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.