Death ligand TRAIL, secreted by CD1a+ and CD14+ cells in blister fluids, is involved in killing keratinocytes in toxic epidermal necrolysis

Abstract

Toxic epidermal necrolysis (TEN) is characterized by an acute detachment and destruction of keratinocytes, affecting large areas of the skin. It is often related to adverse drug reactions. Previous studies have shown that effector CD8+ T cells, which accumulate in the blister fluid, are functionally cytotoxic and act through a classical perforin/granzyme B pathway. It has recently been shown that these cytotoxic T cells also secrete granulysin peptide, which is lethal to keratinocytes. These cytotoxic T cells exert their killer activity against autologous keratinocytes in the presence of the drug. However, they are unlikely to be the only effectors of TEN. We therefore searched for soluble death factors in the blister fluids that might kill keratinocytes. We found that the amounts of interferon-γ, TRAIL and TNF-α proteins were significantly greater in TEN blister fluids than in all controls (normal sera, TEN sera, burns and Eosinophilic pustular folliculitis blister fluids) and TNF-like weak inducer of apoptosis (TWEAK) amounts are also greater in all controls except burns. We showed that these proteins acted in synergy to induce the death of keratinocytes in vitro. We also found that TRAIL and TWEAK were secreted by CD1a+ and CD14+ cells present in the blister fluids. Thus, in addition to MHC class I-restricted cytotoxic T lymphocytes (CTLs), which lyse keratinocytes, ligands secreted by non-lymphoid 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.

The burn wound exudate—An under-utilized resource

“…De Araujo et al [25] analyzed blister fluids to measure cellular components that induce keratinocyte necrosis in toxic epidermal necrolysis (TEN). Specifically, soluble death factors such as Tumor Necrosis Factor (TFN-γ), TNF-related apoptosis-inducing ligand (TRAIL), TNF-α and TNF-like weak inducer of apoptosis (TWEAK) proteins were chosen as candidate variables.…”

Idiosyncratic Adverse Drug Reactions: Current Concepts

“…The cells that mediate the rash are reported to be cytotoxic T cells (Nassif et al, 2004;Wei et al, 2012), but other cells presumably play important roles (de Araujo et al, 2011;Tohyama and Hashimoto, 2012). The molecules that mediate the keratinocyte toxicity in SJS/TEN appear to include Fas (apoptosis antigen 1, CD95) ligand (Downey et al, 2012), granulysin (Chung et al, 2008), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (de Araujo et al, 2011). It is difficult to perform controlled trials to determine the best treatment of this rare rash.…”

“…These are clearly immunemediated reactions, and again there are specific HLA associations with specific drugs; however, unlike DRESS, where the lymphocyte transformation test is often positive Jurado-Palomo et al, 2010), it is typically negative in SJS/TEN (Tang et al, 2012). The cells that mediate the rash are reported to be cytotoxic T cells (Nassif et al, 2004;Wei et al, 2012), but other cells presumably play important roles (de Araujo et al, 2011;Tohyama and Hashimoto, 2012). The molecules that mediate the keratinocyte toxicity in SJS/TEN appear to include Fas (apoptosis antigen 1, CD95) ligand (Downey et al, 2012), granulysin (Chung et al, 2008), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (de Araujo et al, 2011).…”

Drug induced exfoliative dermatitis: state of the art

“…TNF- α has a dual role: interacts with TNF-R1 activating Fas pathway and activates NF-κB leading to cell survival. Although the final result of this dual interaction is still under investigation, it seems that the combination of TNF-α, IFN-γ (also present in TEN patients) and the activation of other death receptors such as TWEAK can lead to apoptosis of keratinocytes [44]. …”