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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Science Immunology  29 Nov 2019:
Vol. 4, Issue 41, eaax7965
DOI: 10.1126/sciimmunol.aax7965

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.

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