Pemphigus is an autoimmune bullous disease characterized by loss of adhesion of keratinocytes that round up in a process known as acantholysis. While the molecular mechanisms underlying acantholysis are still unclear, it is well known that cell detachment is often associated with apoptosis. We have previously detected apoptotic keratinocytes in perilesional, yet undetached, pemphigus skin. Moreover, we have observed that Fas ligand (FasL) levels are significantly higher in untreated pemphigus sera (more than 0.1 ng/ml) than in controls. As pemphigus sera induce apoptosis in cultured human keratinocytes, we wanted to analyze the apoptotic mechanisms in pemphigus. We first confirmed that pemphigus lesions contain apoptotic keratinocytes, by showing caspase-3 activation. In addition, while Fas receptor (FasR) is expressed in the basal and partially in the suprabasal layers in pemphigus vulgaris (PV), it is detected throughout the epidermal layers in muco-cutaneous pemphigus. Furthermore, pemphigus sera-induced keratinocyte apoptosis is partially prevented by pretreatment with either caspase-8 inhibitor or anti-FasL neutralizing antibody. Moreover, caspase-8 activation induced by untreated pemphigus sera is partially inhibited by anti-FasL antibody. Untreated pemphigus sera induce the cleavage of desmoglein 1 and 3 (dsg 1, 3). Moreover, recombinant FasL dose-dependently cleaves dsg 1 and 3 (0.1, 10, 100 ng/ml). Finally, caspase-8 inihibitor prevents dsg cleavage, strongly indicating the critical role of FasL in the pathogenesis of pemphigus. In particular, high levels of FasL, contained in pemphigus sera exert a dual activity, by both inducing keratinocyte apoptosis and dsg cleavage.
|Data di pubblicazione:||2007|
|Titolo:||Fas ligand and pemphigus sera induce desmoglein cleavage and apoptosis in human keratinocytes|
|Autori:||R. Lotti; A. Marconi; F. Truzzi; K. Dallaglio; C. Vaschieri; C. Pincelli|
|Nome del convegno:||68° Annual meeting of the Society for Investigative Dermatology|
|Luogo del convegno:||Los Angeles California|
|Data del convegno:||9-12 maggio 2007|
|Appare nelle tipologie:||Abstract in Rivista|
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