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, vol. 4, No 41, p. 1-13. ISSN 2470-9468. doi:10.1126/sciimmunol.aax7965. 2019.
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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
Original language English
Type of outcome Article in a journal
Field of Study 30102 Immunology
Country of publisher United States of America
Confidentiality degree is not subject to a state or trade secret
WWW 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
Tags 14110114, podil, rivok
Tags International impact, Reviewed
Changed by Changed by: Mgr. Tereza Miškechová, učo 341652. Changed: 6/4/2020 13:19.
Abstract
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 projectName: Určení genových oblastí náchylných ke vzniku mutací ovlivňujících sestřih mRNA
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