Apoptotic pathways in pemphigus

Abstract

Pemphigus is a group of human autoimmune blistering diseases of the skin in which autoantibodies to desmosome cadherins induce loss of cell-cell adhesion (acantholysis). In addition to steric hindrance and activation of intracellular signaling, apoptosis has been suggested to contribute to the mechanism by which pathogenic IgG induces acantholysis. We review the current literature examining the role of apoptosis in pemphigus. Current data suggest that apoptosis is not required for blister induction, but that activation of proapoptotic proteins, including caspase cysteine proteinases, may sensitize cells to the acantholytic effects of pemphigus IgG.

Figure 1

Pemphigus, p38MAPK, acantholysis and apoptosis. Two sequential peaks of p38MAPK activation are observed when keratinocytes are exposed to either PV or PF IgG. (a) Pemphigus IgG binds to dsg and biases the equilibrium of desmosome assembly/disassembly towards disassembly which is linked by an, as yet, undefined mechanism towards activation of p38MAPK. Subsequent p38 dependent alterations in the cell state include RhoA inactivation, dsg endocytosis, HSP27 phosphorylation, keratin intermediate filament retraction, actin, and loss of cell-cell adhesion (acantholysis). (b) A second late peak of p38 activity is observed that is likely a stress response signal induced by loss of cell-cell adhesion and leads to activation of proapoptotic pathways including caspase-3 activation.