Death receptors are a growing family of transmembrane
proteins that can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. Expression and signaling by
death receptors and their respective
ligands is a tightly regulated process essential for key physiologic functions in a variety of organs, including the skin. Several
death receptors and
ligands, Fas and
Fas ligand being the most important to date, are expressed in the skin and have proven to be essential in contributing to its functional integrity. Recent evidence has shown that Fas-induced keratinocyte apoptosis in response to ultraviolet light, prevents the accumulation of pro-carcinogenic p53 mutations by deleting ultraviolet-mutated keratinocytes. Further- more, there is strong evidence that dysregulation of Fas expression and/or signaling contributes to the pathogenesis of
toxic epidermal necrolysis, acute cutaneous
graft versus host disease,
contact hypersensitivity and
melanoma metastasis. With these new developments, strategies for modulating the function of
death receptor signaling pathways have emerged and provided novel therapeutic possibilities. Specific blockade of Fas, for example with
intravenous immunoglobulin preparations that contain specific anti-Fas
antibodies, has shown great promise in the treatment of
toxic epidermal necrolysis and may also be useful in the treatment acute
graft versus host disease. Likewise, induction of death signaling by ultraviolet light can lead to
hapten-specific tolerance, and gene transfer of
Fas ligand to dendritic cells can be used to induce
antigen specific tolerance by deleting
antigen-specific T cells. Further developments in this field may have important clinical implications in cutaneous disease.