J Allergy Clin Immunol

BACKGROUNDNetherton 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).OBJECTIVEWe 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.METHODSWe studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE.RESULTSIntegrated 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.CONCLUSIONSThis 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.KEYWORDSIL-36, Netherton syndrome, T(H)2, T(H)9, ichthyosis linearis circumflexa, scaly erythroderma, type I IFNCopyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.