The Fas/
Fas ligand system triggers the extrinsic apoptotic pathway and is involved in several inflammatory conditions, also at the skin level. The Fas/
Fas ligand cell death pathway plays a major role in anoikis, a type of apoptosis characterized by cell detachment. As
pemphigus is characterized by loss of cell to cell adhesion, we evaluated the role of anoikis and
Fas ligand in this bullous disease. We report that, in suprabasal epidermis from perilesional
pemphigus skin, most keratinocytes are apoptotic. Moreover,
Fas ligand levels are markedly increased in sera from
pemphigus patients, whereas they are undetectable in sera from patients undergoing
steroid treatment. Sera from untreated patients but not from patients under
steroids induce keratinocyte apoptosis.
Pemphigus-sera-induced cell death is partially inhibited by pretreatment with anti-
Fas ligand antibodies and by incubation with
caspase-8 inhibitor
Z-IETD-FMK. Finally,
caspase-8 is activated in keratinocytes provided with sera from
pemphigus patients, whereas cleavage is partially blocked by pretreatment of sera with anti-
Fas ligand antibody. These results suggest that increased
Fas ligand in
pemphigus sera is responsible for keratinocyte apoptosis, which occurs through the activation of a caspase-8-driven extrinsic apoptotic pathway.