Immunodeficiency: primary or acquired
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 without other overt immunological phenotypes, and a novel and complex CTD, which 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 loss-of-expression variant results in low levels of JNK1 protein in the patients’ fibroblasts. These cells display impaired, but not abolished, responses to IL-17A and IL-17F, accounting for the patients’ CMC. This phenotype is rescued by the wild-type JNK1β1 isoform, whereas the mutant isoforms do not display negative dominance in control fibroblasts, consistent with AD JNK1 deficiency by haploinsufficiency. Additionally, the development of patients’ TH17 cells was slightly impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway. Consistently, the patients’ fibroblasts displayed impaired JNK1- and c-Jun/ATF2-dependent, but SMAD2/3-independent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β, probably accounting for the patients’ novel and complex 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.