Netherton syndrome: new advances in the clinic, disease mechanism and treatment

The skin forms a very effective protective barrier against water loss and from the surrounding microflora and allergens. Netherton syndrome (NS) is a rare genetic skin disease with a profound skin barrier defect and constant and severe allergic manifestations. We previously identified SPINK5 encoding LEKTI as the defective gene in NS. Loss-of-function SPINK5 mutations lead to unopposed KLK5 and KLK7 activity, with a dual consequence on skin homeostasis: the stratum corneum is prematurely detached secondary to the proteolytic cleavage of corneodesmosomal cadherins; in parallel, KLK5 activates PAR2, leading to proinflammatory and proallergic cascades triggering the production of pro-Th2 molecules, such as thymic stromal lymphopoietin. These results have shed light on the importance of protease regulation and signaling in skin homeostasis, inflammation and allergy, and have pointed to new therapeutic targets in NS.