INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France.
Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
J Allergy Clin Immunol. 2022 Apr;149(4):1358-1372. doi: 10.1016/j.jaci.2021.08.024. Epub 2021 Sep 17.
Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE).
We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients.
We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE.
Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a T2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a T9 axis with increased CCL22/MDC and CCL17/TARC serum levels.
This study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.
Netherton 综合征（NS）是一种罕见的常染色体隐性皮肤疾病，由编码丝氨酸蛋白酶抑制剂 LEKTI（淋巴上皮 Kazal 型相关抑制剂）的 SPINK5 基因功能丧失性突变引起。NS 患者存在严重的皮肤屏障缺陷，表现为炎症性皮肤损伤，以及伴有特应性表现的浅表鳞屑。他们表现为典型的回旋形线性鱼鳞病（NS-ILC）或鳞片状红皮病（NS-SE）。
我们使用多种分子分析方法的组合，全面描述 NS-ILC 和 NS-SE 患者的皮肤、免疫细胞和过敏表型。
我们研究了一个包含 13 名患者的队列，其中包括 9 名 NS-ILC 和 4 名 NS-SE。
综合多组学分析显示，在病变皮肤和血液中，两种 NS 表型均存在异常的表皮增殖和分化以及 IL-17/IL-36 特征。尽管 NS-ILC 和 NS-SE 病变皮肤的分子谱非常相似，但每种疾病亚型的非病变皮肤均具有独特的分子特征。非病变和病变 NS-SE 表皮均显示 I 型 IFN 信号通路的激活，而病变 NS-ILC 皮肤与非病变 NS-ILC 皮肤的不同之处在于补体激活和中性粒细胞浸润增加。血清细胞因子谱和循环淋巴细胞免疫表型分析显示，NS-ILC 存在 T2 驱动的过敏反应，而 NS-SE 患者主要表现为 T9 轴，血清 CCL22/MDC 和 CCL17/TARC 水平升高。
本研究证实 IL-17/IL-36 为两种 NS 表型的主要信号通路，并揭示了区分 NS-ILC 和 NS-SE 的分子特征。这些结果确定了新的治疗靶点，并为 NS 的精准医学铺平了道路。
