Pathogenesis in Pemphigus Vulgaris: A Central Role for the Armadillo Protein Plakoglobin.

Abstract

In pemphigus vulgaris (PV), autoantibody binding to desmoglein (Dsg) 3 induces loss of intercellu-lar adhesion in skin and mucous membranes. Two hy-potheses are currently favored to explain the underlying molecular mechanisms: (a) disruption of adhesion through steric hindrance, and (b) interference of des-mosomal cadherin-bound antibody with intracellular events, which we speculated to involve plakoglobin. To investigate the second hypothesis we established kerati-nocyte cultures from plakoglobin knockout (PG Ϫ / Ϫ) embryos and PG ϩ / ϩ control mice. Although both cell types exhibited desmosomal cadherin-mediated adhe-sion during calcium-induced differentiation and bound PV immunoglobin (IgG) at their cell surface, only PG ϩ / ϩ keratinocytes responded with keratin retraction and loss of adhesion. When full-length plakoglobin was re-introduced into PG Ϫ / Ϫ cells, responsiveness to PV IgG was restored. Moreover, in these cells like in PG ϩ / ϩ ke-ratinocytes, PV IgG binding severely affected the linear distribution of plakoglobin at the plasma membrane. Taken together, the establishment of an in vitro model using PG ϩ / ϩ and PG Ϫ / Ϫ keratinocytes allowed us (a) to exclude the steric hindrance only hypothesis, and (b) to demonstrate for the first time that plakoglobin plays a central role in PV, a finding that will provide a novel di-rection for investigations of the molecular mechanisms leading to PV, and on the function of plakoglobin in dif-ferentiating keratinocytes.