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

Sci Immunol 2019 11;4(41)

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

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 , 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' T17 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 or , 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 and for the TGF-β-dependent homeostasis of connective tissues.

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.aax7965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014825PMC
November 2019

Publication Analysis

Top Keywords

homeostasis connective
8
tgf-β-dependent homeostasis
8
accounting patients'
8
signaling pathway
8
connective tissues
8
mapk signaling
8
response tgf-β
8
patients' fibroblasts
8
cells impaired
8
chronic mucocutaneous
8
mucocutaneous candidiasis
8
connective tissue
8
patients'
5
eds patients
4
private splice-site
4
ehlers-danlos syndrome
4
patients' cmc
4
consistently patients'
4
patients heterozygous
4
heterozygous private
4

Similar Publications