMMUNOLOGY, WASHINGTON, AMER ASSOC ADVANCEMENT SCIENCE, 2019, 2470-9468

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30102 Immunology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 13.440

RIV identification code

RIV/00216224:14110/19:00108609

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1126/sciimmunol.aax7965

UT WoS

000516638800006

Keywords in English

GROWTH-FACTOR-BETA; EHLERS-DANLOS-SYNDROME; OF-FUNCTION MUTATIONS; NH2-TERMINAL KINASE (JNK)1; INBORN-ERRORS; EXTRACELLULAR-MATRIX; CELL-DIFFERENTIATION; AORTIC-ANEURYSMS; STAT1 MUTATIONS; MARFAN-SYNDROME

Abstract

V originále

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-beta-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-beta-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-beta. Furthermore, they displayed a transcriptional pattern in response to TGF-beta different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-beta-dependent homeostasis of connective tissues.

Links

NV16-34414A, research and development project

Name: Určení genových oblastí náchylných ke vzniku mutací ovlivňujících sestřih mRNA

Citovat

LI, J., M. RITELLI, C. S. MA, G. RAO, T. HABIB, E. CORVILAIN, S. BOUGARN, S. CYPOWYJ, Lucie GRODECKÁ, R. LEVY, V. BEZIAT, L. SHANG, K. PAYNE, D. T. AVERY, M. MIGAUD, S. BOUCHERIT, S. BOUGHORBEL, A. GUENNOUN, M. CHRABIEH, F. RAPAPORT, B. BIGIO, Y. ITAN, B. BOISSON, V. CORMIER-DAIRE, D. SYX, F. MALFAIT, N. ZOPPI, L. ABEL, Tomáš FREIBERGER, H. C. DIETZ, N. MARR, S. G. TANGYE, M. COLOMBI, J. L. CASANOVA, A. PUEL and C. FIESCHI. Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-beta. SCIENCE IMMUNOLOGY. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2019, vol. 4, No 41, p. 1-13. ISSN 2470-9468. Available from: https://dx.doi.org/10.1126/sciimmunol.aax7965.

@article{1637576,
   author = {Li, J. and Ritelli, M. and Ma, C. S. and Rao, G. and Habib, T. and Corvilain, E. and Bougarn, S. and Cypowyj, S. and Grodecká, Lucie and Levy, R. and Beziat, V. and Shang, L. and Payne, K. and Avery, D. T. and Migaud, M. and Boucherit, S. and Boughorbel, S. and Guennoun, A. and Chrabieh, M. and Rapaport, F. and Bigio, B. and Itan, Y. and Boisson, B. and CormierandDaire, V. and Syx, D. and Malfait, F. and Zoppi, N. and Abel, L. and Freiberger, Tomáš and Dietz, H. C. and Marr, N. and Tangye, S. G. and Colombi, M. and Casanova, J. L. and Puel, A. and Fieschi, C.},
   article_location = {WASHINGTON},
   article_number = {41},
   doi = {http://dx.doi.org/10.1126/sciimmunol.aax7965},
   keywords = {GROWTH-FACTOR-BETA; EHLERS-DANLOS-SYNDROME; OF-FUNCTION MUTATIONS; NH2-TERMINAL KINASE (JNK)1; INBORN-ERRORS; EXTRACELLULAR-MATRIX; CELL-DIFFERENTIATION; AORTIC-ANEURYSMS; STAT1 MUTATIONS; MARFAN-SYNDROME},
   language = {eng},
   issn = {2470-9468},
   journal = {SCIENCE IMMUNOLOGY},
   title = {Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-beta},
   url = {https://immunology.sciencemag.org/content/4/41/eaax7965},
   volume = {4},
   year = {2019}
}

TY  - JOUR
ID  - 1637576
AU  - Li, J. - Ritelli, M. - Ma, C. S. - Rao, G. - Habib, T. - Corvilain, E. - Bougarn, S. - Cypowyj, S. - Grodecká, Lucie - Levy, R. - Beziat, V. - Shang, L. - Payne, K. - Avery, D. T. - Migaud, M. - Boucherit, S. - Boughorbel, S. - Guennoun, A. - Chrabieh, M. - Rapaport, F. - Bigio, B. - Itan, Y. - Boisson, B. - Cormier-Daire, V. - Syx, D. - Malfait, F. - Zoppi, N. - Abel, L. - Freiberger, Tomáš - Dietz, H. C. - Marr, N. - Tangye, S. G. - Colombi, M. - Casanova, J. L. - Puel, A. - Fieschi, C.
PY  - 2019
TI  - Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-beta
JF  - SCIENCE IMMUNOLOGY
VL  - 4
IS  - 41
SP  - 1-13
EP  - 1-13
PB  - AMER ASSOC ADVANCEMENT SCIENCE
SN  - 24709468
KW  - GROWTH-FACTOR-BETA
KW  - EHLERS-DANLOS-SYNDROME
KW  - OF-FUNCTION MUTATIONS
KW  - NH2-TERMINAL KINASE (JNK)1
KW  - INBORN-ERRORS
KW  - EXTRACELLULAR-MATRIX
KW  - CELL-DIFFERENTIATION
KW  - AORTIC-ANEURYSMS
KW  - STAT1 MUTATIONS
KW  - MARFAN-SYNDROME
UR  - https://immunology.sciencemag.org/content/4/41/eaax7965
L2  - https://immunology.sciencemag.org/content/4/41/eaax7965
N2  - Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-beta-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-beta-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-beta. Furthermore, they displayed a transcriptional pattern in response to TGF-beta different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-beta-dependent homeostasis of connective tissues.
ER  -

LI, J., M. RITELLI, C. S. MA, G. RAO, T. HABIB, E. CORVILAIN, S. BOUGARN, S. CYPOWYJ, Lucie GRODECKÁ, R. LEVY, V. BEZIAT, L. SHANG, K. PAYNE, D. T. AVERY, M. MIGAUD, S. BOUCHERIT, S. BOUGHORBEL, A. GUENNOUN, M. CHRABIEH, F. RAPAPORT, B. BIGIO, Y. ITAN, B. BOISSON, V. CORMIER-DAIRE, D. SYX, F. MALFAIT, N. ZOPPI, L. ABEL, Tomáš FREIBERGER, H. C. DIETZ, N. MARR, S. G. TANGYE, M. COLOMBI, J. L. CASANOVA, A. PUEL and C. FIESCHI. Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-beta. \textit{SCIENCE IMMUNOLOGY}. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2019, vol.~4, No~41, p.~1-13. ISSN~2470-9468. Available from: https://dx.doi.org/10.1126/sciimmunol.aax7965.

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