FIGURE 5.

Two-hit hypothesis for the role of p38 MAPK in PV pathogenesis. Binding of PV mAbs to Dsg3 directly causes loss of desmoglein-mediated adhesion, leading to Nikolsky-positive blisters (Fig. 2). Pathogenic anti-Dsg3 PV mAbs cause Dsg3 (but not desmocollin 3) endocytosis (17), which is not always associated with p38 activation (Fig. 1). Loss of cell-cell adhesion subsequently activates p38, which promotes internalization of both Dsg3 and desmocollin 3 (Fig. 3) and depletion of multiple desmosomal molecules (Fig. 4). Therefore, PV mAbs cause the direct p38-independent loss of Dsg3-mediated adhesion, which is the initial pathogenic event in PV. These specific pathogenic effects are augmented by subsequent activation of p38 MAPK, leading to depletion of multiple desmosomal molecules, which may facilitate spontaneous blister formation in PV.