dermatologic disorders
Atopic Dermatitis (Eczema)
Pathophysiology of Atopic Dermatitis
All of the following contribute to the development of atopic dermatitis: Genetic factors Epidermal barrier dysfunction Immunologic mechanisms Environmental triggers Genes implicated in atopic dermatitis are those encoding epidermal and immunologic proteins. A major predisposing factor for atopic dermatitis is the existence in many patients of a loss-of-function mutation in the gene encoding for the filaggrin protein ( Pathophysiology reference ). Filaggrin is a component of the cornified cell envelope produced by differentiating keratinocytes. It is ultimately critical to building the hygroscopic barrier of the stratum corneum (also called the natural moisturizing factor). About 10% of European populations are heterozygous carriers of loss-of-function filaggrin mutations. Presence of these mutations (as well as more intragenic copy mutations) increases the risk of more severe atopic dermatitis and higher IgE levels. Filaggrin mutations are also associated with peanut allergy and asthma, even in the absence of atopic dermatitis. These recent molecular insights provide new understanding of atopic dermatitis and how the cutaneous inflammation, a T-cell–mediated delayed-type hypersensitivity, relates to allergic conditions with immediate-type hypersensitivities such as asthma and allergic rhinitis (hay fever). The epidermal skin barrier defect due to filaggrin mutations explains the development of xerosis and the predisposition to skin irritation. This results in the manifestation of atopic dermatitis, which is not an allergic reaction. The cutaneous inflammation, in contrast, is a T-cell–mediated delayed-type hypersensitivity and includes a Th2-dominant component in the skin. This hypersensitivity downregulates antimicrobial peptides (eg, beta-defensins), which explains why patients with atopic dermatitis are predisposed to developing bacterial and viral skin infections. The increased penetration of skin irritants and allergens also results in a Th2-dominant inflammation, which also drives IgE production and predisposes to immediate-type hypersensitivities. However, because the major mechanism mediating atopic dermatitis is delayed cell-mediated immunity, avoidance of immediate-type allergens (eg, pollen, dust mites) usually does not improve atopic dermatitis. Although immediate-type hypersensitivities (eg, asthma, allergic rhinitis) result from the skin barrier defect, they do not drive the T-cell–mediated cutaneous inflammation of atopic dermatitis. In patients with atopic diathesis, atopic dermatitis typically precedes allergic rhinoconjunctivitis and asthma. Sometimes, this sequence is called the "atopic march" and occurs because the skin barrier defect is the primary deficiency in atopic conditions. 1.Brown SJ, McLean WH: One remarkable molecule: Filaggrin.J Invest Dermatol132(3 Pt 2):751–762, 2012. doi: 10.1038/jid.2011.393 