Pemphigus (PV) is a life-threatening mucocutaneous autoimmune blistering disease. It is often associated with autoantibodies to the desmosomal adhesion proteins Desmoglein 3 (DSG3) and Desmoglein 1 (DSG1). Recently, auto-antigens, such as desmocollins and others have been described in PV and in atypical pemphigus forms such as Pemphigus Herpetiformis, Pemphigus Vegetans and Paraneoplastic Pemphigus. Desmocollins belong to a cadherin subfamily that provides structure to the desmosomes and play an important role in cell-to-cell adhesion. In order to verify the pathogenic activity of anti-Desmocollin 3 (DSC3) antibodies, we developed an active disease model of pemphigus expressing anti-DSC3 autoantibodies or anti-DSC3 and anti-DSG3 antibodies. This approach included the adoptive transfer of DSC3 and/or DSG3 lymphocytes to Rag2-/- immunodeficient mice that express DSC3 and DSG3.  Our results show that the presence of anti-DSC3 auto-antibodies is sufficient to determine the appearance of a pathological phenotype relatable to pemphigus, with intense erythema and patchy hair loss, but with features not completely super-imposable to those observed in the DSG3 active model, suggesting that the DSC3 active model might mimic the atypical pemphigus. Moreover, the presence of both anti-DSC3 and anti-DSG3 antibodies determines a more severe phenotype with highly frequent erosions on forelegs and exacerbated erythema and alopecia. At the histological level, along with classical acantholysis, DSC3/DSG3 mouse model presents areas of focal epidermal spongiosis and some inflammatory cells infiltrating the dermis, including eosinophils. Moreover DSC3/DSG3 mouse model displays a slower response to prednisolone, as compared to DSC3 model. In conclusion, we have developed an adult DSC3 pemphigus mouse model that differs from the DSG3 model and supports the concept that antigens other than desmogleins may be responsible for different phenotypes in human pemphigus.

DEVELOPMENT OF A DESMOCOLLIN-3 ACTIVE MOUSE MODEL RECAPITULATING HUMAN ATYPICAL PEMPHIGUS