Caspase-activation powers anti-Desmoglein 3-induced acantholysis in human epidermis

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease caused by circulating autoantibodies against desmoglein (Dsg) 1 and 3. Whether acantholysis in PV results exclusively from antibody binding to Dsg3, or involves additional factors remains controversial. Given that Fas-Ligand (FasL), an activator of apoptotic caspase-8, is increased in the serum and the skin of patients with PV, we investigated the role of caspases in anti-Dsg3-mediated acantholysis using both ex vivo and in vitro models. Our results demonstrate that anti-Dsg3 antibodies induce acantholysis ex vivo in the absence of caspase activation, primarily through the redistribution of Dsg3 to intracellular compartments. FasL-induced caspase activation leads to a synergistic amplification of anti-Dsg3-mediated loss of cell adhesion by promoting Dsg3 cleavage. This dual mechanism provides new insights into the disease heterogeneity of PV and may also explain the rapid response of PV to high-dose glucocorticosteroids despite the persistence of antibodies.