Classic atopic dermatitis is complicated by asthma, allergic rhinitis, and food allergies, cumulatively referred to as atopic diseases. Recent discoveries of mutations in the filaggrin gene as predisposing factors for atopic diseases have refocused investigators’ attention on epidermal barrier dysfunction as a causative mechanism. The three musketeers of the epidermal barrier are as follows: the stratum corneum (air-liquid barrier), tight junctions (liquid-liquid barrier), and the Langerhans cell network (immunological barrier). Clarification of the molecular events underpinning epidermal barrier function and dysfunction should lead to a better understanding of the pathophysiological mechanisms of atopic diseases.
To evaluate the impact of filaggrin deficiency on skin barrier function, we generated filaggrin knockout (KO) mice. Filaggrin KO mice exhibited dry and scaly skin, but did not develop any spontaneous dermatitis. Permeability assay using calcein-encapsulating liposomes demonstrated that filaggrin-deficiency allows its penetration through SC. Barrier defect in filaggrin KO mice led to enhanced hapten-induced contact hypersensitivity responses and humoral responses to topically immunized protein antigens. Using 3D visualization method of epidermal TJs in mouse ear skin, we demonstrated that activated Langerhans cells (LC) extend their dendrites beyond tight junctions (TJ) to capture external antigens. We, then, demonstrated preemptive immunity is evoked against the captured antigens with a murine model for staphylococcal scaled skin syndrome (SSSS), a severe blistering disease caused by skin infection of exfoliative toxin (ET)-producing Staphylococcus aureus. Percutaneous humoral responses elicited by LCs highlight an efficient mechanism by which immunity to potentially pathogenic skin-surface microbes is provided without disrupting tight junction barriers, and demonstrate an important role for LCs in host defense in vivo.Â