The N-Terminal Fraction of Desmoglein 3 Encompassing its Immunodominant Domain is Present in Human Serum: Implications for Pemphigus Vulgaris Autoimmunity

Pemphigus vulgaris (PV) is considered as an autoimmune disease against a tissue-restricted antigen, desmoglein 3, a 130 kDa glycoprotein expressed by keratinocytes of skin and mucous membranes. Therefore, a breakdown of peripheral tolerance is generally invoked to explain this horror autotoxicus. The availability of a self-antigen and the strength of antigenic stimulation represent critical points in the regulation of immune system homeostasis. Our study shows for the first time that the immunodominant fraction of the PV self-antigen is present in sera of healthy individuals and patients as a circulating 30 kDa fragment (sDsg3). These findings provide a good explanation for the N-terminal specificity of antibody production and peptide recognition in PV patients by B and T cell, respectively. Moreover, the presence of the sDsg3 in human sera could allow to reconsider pemphigus as a disease against a circulating antigen; once produced, PV-autoantibodies also recognize the 130 kDa epidermal antigen desmoglein 3 on keratinocyte surface (kDsg3), thus triggering the acantholysis and the clinical manifestations of pemphigus.