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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

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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' T(H)17 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.
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

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MLA
Li, Juan, et al. “Chronic Mucocutaneous Candidiasis and Connective Tissue Disorder in Humans with Impaired JNK1-Dependent Responses to IL-17A/F and TGF-β.” SCIENCE IMMUNOLOGY, vol. 4, no. 41, 2019.
APA
Li, J., Ritelli, M., Ma, C. S., Rao, G., Habib, T., Corvilain, E., … Puel, A. (2019). Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β. SCIENCE IMMUNOLOGY, 4(41).
Chicago author-date
Li, Juan, Marco Ritelli, Cindy S Ma, Geetha Rao, Tanwir Habib, Emilie Corvilain, Salim Bougarn, et al. 2019. “Chronic Mucocutaneous Candidiasis and Connective Tissue Disorder in Humans with Impaired JNK1-Dependent Responses to IL-17A/F and TGF-β.” SCIENCE IMMUNOLOGY 4 (41).
Chicago author-date (all authors)
Li, Juan, Marco Ritelli, Cindy S Ma, Geetha Rao, Tanwir Habib, Emilie Corvilain, Salim Bougarn, Sophie Cypowyj, Lucie Grodecká, Romain Lévy, Vivien Béziat, Lei Shang, Kathryn Payne, Danielle T Avery, Mélanie Migaud, Soraya Boucherit, Sabri Boughorbel, Andrea Guennoun, Maya Chrabieh, Franck Rapaport, Benedetta Bigio, Yuval Itan, Bertrand Boisson, Valérie Cormier-Daire, Delfien Syx, Fransiska Malfait, Nicoletta Zoppi, Laurent Abel, Tomáš Freiberger, Harry C Dietz, Nico Marr, Stuart G Tangye, Marina Colombi, Jean-Laurent Casanova, and Anne Puel. 2019. “Chronic Mucocutaneous Candidiasis and Connective Tissue Disorder in Humans with Impaired JNK1-Dependent Responses to IL-17A/F and TGF-β.” SCIENCE IMMUNOLOGY 4 (41).
Vancouver
1.
Li J, Ritelli M, Ma CS, Rao G, Habib T, Corvilain E, et al. Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β. SCIENCE IMMUNOLOGY. 2019;4(41).
IEEE
[1]
J. Li et al., “Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β,” SCIENCE IMMUNOLOGY, vol. 4, no. 41, 2019.
@article{8638617,
  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' T(H)17 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.},
  articleno    = {eaax7965},
  author       = {Li, Juan and Ritelli, Marco and Ma, Cindy S and Rao, Geetha and Habib, Tanwir and Corvilain, Emilie and Bougarn, Salim and Cypowyj, Sophie and Grodecká, Lucie and Lévy, Romain and Béziat, Vivien and Shang, Lei and Payne, Kathryn and Avery, Danielle T and Migaud, Mélanie and Boucherit, Soraya and Boughorbel, Sabri and Guennoun, Andrea and Chrabieh, Maya and Rapaport, Franck and Bigio, Benedetta and Itan, Yuval and Boisson, Bertrand and Cormier-Daire, Valérie and Syx, Delfien and Malfait, Fransiska and Zoppi, Nicoletta and Abel, Laurent and Freiberger, Tomáš and Dietz, Harry C and Marr, Nico and Tangye, Stuart G and Colombi, Marina and Casanova, Jean-Laurent and Puel, Anne},
  issn         = {2470-9468},
  journal      = {SCIENCE IMMUNOLOGY},
  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},
  number       = {41},
  pages        = {13},
  title        = {Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β},
  url          = {http://dx.doi.org/10.1126/sciimmunol.aax7965},
  volume       = {4},
  year         = {2019},
}

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