**5. Conclusion**

148 Atopic Dermatitis – Disease Etiology and Clinical Management

breakdown of the epidermal barrier. It can be summarized that these functions include the permeability barrier, which prevents transcutaneous evaporative water loss, and an antimicrobial barrier, which simultaneously encourages colonization by nonpathogenic ''normal'' flora (Elias, 2007). According to the report by Selander et al. (2009), approximately 50% of adult AD patients have allergen-specific IgE reactivity to the skin commensal yeast *Malassezia* spp. Due to the ruptured skin barrier in AD, it is likely that *Malassezia* come into contact with mast cells, which are known to be involved in AD. Since mast cells are located in the superficial dermis close to blood vessels, they are advantageously positioned to react with allergens diffusing through a ruptured epidermis. They are, therefore, recognized as key effector cells during IgE-associated Th2 type immune responses (Galli et al., 2005), and cross-linking of the high-affinity IgE receptor (FcεRI) leads to release of potent inflammatory mediators (Turner & Kinet, 1999) such as histamine, proteases, chemotactic factors, cytokines, and metabolites of arachidonic acid (Henz et al., 2001). Mast cells have a wide variety of cell surface receptors that can interact directly with pathogens, including Toll-like receptors (TLRs), which are involved in innate immune recognition of invading microorganisms (Qiao et al., 2006). Fungal products such as zymosan can activate mast cells through TLR2 (Marshall, 2004). It has recently been reported that a synergistic activation between TLR2 and FcεRI can occur in mast cells, resulting in increased production of inflammatory cytokines (Qiao et al., 2006) (Fig. 3). Although both a defective epidermal permeability (Sugarman et al., 2003; Seidenari & Giusti, 1995; Proksch et al., 2006; Chamlin et al., 2002; Eberlein-Konig et al., 2000) and a propensity to secondary infection (Boguniewicz et al., 2006; Baker, 2006) are well-recognized features of AD, these abnormalities have been widely assumed to

reflect downstream consequences of a primary immunologic abnormality.

Fig. 3. Skin barrier dysfunction in combination with skin indigenous *Malassezia* as an exacerbating factor in atopic dermatitis (AD). Due to the ruptured skin barrier in AD, it is likely that *Malassezia* and/or its products come into contact with mast cells which have a wide variety of cell surface receptors that interact directly with pathogens, including Tolllike receptors (TLRs). A synergistic activation between TLR and IgE receptor (Fcε RI) can

occur in mast cells, resulting in increased production of inflammatory cytokines.

Well-known representative fungi that exacerbate AD are the resident fungi in the skin, *Malassezia* spp. such as *M. furfur*, *M. globosa* and *M. restricta*, and the resident fungus in the intestinal tract, *C. albicans*. The lipophilic fungus *M. furfur* indigenously inhabits the seborrheic region of the body such as the face, cervical part, and upper part of back. It was also reported that the fungus may be implicated in rosacea-like dermatitis and edematous erythema, which are chronic and intractable symptoms characteristic to the face in adulttype AD. Regarding the underlying mechanism by which clinical manifestation of AD is affected in the presence of *M. furfur*, the following points have been proposed: 1) antigenspecific inflammation caused via activation of antigen-specific T cells, and 2) dysfunction of skin barrier. A defect of skin barrier readily allows penetration of multiple antigens or haptens, which enhances allergic inflammation, and vice versa. That is, an allergic inflammation derived from the immunological abnormalities damages barrier functions. This sequence cycle could answer the question as to why AD patients show IgE production against, and contact hypersensitivity to, various antigens or haptens. Gut colonization of *C. albicans* is also regarded as the other fungal factor exacerbating AD by promoting sensitization against food antigens, at least partly due to mast cell-mediated hyperpermeability in the gastrointestinal mucosa.
