Pemphigus Vulgaris (PV), Pemphigus Foliaceus (PF) and Bullous Pemphigoid (BP) are a group of rare organ-specific diseases that affect skin and mucous membranes. Each subtype of pemphigus has its own anti-Desmogleins (Dsgs) autoantibodies profile: Dsg1 is the auto-antigen in PF whereas Dsg3 is the in PV. We identified 2 PF patients with positive levels of anti-Dsg3 Abs and also 4 healthy blood donors with high levels of anti-Dsg1 Abs and anti-Dsg3 Abs. The purpose of this study was to examine epitopes recognized by anti-Dsg1/anti-Dsg3 Abs and to identify potential autoreactive HLAII-restricted helper T cell epitopes shared among Dsg1+/Dsg3+ subjects that could explain the simultaneous occurrence of these auto-Abs. On IIF, only one PF patients had antibodies to the keratinocyte surface. Interestingly, the ELISA for BP180 was also positive in 2 healthy blood donors. IP-IB analysis showed immunoreactivity to more than one EC domain of Dsg1 and towards the C-terminal EC5 domain of Dsg3. MHC II gene analysis demonstrated that all healthy blood donors had at least one protective allele associated to PF. We confirm in this study that the onset and course of this disease depend on a variable interaction between predisposing and inducing genetic, environmental, hormonal, and immunological factors.