Fogo selvagem (FS) is an autoimmune disease caused by IgG autoantibodies to desmoglein I (DG-I), a desmosomal glycoprotein. We have previously shown that the autoantibodies in these patients are pathogenic and restricted mainly to the IgG4 subclass. The purpose of this study was to determine if the Fc domain or the valence of FS autoantibodies were relevant in the induction of epidermal disease in neonatal mice. IgG4 was prepared from sera of FS patients by anion exchange chromatography, and digested with pepsin to yield F(ab')2 fragments. Monovalent FS Fab' were made by reduction and alkylation of FS F(ab')2. Intact FS IgG4, FS F(ab')2, and FS Fab' fragments were injected into neonatal mice. Intact FS IgG4 and both FS IgG fragments were pathogenic. The disease in the animals was dose dependent, and on the molar basis, FS Fab' fragments were more potent and efficient in producing disease than whole FS IgG. These results suggest: (a) simple binding of FS autoantibodies to DG-I may trigger keratinocyte detachment and epidermal disease; (b) DG-I may represent a keratinocyte cell adhesion molecule; and (c) complement activation and surface cross-linking may not be relevant in keratinocyte detachment.