Cytokine network and dysregulated apoptosis in atopic dermatitis

Activation and skin-selective homing of peripheral blood memory/effector T cells and effector functions in the skin represent sequential immunological events in the pathogenesis of atopic dermatitis (AD). T cells infiltrating the skin utilize the cutaneous lymphocyte-associated antigen (CLA) and other receptors to recognize and cross the vascular endothelium. In the peripheral blood of AD patients, both CD4+ and CD8 subsets of CLA+CD45RO+ T cells are in an activated state with high CD25, HLA-DR, and CD40-ligand expression. They express upregulated Fas and Fas-ligand and undergo activation-induced apoptosis. After homing to skin these T cells form dermal infiltrates which play a key role in the pathogenesis of the disease. Skin-infiltrating T cells in AD are protected from activation-induced cell death, although they express both Fas and Fas-ligand. They are protected from apoptosis by cytokines such as IL-2, IL-4, and IL-15 and extracellular matrix components such as fibronectin and transferrin. CLA+, skin-homing T cells may play a role in peripheral blood eosinophilia and hyper IgE production by high IL-5 and IL-13 expression, respectively. These T cells secrete IFN-gamma in the skin, which upregulates Fas on keratinocytes and renders them susceptible to apoptosis. Keratinocyte apoptosis is induced by Fas-ligand, either soluble or expressed on the surface of T cells, leading to eczema formation. Here we discuss the mechanisms of skin-selective T cell homing and activation, and emphasize the concept of dysregulated apoptosis of T cells, eosinophils, and keratinocytes as essential pathogenetic episodes in AD and other eczematous disorders.