St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Sci Immunol. 2019 Nov 29;4(41). doi: 10.1126/sciimmunol.aax7965.
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 , 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' T17 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 or , 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 and for the TGF-β-dependent homeostasis of connective tissues.
慢性黏膜皮肤念珠菌病（CMC）的遗传病因会破坏人类黏膜表面的 IL-17A/F 依赖性免疫，而结缔组织疾病（CTD）的遗传病因则经常损害 TGF-β 依赖的结缔组织稳态。涉及的信号通路尚不完全清楚。我们报告了一个三代家族，其具有常染色体显性（AD）CMC 和以前未描述的 CTD 形式的组合，该 CTD 在临床上与埃勒斯-当洛斯综合征（EDS）重叠。患者为编码 c-Jun N 末端激酶 1（JNK1）的基因的一个私有剪接位点变体的杂合子，JNK1 是 MAPK 信号通路的一个组成部分。该变体在患者的成纤维细胞中表现为表达缺失和功能丧失，这些成纤维细胞由于单倍不足而显示出 AD JNK1 缺乏。这些细胞对 IL-17A 和 IL-17F 的反应受损，但没有被完全抑制。此外，患者的 T17 细胞在体外和体内的发育受损，这可能是由于 JNK1 参与 TGF-β 反应途径，并进一步解释了患者的 CMC。一致地，患者的成纤维细胞显示出 TGF-β 反应性通路中 JNK1 和 c-Jun/ATF-2 依赖性关键细胞外基质（ECM）成分和调节剂的诱导受损，但对 TGF-β 反应性的 EDS 致病基因产物没有诱导受损，在响应 TGF-β 时，它们表现出与由 或 突变引起的 Loeys-Dietz 综合征患者的成纤维细胞不同的转录模式，进一步解释了患者复杂和不寻常的 CTD 表型。这种自然实验表明，人类 JNK1 依赖性 MAPK 信号通路的完整性对于针对 和 TGF-β 的黏膜皮肤 IL-17A/F 依赖性免疫至关重要。
