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 1

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(a) Representative histologic findings of acute eczematous dermatitis. A...
(a) Representative histologic findings of acute eczematous dermatitis. A dense subepidermal inflammatory infiltrate and marked epidermal acantholytic and spongiotic changes progress to vesicle formation. Hematoxylin/eosin staining. ×400. (b–d) Signs of KC injury after coculture with autologous T cells. Photomicrographs from 96-well plates with an inverted microscope equipped with phase contrast. ×200. (b) Intact monolayer of cultured third-passage primary human KCs. The KCs are relatively uniform in size and morphology. (c) Intact monolayer of KCs after 3 days in coculture with unstimulated autologous CD45RO+ T cells. (d) Partly destroyed monolayer of KCs after 3 days in coculture with autologous CD45RO+ T cells stimulated with anti-CD2, anti-CD3, and anti-CD28 mAb’s. (e and f) Induction of KC apoptosis in vitro. Identification of apoptotic nuclei with HOECHST staining. ×200. (e) Intact monolayer of KCs after 3 days of coculture in Transwell plates with unstimulated CD45RO+ T cells. (f) Induction of KC apoptosis after coculture in Transwell plates with stimulated CD45RO+ T cells. Note bright, condensed nuclei and nuclear fragmentation (arrows), signs of KC apoptosis.