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1. Introduction
Atopic dermatitis (AD) is a chronic inflammatory dermatitis disease characterized by severe itching, eczematous skin eruption, asteatosis, and red, swollen, and cracked skin [1]. The general pathogenesis of AD has not been unknown, but AD-related symptoms including repeated worsening or recurrence are primarily assumed to be caused by two reasons. One reason is the induction of allergic inflammation based on immune system disorder, called “inside-out” while the other reason is epidermal permeability barrier dysfunction induced by external stress, called “outside-in” [1–4]. Immune system disorder, especially, has been focused on as the fundamental cause of AD. An association between AD and IgE has been proven by the evidence that serum IgE increases in proportion to the symptoms of eczema, asthma, and allergic rhinitis. Moreover, serum IgE level has been shown to increase in basophils after exposure to antigens and the existence of an IgE receptor has been demonstrated in mast cell and basophils. This phenomenon is referred to as the “IgE-mediated sensitization.” However, when patients were given oral immunosuppressive drugs to improve the symptoms, they did not respond and serum IgE levels did not decrease proportionally. Factors other than IgE were subsequently identified and the condition was called “non-IgE-mediated sensitization” [5]. The original model of AD pathogenesis attributed the disease development to an imbalance in cell-mediated helper T (Th) 1 versus Th2 cell response [6]. Th1 cells primarily produce interferon- (INF-) γ and tumor necrosis factor-α (TNF-α), which are required for cell-mediated inflammatory reactions while Th2 cells secrete IL-4, IL-5, IL-10, and IL-13, which mediate B cell activation and IgE production in mast cells [7]. Recently, AD studies have reported that numerous mast cells are present in the skin of patients with AD [8]. Activated mast cells induced by external stress secrete vasodilatory substances including a variety of protease, histamine, and numerous cytokines, which induce protein- (e.g., TNF-α- and IL-6-) mediated cell signaling that subsequently induces allergic inflammation [9]. These observations provide reasonable evidence that AD precedes other allergic disease such as allergic asthma and rhinitis [10]. This suggests...