Blunder Stefan, Hermann-Kleiter Natascha, Mahmuti Rita, Hermann Martin, Ortner Daniela, Reider Daniela, Moosbrugger-Martinz Verena, Del Frari Barbara, Stoitzner Patrizia, Dubrac Sandrine, Schmuth Matthias, Gruber Robert
Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Cell Genetics, Department for Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Exp Dermatol. 2025 May;34(5):e70113. doi: 10.1111/exd.70113.
Netherton syndrome (NS) is a rare ichthyosis caused by SPINK5-null mutations, resulting in erythroderma, ichthyosis linearis circumflexa, and atopic diathesis. Elevated serum IgE levels and activation of the KLK5-PAR2-TSLP axis suggest involvement of Th2-skewed immunity in NS. In this pilot study, we investigated the effects of IL-4/IL-13 blocking with dupilumab on NS features. At baseline, Th2-chemokines CCL11, CCL17, CCL18, CCL26, and serum IgE were more elevated in atopic dermatitis (AD) than in NS vs. controls (ctrls). AD exhibited elevated serum levels of CCL27, LDH, and eosinophils, while NS showed higher levels of IL-9 and IL-18. Epidermal aberrations, including acanthosis and SC-detachment, were present in NS versus ctrls. The number of CD3+ T cells increased, while CD1a + Langerhans cell numbers decreased in NS skin. Amounts of KLK5 were reduced, and the distribution of KLK7 was abnormal in NS epidermis as compared to ctrls. Reduced amounts of FLG, CDSN, and DSG1 highlight impaired keratinocyte late differentiation in NS. Amounts of epidermal TSLP were diminished. Upon dupilumab treatment, clinical improvement in NS began as early as week 8 and continued up to 30 months, with no serious side effects reported. Serum levels of IgE, CCL17, CCL26, IFN-γ and IL-18 decreased upon IL-4/IL-13 blockade, and alterations of cutaneous immune cells improved in NS. Furthermore, the epidermal protease inhibitor WFDC12 expression increased after dupilumab treatment, concurring with improved and partially normalised epidermal structure, including increased FLG, CDSN, and DSG1. These data highlight Th2-skewed immunity in NS and emphasise the amelioration of NS features through dupilumab treatment.
Netherton综合征（NS）是一种由SPINK5基因无效突变引起的罕见鱼鳞病，可导致红皮病、回旋线状鱼鳞病和特应性素质。血清IgE水平升高以及KLK5-PAR2-TSLP轴的激活提示Th2偏向性免疫参与了NS的发病过程。在这项初步研究中，我们调查了使用度普利尤单抗阻断IL-4/IL-13对NS症状的影响。在基线时，与NS和对照组相比，特应性皮炎（AD）中Th2趋化因子CCL11、CCL17、CCL18、CCL26以及血清IgE水平升高更为明显。AD患者血清中CCL27、乳酸脱氢酶（LDH）和嗜酸性粒细胞水平升高，而NS患者IL-9和IL-18水平较高。与对照组相比，NS患者存在包括棘层肥厚和颗粒层分离在内的表皮异常。NS患者皮肤中CD3 + T细胞数量增加，而CD1a + 朗格汉斯细胞数量减少。与对照组相比，NS患者表皮中KLK5含量降低，KLK7分布异常。丝聚蛋白（FLG）、内披蛋白（CDSN）和桥粒芯糖蛋白1（DSG1）含量减少，突出了NS患者角质形成细胞晚期分化受损。表皮胸腺基质淋巴细胞生成素（TSLP）含量减少。使用度普利尤单抗治疗后，NS患者最早在第8周开始出现临床改善，并持续至30个月，且未报告严重副作用。IL-4/IL-13阻断后，NS患者血清IgE、CCL17、CCL26、干扰素-γ（IFN-γ）和IL-18水平降低，皮肤免疫细胞变化得到改善。此外，度普利尤单抗治疗后表皮蛋白酶抑制剂WFDC12表达增加，同时表皮结构改善并部分恢复正常，包括FLG、CDSN和DSG1增加。这些数据突出了NS中Th2偏向性免疫，并强调了度普利尤单抗治疗对NS症状的改善作用。
