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

J. Li, M. Ritelli, CS. Ma, G. Rao, T. Habib, E. Corvilain, S. Bougarn, S. Cypowyj, L. Grodecká, R. Lévy, V. Béziat, L. Shang, K. Payne, DT. Avery, M. Migaud, S. Boucherit, S. Boughorbel, A. Guennoun, M. Chrabieh, F. Rapaport, B. Bigio, Y. Itan,...

. 2019 ; 4 (41) : . [pub] 20191129

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20025479

Grantová podpora
R01 AI127564 NIAID NIH HHS - United States
UL1 TR001866 NCATS NIH HHS - United States
NV16-34414A MZ0 CEP - Centrální evidence projektů

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-β-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-β-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-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β 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-β-dependent homeostasis of connective tissues.

Center for Medical Genetics Ghent University Hospital 9000 Ghent Belgium

Division of Biology and Genetics Department of Molecular and Translational Medicine University of Brescia 25123 Brescia Italy

Immunology Division Garvan Institute of Medical Research Darlinghurst New South Wales 2010 Australia

Immunology Division Garvan Institute of Medical Research Darlinghurst New South Wales 2010 Australia St Vincent's Clinical School Faculty of Medicine University of New South Wales Sydney New South Wales 2010 Australia

Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM U1163 Necker Hospital for Sick Children 75015 Paris France University of Paris Imagine Institute 75015 Paris France

McKusick Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD 21205 USA Howard Hughes Medical Institute Baltimore MD 21205 USA

Molecular Genetics Laboratory Centre for Cardiovascular Surgery and Transplantation Brno 65691 Czech Republic

Molecular Genetics Laboratory Centre for Cardiovascular Surgery and Transplantation Brno 65691 Czech Republic Faculty of Medicine and Central European Institute of Technology Masaryk University Brno 62500 Czech Republic

Sidra Medicine P O Box 26999 Doha Qatar

Sidra Medicine P O Box 26999 Doha Qatar College of Health and Life Sciences Hamad Bin Khalifa University P O Box 34110 Doha Qatar

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY 10065 USA

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY 10065 USA Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM U1163 Necker Hospital for Sick Children 75015 Paris France University of Paris Imagine Institute 75015 Paris France

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY 10065 USA Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM U1163 Necker Hospital for Sick Children 75015 Paris France University of Paris Imagine Institute 75015 Paris France Pediatric Hematology Immunology Unit Necker Hospital for Sick Children 75015 Paris France Howard Hughes Medical Institute New York NY 10065 USA

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY 10065 USA The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York NY 10029 USA Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY 10029 USA

University of Paris Imagine Institute 75015 Paris France Department of Medical Genetics INSERM U1163 Necker Hospital for Sick Children 75015 Paris France

Citace poskytuje Crossref.org

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