Dominant autoimmune epitopes recognized by pemphigus antibodies map to theN-terminal adhesive region of desmogleins

Desmoglein (Dsg) is a cadherin-type adhesion molecule found in desmosomes. Dsg1 and Dsg3 are the target Ags in the autoimmune blistering diseases pemp higus foliaceus (PF) and pemphigus vulgaris (PV), respectively. To map conf ormational epitopes of Dsg1 and Dsg3 in PF and PV, we generated Dsg1- and D sg3-domain-swapped molecules and point-mutated Dsg3 molecules with Dsg1-spe cific residues by baculovirus expression. The swapped domains were portions of the N-terminal extracellular domains of Dsg1 (1-496) and Dsg3 (1-566), which have similar structures but distinct epitopes. The binding of autoant ibodies to the mutant molecules was assessed by competition ELISAs. Domain- swapped molecules containing the N-terminal 161 residues of Dsg1 and Dsg3 y ielded > 50% competition in 30/43 (69.8%) PF sera and 31/40 (77.5%) PV sera , respectively. Furthermore, removal of Abs against the 161 N-terminal resi dues of Dsg1 by immunoadsorption eliminated the ability of PIT sera to indu ce cutaneous blisters in neonatal mice. Within these N-terminal regions, mo st of the epitopes were mapped to residues 26-87 of Dsg1 and 25-88 of Dsg3. Furthermore, a point-mutated Dsg3 molecule containing Dsg1-specific amino acid substitutions (His(25), Cys(28), Ala(29)) reacted with anti-Dsg1 IgG, thus defining one of the epitopes of Dsg1. Using the predicted three-dimens ional structure of classic cadherins as a model, these findings suggest tha t the dominant autoimmune epitopes in both PF and PV are found in the N-ter minal adhesive surfaces of Dsgs.