T cell–mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis
Axel Trautmann, … , Kurt Blaser, Cezmi A. Akdis
Axel Trautmann, … , Kurt Blaser, Cezmi A. Akdis
Published January 1, 2000
Citation Information: J Clin Invest. 2000;106(1):25-35. https://doi.org/10.1172/JCI9199.
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Article

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

Abstract

Clinical and histologic similarities between various eczematous disorders point to a common efferent pathway. We demonstrate here that activated T cells infiltrating the skin in atopic dermatitis (AD) and allergic contact dermatitis (ACD) induce keratinocyte (KC) apoptosis. KCs normally express low levels of Fas receptor (FasR) that can be substantially enhanced by the presence of IFN-γ. KCs are rendered susceptible to apoptosis by IFN-γ when FasR numbers reach a threshold of approximately 40,000 per KC. Subsequently, KCs undergo apoptosis induced by anti-FasR mAb’s, soluble Fas ligand, supernatants from activated T cells, or direct contact between T cells and KCs. Apoptotic KCs show typical DNA fragmentation and membrane phosphatidylserine expression. KC apoptosis was demonstrated in situ in lesional skin affected by AD, ACD, and patch tests. Using numerous cytokines and anti-cytokine neutralizing mAb’s, we found no evidence that cytokines other than IFN-γ participate in this process. In addition, apoptosis-inducing pathways other than FasR triggering were ruled out by blocking T cell–induced KC apoptosis by caspase inhibitors and soluble Fas-Fc protein. Responses of normal human skin and cultured skin equivalents to activated T cells demonstrated that KC apoptosis caused by skin-infiltrating T cells is a key event in the pathogenesis of eczematous dermatitis.

Authors

Axel Trautmann, Mübeccel Akdis, Daniela Kleemann, Frank Altznauer, Hans-Uwe Simon, Thomas Graeve, Michaela Noll, Eva-B. Bröcker, Kurt Blaser, Cezmi A. Akdis

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Figure 6

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Demonstration of apoptotic KCs in AD, atopy patch tests, ACD, and in vit...
Demonstration of apoptotic KCs in AD, atopy patch tests, ACD, and in vitro induced eczematous dermatitis. Skin sections were subjected to TUNEL (a, b, e–g) or HOECHST staining (c, d) without counterstaining. (a) Healthy normal skin as a negative control (left); lesional skin of acute AD (right). Red condensed and partly fragmented nuclei indicate positive staining of apoptotic KCs (some of these are indicated by arrows). ×400. (b) Left: Acute ACD; 2+ patch test 48 hours after exposure to 5% nickel sulfate. Right: 2+ atopy patch test 72 hours after exposure to 10,000 protein nitrogen units of house dust mite. ×400. (c) Normal, healthy skin as a negative control. ×200. (d) Left: Lesional skin of acute AD. Right: Acute ACD. 2+ patch test 48 hours after exposure to 5% nickel sulfate. Apoptotic cells show condensed or fragmented nuclei (some of these are indicated by arrows). ×400. (e) Normal human skin after 3 days of in vitro culture with unstimulated CD45RO+ T cells. Left: No TUNEL-stained KCs are detectable. Right: Normal human skin after 3 days of in vitro culture exposed to stimulated CD45RO+ T cells. Features of spongiosis and numerous apoptotic KCs are detectable (arrows). ×200. (f) Cultured skin equivalent after 3 weeks of in vitro culture. Left: KC layers and the stratum corneum are visible (hematoxylin/eosin staining). Right: TUNEL staining. No TUNEL-stained nuclei are detectable. ×400. (g) Cultured skin equivalent after 3 days exposed to stimulated CD45RO+ T cells. There are signs of KC damage (left). With the TUNEL technique, several apoptotic nuclei are stained in the basal and suprabasal epidermis (arrows, right). Results shown in e–g are representative of two experiments with healthy skin and three experiments with cultured skin equivalents.