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.

中文翻译：

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慢性粘膜皮肤念珠菌病和结缔组织疾病的人，对IL-17A / F和TGF-β的JNK1依赖性反应受损。

慢性粘膜皮肤念珠菌病（CMC）的遗传病因破坏了粘膜表面人类IL-17A / F依赖的免疫力，而结缔组织疾病（CTD）的遗传病因常常损害结缔组织的TGF-β依赖的体内稳态。涉及的信号通路尚不完全清楚。我们报告了三代家庭，他们的CMC是常染色体显性遗传（AD）组合，并且以前没有描述过的CTD形式在临床上与Ehlers-Danlos综合征（EDS）重叠。这些患者对MAPK8的一个私人剪接位点变异体是杂合的，MAPK8是编码c-Jun N末端激酶1（JNK1）的基因，该基因是MAPK信号传导途径的组成部分。该变体是患者成纤维细胞中的表达缺失和功能丧失，其通过单倍剂量不足表现出AD JNK1缺乏。这些细胞已经受损，但没有消失，对IL-17A和IL-17F的反应。此外，患者TH17细胞的发育在体内和体外均受到损害，可能是由于JNK1参与了TGF-β反应途径并进一步解释了患者的CMC。一致地，患者的成纤维细胞对TGF-β的反应显示出对关键的细胞外基质（ECM）成分和调节剂的JNK1和c-Jun / ATF-2依赖性诱导受损，但对引起EDS的基因产物没有减弱。此外，它们显示出对TGF-β的转录模式，与TGFBR2或SMAD3突变引起的Loeys-Dietz综合征患者的成纤维细胞的转录模式不同，这进一步说明了患者的复杂而异常的CTD表型。