T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis

Clinical and histologic similarities between various eczematous disorders p oint to a common efferent pathway. We demonstrate here that activated T cel ls infiltrating the skin in atopic dermatitis (AD) and allergic contact der matitis (ACD) induce keratinocyte (KC) apoptosis. KCs normally express low levels of Fas receptor (FasR) that can be substantially enhanced by the pre sence of IFN-gamma. KCs are rendered susceptible to apoptosis by IFN-gamma when FasR numbers reach a threshold of approximately 40,000 per KC. Subsequ ently, KCs undergo apoptosis induced by anti-FasR mAb's, soluble Fas ligand , supernatants from activated T cells, or direct contact between T cells an d KCs. Apoptotic KCs show typical DNA fragmentation and membrane phosphatid ylserine expression. KC apoptosis was demonstrated in situ in lesional skin affected by AD, ACD, and patch tests. Using numerous cytokines and anticyt okine neutralizing mAb's, we found no evidence that cytokines other than IF N-gamma participate in this process. In addition, apoptosis-inducing pathwa ys other than FasR triggering were ruled out by blocking T cell-induced KC apoptosis by caspase inhibitors and soluble Fas-Fc protein. Responses of no rmal human skin and cultured skin equivalents to activated T cells demonstr ated that KC apoptosis caused by skin-infiltrating T cells is a key event i n the pathogenesis of eczematous dermatitis.