Death ligand TRAIL, secreted by CD1a+ and CD14+ cells in blister fluids, is involved in killing keratinocytes in toxic epidermal necrolysis.
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.
Inserm, U976, Univ Paris-Diderot, Paris, F-75010, France.
Elisabeth
E
de Araujo
Valérie
V
Dessirier
Geneviève
G
Laprée
Laurence
L
Valeyrie-Allanore
Nicolas
N
Ortonne
Efstathios N
EN
Stathopoulos
Martine
M
Bagot
Armand
A
Bensussan
Maja
M
Mockenhaupt
Jean-Claude
JC
Roujeau
Andreas
A
Tsapis
D018949:Antigens, CD1 / Q000378:metabolism*; D017209:Apoptosis; D001706:Biopsy; D001768:Blister / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation; D000074049:Cytokine TWEAK; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015603:Keratinocytes / Q000473:pathology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D013262:Stevens-Johnson Syndrome / Q000378:metabolism* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
D018949:Antigens, CD1; C419393:CD1a antigen; D000074049:Cytokine TWEAK; D018950:Lipopolysaccharide Receptors; D053221:TNF-Related Apoptosis-Inducing Ligand; C109743:TNFSF12 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma