Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by cell-cell detachment within the stratified epithelium (
acantholysis) caused by
IgG autoantibodies.
Intravenous immunoglobulin (
IVIg)
therapy effectively treats PV, but the mechanism is not fully understood. To further understand
acantholysis and the efficacy of
IVIg, we measured effects of
IgG fractions from PV patients on keratinocyte death processes. Using IgGs from representative PV patients who improved with
IVIg, we identified apoptotic and oncotic signaling pathways in in vitro and in vivo PV models. We identified two groups of PV patients, each producing
autoantibodies activating predominantly either apoptotic or oncotic cell death pathway. Experimental treatments with
caspase 3 or
calpain inhibitors demonstrated that PV IgGs induced
acantholysis through both pathways. Upstream, the apoptotic signaling involved activation of
caspases 8 and 3 and up-regulation of
Fas ligand mRNA, whereas
calpain-mediated cell death depended on elevated intracellular free Ca(2+).
IVIg reduced PV
IgG-mediated
acantholysis and cell death and up-regulated the
caspase inhibitor FLIP and the
calpain inhibitor calpastatin. These results indicate that in different PV patients,
IgG-induced
acantholysis proceeds predominantly via distinct, yet complementary, pathways of programmed cell death differentially mediated by apoptosis and oncosis effectors, with
IVIg protecting target cells by up-regulating endogenous
caspase and
calpain inhibitors.