1. ^*Inserm U 448, Hôpital Henri Mondor, Université Paris XII, Créteil, France
2. ^†Department of Dermatology, Hôpital Henri Mondor, Université Paris XII, Créteil, France
3. ^‡Inserm U 532, Hôpital Saint-Louis, Paris, France
4. ^§Inserm U99, Hôpital Henri Mondor, Université Paris XII, Créteil, France

Correspondence: Jean-Claude Roujeau, MD, Service de Dermatologie, Hôpital Henri Mondor, 94010, Créteil, France. Email: jean-claude.roujeau@hmn.ap-hop-paris.fr

Received 27 January 2004; Revised 7 June 2004; Accepted 8 June 2004; Published online 7 October 2004.

Abstract

Toxic epidermal necrolysis is a rare disease observed as a consequence of adverse reactions to drugs. It results in the widespread apoptosis of epidermal cells and has a high mortality rate. The mechanisms leading to this apoptosis are not yet elucidated. We investigated whether the cytokines present in the blister fluid, which accumulates under necrotic epidermis, originated from T lymphocytes and may play a role in the propagation of keratinocyte apoptosis. Interferon gamma (IFN-), soluble tumor necrosis factor alpha (TNF-), soluble Fas ligand (sFas-L) were present in much higher concentration in the blister fluids of 13 toxic epidermal necrolysis (TEN) patients than in control fluids from burns. The results of RT-PCR studies, however, indicated that only IFN- and to a lesser extent interleukin (IL)-18 were produced by mononuclear cells present in the fluid. That suggests that the other cytokines also present (TNF-, sFas-L, IL-10) rather originated from activated keratinocytes. Fas-L was indeed overexpressed on the membranes of keratinocytes in lesional skin in situ. The Th1 profile of T lymphocyte activation found in the blister fluid of patients with TEN is consistent with a key role for drug-specific cytotoxic T lymphocytes (CTL) as previously reported, the activation of keratinocytes by IFN- making them sensitive to cell-mediated cytolysis. We propose the hypothesis that the production of Fas-L, TNF-, and IL-10 by keratinocytes could be a defense mechanism against CTL rather than a way of propagating apoptosis among epidermal cells.