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.
Akdis
M
M
Swiss Institute of Allergy and Asthma Research, Davos, Switzerland. akdisac@siaf.unizh.ch
Trautmann
A
A
Klunker
S
S
Blaser
K
K
Akdis
C A
CA
D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D000954:Antigens, Surface / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D003876:Dermatitis, Atopic / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D016201:Receptors, Lymphocyte Homing / Q000276:immunology; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; C063419:CTAGE1 protein, human; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007378:Interleukins; D008024:Ligands; D008562:Membrane Glycoproteins; D016201:Receptors, Lymphocyte Homing; D019014:fas Receptor; D007371:Interferon-gamma