**5. Clinical presentation**

252 Atopic Dermatitis – Disease Etiology and Clinical Management

In normal individuals there are three factors that contribute to intact epidermal barrier function; structural proteins, lipids and proteases. Alterations in these components contribute to epidermal barrier dysfunction in AD patients. Additionally, genetic dysfunctions can be classified into two distinct groups; mutations occurring in genes encoding for epithelial structures and mutations occurring in genes encoding for elements of the immune system (Bieber, 2008). Lastly, immunological dysfunction appears to play a critical role in the pathogenesis of AD and involves alterations in T-cells, B-cells, eosinophils and IgE production.

There are several factors that lead to epidermal barrier dysfunction including changes in the stratum corneum, decreases in lipid levels and loss of function of a crucial protein called filaggrin. This is compounded by alterations in the expression of enzymes, such as peptidases within the epidermal layer leading to further breakdown of this protective barrier. Ultimately, the disruption of the epidermal barrier facilitates the penetration of environmental allergens and promotes allergic skin inflammation (Bieber 2008; Caubet &

Researchers have identified several candidate genes that contribute to both the structural and immunological dysfunctions seen in AD. There is a genetically determined dominance of Th2 cells, which produce cytokines including Interleukin-4 (IL-4), Interleukin-5 (IL-5) and Interleukin-13 (IL-13). These cytokines play a role in the synthesis of IgE, which is upregulated in 85% of patients with AD. Additionally, there is a loss of function mutation in the gene encoding for the protein filaggrin, which is a crucial protein in cutaneous barrier

The immunological factors that contribute to AD are multifactorial and complex. As stated previously, disruptions in the epidermal barrier facilitate the penetration of allergens. These allergens are presented to the Langerhans Cells (LCs) located within the epidermal layer, which migrate to the lymphoid organs where they present the allergen to the Th2 cells. (Callard & Harper 2007) Additionally, activated dendritic cells serve to stimulate memory Th2 cells and migrate to the lymph nodes where they further increase the systemic pool of Th2 cells by stimulating naïve T-cells. This increase in circulating T-cells results in the development of skin lesions through the production of inflammatory cytokines IL-4, IL-13, IL-5 and IL-12. Further promotion of the inflammatory response is modulated by Th2 cells through the upregulation of adhesion molecules on endothelial cells and increases in high affinity receptors for IgE on LCs and other antigen presenting cells. Lastly, eosinophils appear to play a role through secretion of cytolytic proteins resulting in further damage to

Other immunological factors that contribute to the pathogenesis of the disease include a down regulation of toll-like receptors (TLRs) within the epidermal cells. These TLRs serve to bind bacterial, fungal and viral structures leading to the activation of epithelial cells to produce antimicrobial peptides. These receptors are down regulated in the presence of IL-4, IL-13 and IL-10 in patients with AD The result is patients are at an increased risk of developing skin infections and are often colonized with *Staphylococcus Aureus* (Bieber, 2008).

**4.1 Structural factors** 

Eigenmann 2010).

**4.2 Genetic factors** 

**4.3 Immunological factors** 

function (Bieber 2008; Caubet & Eigenmann, 2010).

the epithelial cells (Caubet & Eigenmann 2010).

The clinical appearance of AD varies with disease severity. At all stages, patients have dry skin. Intensely pruritic, erythematous papules associated with exudates are seen in the acute phase of AD in infants. In the infantile stage (0-2 years old), the distribution of the rash is normally located on the face, chin, cheeks, scalp, trunk and extensor surfaces, but not on the nose or the diaper area (Deshazo, 2009). As the disease becomes more chronic, there is associated lichenification and the distribution of the rash is mostly seen on the wrists, ankles and neck in the childhood stage (2 years old-puberty) (Deshazo, 2009; Lipozencic, 2010). Approximately, 40% of childhood AD persists into adulthood (Bettrani, 2007). The distribution of rash in adults is similar to the childhood form mostly noticeable on the upper arms, back, wrists, dorsa of hands, fingers, feet and toes (Deshazo, 2009). The presence of pustules within areas of dermatitis suggests a secondary infection. Lesions with a less distinct distribution should prompt a search for an alternative diagnosis.
