Pemphigus as a paradigm of autoimmunity and cell adhesion.

Pemphigus is a group of autoimmune blistering diseases of the skin and mucous membranes that are characterized histologically by intraepidermal blisters due to the loss of cell-cell adhesion of keratinocytes and immunopathologically by the finding of pathogenic IgG autoantibodies directed against the cell surface of keratinocytes. Identification of the target antigens has redefined pemphigus as an autoimmune disease against desmosomal cadherin or desmoglein. The IgG autoantibody-mediated functional inhibition of desmoglein which plays an important role in the cell-cell adhesion of keratinocytes results in blister formation. Patients with pemphigus vulgaris and pemphigus foliaceus have IgG autoantibodies against desmoglein3 and desmoglein1, respectively. Even complex clinical variations of pemphigus vulgaris and foliaceus are now logically explained by the desmoglein compensation theory. As an extension of this theory, the exfoliative toxin produced by Staphylococcus aureus, which causes staphylococcal scalded skin syndrome and bullous impetigo, was found to specifically cleave desmoglein1 and induce the identical histology to pemphigus foliaceus. Another recent innovation has been the development of an active disease mouse-model for pemphigus using autoantigen knockout mice, in which self-tolerance of the defective gene product is not acquired. When splenocytes from desmoglein3 knockout mice are adoptively transferred into mice expressing desmoglein3, anti-desmoglein3 IgG is stably produced in the recipient mice that develop the phenotype of pemphigus vulgaris. This model will be valuable not only for dissecting the cellular and molecular mechanisms in pathogenic antibody production but also for developing novel therapeutic strategies.