The Caspase Pathway as a Possible Therapeutic Target in Experimental Pemphigus

Abstract

Apoptosis plays a role in pemphigus IgG-dependent acantholysis; theoretically, the blockade of the caspase pathway could prevent the blistering that is caused by pemphigus autoantibodies. Using this strategy, we attempted to block the pathogenic effect of pemphigus IgG in Balb/c mice by using the caspase inhibitor Ac-DEVD-CMK. This inhibitor was administrated before the injection of pemphigus IgG into neonatal mice. The main results of the present investigation are as follows: (1) pemphigus IgG induces intraepidermal blisters in Balb/c neonatal mice; (2) keratinocytes around the blister and acantholytic cells undergo apoptosis; (3) the caspases inhibitor Ac-DEVD-CMK prevents apoptosis; (4) the inhibition of the caspase pathway prevents blister formation. In conclusion, inhibition of the caspase pathway may be a promising therapeutic tool that can help in the treatment of pemphigus flare ups.

Preclinical Studies Identify Non-Apoptotic Low-Level Caspase-3 as Therapeutic Target in Pemphigus Vulgaris

“…In our PV models, no evidence for a robust caspase-3 activation has been revealed, as it would be expected in case of apoptosis [ 15 ]. However, caspase inhibitors were reported to reduce blistering in neonatal mice injected with PVIgG [ 29 , 30 ]. Furthermore, low-level caspase-3 activity has been associated with keratinocyte terminal differentiation [ 19 , 56 ] but was not detected by immunoblotting applied here ( Fig.…”

“…Based on the initial observation of TUNEL (TdT-mediated dUTP-biotin nick end labeling)-positive cells in lesional skin of PV patients [ 27 , 28 ], apoptosis was also proposed to be involved in PV pathogenesis. Independent reports on caspase activation in the neonatal PV mouse model and reduced blistering after caspase-3 inhibitor treatment supported this claim [ 29 , 30 ]. Accordingly, “acantholysis and apoptosis” were discussed to be “inseparable in PV”, invoking a process termed “apoptolysis” where acantholysis proceeds along apoptotic pathways resulting in cell death [ 31 , 32 ].…”

“…Accordingly, “acantholysis and apoptosis” were discussed to be “inseparable in PV”, invoking a process termed “apoptolysis” where acantholysis proceeds along apoptotic pathways resulting in cell death [ 31 , 32 ]. Inhibition of apoptotic pathway components including FasL was therefore suggested as potential therapy for PV patients [ 28 , 30 , 31 , 32 , 33 ]. However, doubts have been cast on the involvement of apoptosis, primarily because two independent studies failed to reveal TUNEL positive cells or apoptotic cell morphology by electron microscopy in systematic surveys of PVIgG-treated cultured HaCat keratinocytes and skin explants as well as PV patients’ skin biopsies [ 34 , 35 ].…”

Pénfigo vulgar tipo cutáneo: Caso clínico

“…Agregar pimecrolimus 1% tópico al tratamiento con prednisona y azatioprina pareciera ser efectivo 20 . Tacrolimus sistémico 21 , antimaláricos nuevos como la daphentina 22 , administración de altas dosis de péptidos de Dsg3 11 , inhibidores de caspasas 23 y el transplante alogénico de médula ósea 24 podrían considerarse como alternativas a futuro.…”

What is new in autoimmune vesicobullous disorders?

“…[42] Because apoptosis sensitizes the cells to the acantholytic effects of PV-IgG, the blockade of the caspase pathway could prevent the blistering in pemphigus. Pacheco-Tovar et al [43] studied the effects of caspase inhibitor Ac-DEVD-CMK in BALB/c mice where pemphigus had been induced experimentally and found the caspase inhibitor to block apoptosis and prevent blistering. It has also been studied that hyperadhesion of desmosomes makes them more resistant to acantholysis in experimental PV.…”