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

Abstract

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.

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

“…Recently-reported gene defects have been found for most categories of inborn errors of immunity, including novel causes of: SCID ( PAX1 [ 5 , 6 ], SLP76 [ 7 ]); CID ( MCM10 [ 8 ], IL6ST [ 9 – 11 ]); Predominantly antibody deficiencies ( FNIP1 [ 14 , 15 ], PIK3CG [ 16 , 17 ], CTNNBL1 [ 18 ], TNFSF13 [ 19 ]); Autoinflammatory diseases ( SOCS1 [ 20 – 22 ], TET2 [ 23 ], CEBPE [ 24 ], CDC42 [ 33 – 39 ], LSM11 , RNU7–1 [ 32 ], STAT2 [ 40 , 41 ], RIPK1 [ 42 , 43 ], NCKAP1L [ 44 – 46 ]), UBA1 (somatic mutations) [ 47 ]; and Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ). …”

“…Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ).…”

The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside

“…This may be due to the anti-IL-17 biologics mainly inhibit the Th17 cytokines and mediate an imbalance in the Th2/Th17 immune response, thus leading to eczematous eruptions (102)(103)(104). The deficiency of Th17 cells, IL-17RA, and IL-17F are essential for host defense against fungal pathogens in mucocutaneous and oral epithelial cells (105)(106)(107)(108)(109). The risk of chronic mucocutaneous candidiasis increases in patients received IL-17 blockades (secukinumab, ixekizumab, brodalumab, or bimekizumab) (94,96,110).…”

Plasticity of Treg and imbalance of Treg/Th17 cells in patients with systemic sclerosis modified by FK506

“…The production of ECM responses to Th17 cells. 40 And Th17 cell specifically secrete angiogenic factor, contribute to angiogenesis. 41 Treg and Th17 cells were served as hallmark of SSc, act as pro-fibrotic T cells.…”