Evaluation of the Potential Role of Cytokines in Toxic Epidermal Necrolysis

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-gamma), soluble tumor necrosis factor alpha (TNF-alpha), 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-gamma 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-alpha, 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-gamma making them sensitive to cell-mediated cytolysis. We propose the hypothesis that the production of Fas-L, TNF-alpha, and IL-10 by keratinocytes could be a defense mechanism against CTL rather than a way of propagating apoptosis among epidermal cells.

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

“…T cells in lesions express perforin and GrB, and it has been suggested that T cells may trigger keratinocyte cell death in these skin conditions. [176][177][178][179][180] Vascular Diseases Atherosclerosis Atherosclerosis a lipid-driven inflammatory disease responsible for the majority of heart attacks, strokes, and lower limb loss, and, as such, is now the leading cause of death world-wide. [294][295][296][297] The most abundant inflammatory and immune cells in atherosclerotic lesions are T lymphocytes and macrophages, and their role in atherosclerosis is well documented.…”

Severe Obliterative Bronchitis Associated with Stevens-Johnson Syndrome

“…Involvement of cytotoxic T cells and the molecular cytotoxicity of Fas and cytotoxic enzymes, including granzyme B, perforin, and granulysin have been shown in SJS/TEN (25,27). Cytokines including tumor necrosis factor alpha (TNF-α) and inter- feron gamma (IFN-γ) were found to be overexpressed in the lesional skin (24,25,28,29). Wuepper et al demonstrated that immunocomplexes were detected in the serum and dermal/mucosal lesions of severely affected SJS patients (30), and those immunocomplexes were thought to be a possible cause of chronic pulmonary complications after SJS/ TEN (23).…”

Severe Drug-Induced Skin Reactions: Clinical Pattern, Diagnostics and Therapy

“…This is the first sign that lesional T lymphocytes exhibit a direct cytotoxic response towards autologous cells without prior re-stimulation. [Nassif, et al, 2004b] In addition, ligands such as TRAIL (tumor necrosis factor related apoptosis inducing ligand) and TWEAK (TNF-like weak inducer of apoptosis) are secreted by CD1a+ and CD14+ cells capable of inducing keratinocyte death in an MHC class I-independent manner, also seem to be present in the blister fluids of patients with TEN. [de Araujo, et al, 2011] 2.3 Differential diagnoses histopathologically Erythema (exsudativum) multiforme majus (E(E)MM) and SJS/TEN share a similar histology.…”