Pemphigus vulgaris (PV) is an acquired immunobullous disorder. At the early stage of the disease (mucosal PV), patients display only autoimmunity to
desmoglein (Dsg) 3 and develop mucosal
blisters; while at the later stage of the disease (mucocutaneous PV), patients exhibit non-cross-reactive autoimmunity to both Dsg3 and Dsg1 and acquire cutaneous as well as mucosal
blisters. At these two disease stages, Dsg3
autoantibodies exhibit different tissue-binding patterns and pathogenic activities, suggesting that they may recognize distinct
epitopes. To test this hypothesis and to investigate the mechanism underlying the disease transition, we studied Dsg3
autoantibody epitopes from mucosal PV patients and patients exhibiting disease transition to mucocutaneous PV. We demonstrated that
autoantibodies from the majority of mucosal PV patients target
epitopes at the COOH-terminal portion of the Dsg3 ectodomain. Interestingly, only
autoantibodies against the Dsg3 NH2-terminal
epitope(s) are able to bind human skin. Moreover, we discovered that the intramolecular
epitope spreading from Dsg3(87-566) to Dsg3(1-88) is a critical step that precedes the intermolecular
epitope spreading from Dsg3 to Dsg1. During disease transition, this mechanism dictates the development of Dsg3
autoantibodies that recognize human skin and lead to expression of cutaneous PV lesions.