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

Human JNK1 is essential for IL-17A/F–dependent mucocutaneous immunity to Candida and for TGF-β–dependent homeostasis of connective tissues. Putting JNK1 on the immunodeficiency map Impaired TH17 immunity is the shared element among the group of inherited immunodeficiencies associated with chronic mucocutaneous candidiasis (CMC). Li et al. studied three patients from a single family who had CMC associated with an atypical form of connective tissue disorder with some features of Ehlers-Danlos syndrome. Whole-exome sequencing identified a previously unreported loss-of-function splice-site mutation in the MAPK8 gene encoding c-Jun N-terminal kinase 1 (JNK1) that causes JNK1 haploinsufficiency with autosomal dominant inheritance. The complex clinical phenotype in these patients results from defects in signaling downstream of both IL-17 and TGF-β cytokines. These findings demonstrate that JNK1-mediated signaling plays a critical role in maintaining normal immunity to Candida as well as supporting TGF-β–dependent homeostasis of connective tissues. 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.

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