Abstract
Pemphigus vulgaris (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 (PH), Pemphigus Vegetans (PVeg), and Paraneoplastic Pemphigus (PP). 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, 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 and a slower response to prednisolone. 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.
Highlights
The term pemphigus gathers together a group of chronic life-threatening autoimmune disorders characterized by blistering of the skin and of mucous membranes
We show that Desmocollin 3 (DSC3) mouse recapitulates aspects of the human atypical pemphigus, and that DSC3/DSG3 mice express a more severe phenotype that fail to respond to systemic steroids
Extracellular domains of the murine DSG3 and DSC3 were cloned (Figure 1A) and both recombinant DSG3 and DSC3 were produced by insect cells infected by baculovirus as described in the methods section
Summary
The term pemphigus gathers together a group of chronic life-threatening autoimmune disorders characterized by blistering of the skin and of mucous membranes. Blistering is caused by loss of cell-to-cell adhesion (acantholysis) determined by the presence of autoantibodies targeting the surface of keratinocytes. Non-Desmoglein antigens and autoantibodies have been detected in PV and other forms of pemphigus, such as atypical pemphigus [4, 5]. These forms of pemphigus are characterized by the absence of Desmoglein autoantibodies and by the presence of different non-DSG autoantibodies that might act in synergy to develop the pathological phenotype of atypical pemphigus [6]. DSC1 and DSC3 auto-antibodies have been found in several forms of atypical pemphigus, in the absence or- less frequently- in the presence of anti-DSG autoantibodies [10, 11]
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