Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses

Background: 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). Objective: 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. Methods: We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE. Results: 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 TH2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a TH9 axis with increased CCL22/MDC and CCL17/TARC serum levels. Conclusions: 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.

Automated summary

This study comprehensively characterizes the skin, immune cells, and allergic phenotypes of Netherton syndrome through multiple molecular profiling methods. The results reveal abnormal epidermal proliferation and differentiation, as well as IL-17/IL-36 signatures in both NS-ILC and NS-SE. Distinct molecular features are found between nonlesion and lesion skin of each disease subtype. Serum cytokine profiling and immunophenotyping show different allergic responses in NS-ILC and NS-SE patients.