Abstract
The autoimmune blistering skin diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are mediated by autoantibodies (IgG) against the desmosomal cadherins desmoglein 1 (Dsg 1) and Dsg 3. Recently we demonstrated that PF IgG do not reduce Dsg 1-mediated adhesion by steric hindrance but rather required cell-dependent mechanisms (J. Clin. Invest. 2005, Oct 6 Epub). Here we provide evidence that PV-IgG (directed to Dsg 1 and Dsg 3) and PF-IgG (directed to Dsg 1) induce skin blistering by inhibition of Rho family GTPases. PV-IgG and PF-IgG caused epidermal blistering in biopsies of human skin and intercellular gap formation in cultured keratinocytes. Moreover, autoantibodies reduced Dsg 1-mediated binding assessed by laser tweezers and inactivated cellular Rho family GTPases. Both PV-IgG and PF-IgG induced inactivation of Rho A whereas PV-IgG additionally inhibited Rac 1 and Cdc42. Concomitant activation of these GTPases by E. coli cytotoxic necrotizing factor 1 (CNF-1) outbalanced autoantibody-induced Rho-GTPase inactivation and largely abolished antibody-induced effects on human epidermis and cultured keratinocytes. These data indicate that inactivation of Rho-GTPases is important for pemphigus pathogenesis. DFG SFB487
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