Figure 3. T cell involvement in the immune pathogenesis of PV.

PV is the prototype of an autoantibody-mediated immunobullous skin disorder and is characterized by a loss of intraepidermal adhesion primarily caused by autoantibodies belonging to the IgG4 and, to a lesser extent, IgG1 subclasses specific for Dsg3 and Dsg1, components of the desmosomal adhesion complex of epidermal keratinocytes that are connected to the keratin cytoskeleton through interaction with the intracellular plaque proteins plakoglobin (PKG) and desmoplakin (DP; inset). IgG production by autoreactive B cells is presumably regulated by Dsg3- and Dsg1-reactive Th1 and Th2 cells. The Dsg3-reactive Th cells recognize epitopes of the Dsg3 ectodomain in association with the HLA class II alleles HLA-DRβ1*0402 and HLA-DQβ1*0503 presented by APCs including dendritic cells and B cells. Dsg3-reactive Th cells that recognize identical epitopes are also found in healthy carriers of the aforementioned PV-associated HLA class II alleles. Thus Tregs may be critical in maintaining peripheral B cell tolerance to Dsg3. This contention is supported by the finding that Dsg3-reactive Tr1s are more frequently detected in healthy individuals than in patients with PV.