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Netherton syndrome is a rare autosomal recessive skin disease caused by loss-of-function mutations in SPINK5 encoding LEKTI protein that results in unopposed activity of epidermal kallikrein-related peptidases (KLKs), mainly KLK5, KLK7, and KLK14. Although the function of KLK5 and KLK7 has been previously studied, the role of KLK14 in skin homeostasis and its contribution to Netherton syndrome pathogenesis remains unknown. We generated a transgenic murine model overexpressing human KLK14 (TghKLK14) in stratum granulosum. TghKLK14 mice revealed increased proteolytic activity in the granular layers and in hair follicles. Their hair did not grow and displayed major defects with hyperplastic hair follicles when hKLK14 was overexpressed. TghKLK14 mice displayed abnormal epidermal hyperproliferation and differentiation. Ultrastructural analysis revealed cell separation in the hair cortex and increased thickness of Huxley's layer. Desmoglein (Dsg) 2 staining was increased, whereas Dsg3 and Dsg4 were markedly reduced. In vitro studies showed that hKLK14 directly cleaves recombinant human DSG3 and recombinant human DSG4, suggesting that their degradation contributes to hair abnormalities. Their skin showed an inflammatory signature, with enhanced expression of IL-36 family members and their downstream targets involved in innate immunity. This in vivo study identifies KLK14 as an important contributor to hair abnormalities and skin inflammation seen in Netherton syndrome., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Netherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete., Results: We analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17 years, and healthy age-matched controls. The proportion of B cells (CD19 + ) and naïve B cells (CD27 - , IgD + ) were high while memory B cells (CD27 + ) and switched memory B cells (CD27 + IgM - IgD - ), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21 low , CD38l ow ) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naïve CD4 + T cells was reduced significantly and the proportion of CD8 + T central memory significantly elevated. An increased proportion of CD57 + CD8 + T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16 + and CD27 - NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity. The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L + T cells, naïve CD4 + and CD27 + CD8 + T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naïve T cells and terminal differentiated effector memory CD8 + cells and decreased the proportion of activated B cells and plasmablasts in three patients studied., Conclusions: This study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial.

Netherton syndrome (NS) is a severe genodermatosis characterized by abnormal scaling and constant atopic manifestations. NS is caused by mutations in SPINK5 (Serine Protease INhibitor Kazal-type 5), which encodes LEKTI (LymphoEpithelial Kazal Type-related Inhibitor). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. Whereas a skin barrier defect is generally regarded as a major cause for atopy, we previously identified a cell-autonomous signaling cascade that triggers pro-Th2 cytokine thymic stromal lymphopoietin (TSLP) production in LEKTI-deficient epidermis. This signaling is initiated by unrestricted kallikrein 5 (KLK5) activity, which directly activates proteinase-activated receptor 2 (PAR2)-mediated expression of TSLP and favors a cutaneous proallergic microenvironment independently of the environment and of the adaptive immune system. To further confirm these results in vivo, we generated Spink5/Par2 double knockout (DKO) mice. At embryonic day 19.5, these mice display a dramatic decrease in TSLP expression, although stratum corneum detachment persists, confirming the role of the KLK5-PAR2 cascade in TSLP-mediated early proallergic signaling. However, deletion of Par2 in adult DKO-grafted skin does not rescue the inflammatory phenotype probably resulting from stratum corneum detachment. We conclude that several mechanisms trigger and maintain the inflammatory phenotype in NS. These include skin barrier impairment, mechanical stress secondary to stratum corneum detachment, as well as protease-induced proinflammatory and proallergic pathways, including PAR2-mediated overexpression of TSLP.