Research letter

Duality of Netherton syndrome manifestations and response to ixekizumab

Allergic diseases are a heterogeneous group of disorders resulting from exaggerated type 2 inflammation. Although typically viewed as polygenic multifactorial disorders caused by the interaction of several genes with the environment, we have come to appreciate that allergic diseases can also be caused by monogenic variants affecting the immune system and the skin epithelial barrier. Through a myriad of genetic association studies and high-throughput sequencing tools, many monogenic and polygenic culprits of allergic diseases have been described. Identifying the genetic causes of atopy has shaped our understanding of how these conditions occur and how they may be treated and even prevented. Precision diagnostic tools and therapies that address the specific molecular pathways implicated in allergic inflammation provide exciting opportunities to improve our care for patients across the field of allergy and immunology. Here, we highlight offender genes implicated in polygenic and monogenic allergic diseases and list targeted therapeutic approaches that address these disrupted pathways.

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 T_H2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a T_H9 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.