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

ABSTRACT: Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTD) 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 novel 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/ATF2-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 and 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137108 | GEO | 2019/11/29

REPOSITORIES: GEO