Deciphering the signaling events in Dsg1 and Dsg3 antibody-induced pathology to investigate possible impacts for the onset of new autoimmune reactions

Pemphigus is an organ-specific autoimmune disease of the skin and/or mucous membranes. In the majority of cases, pemphigus is caused by autoantibodies targeting desmosomal proteins that are required to maintain cell-cell contacts between keratinocytes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are the primary subtypes, characterized by the presence of anti-Dsg1 and/or anti-Dsg3 autoantibodies that foster different clinical outcomes.

The project aims to identify differences in the signalling pathways of oral and skin keratinocytes following stimulation by Dsg1 and/or Dsg3 antibodies and to explore their relevance in autoimmune diseases, potentially leading to new treatment strategies.

Using immunostaining, a human skin keratinocyte and an oral mucosal cell line will be characterized and compared for their Dsg1 and Dsg3 expression and other keratinocyte-specific markers. To identify kinome changes, I am going to stimulate both cell lines with Dsg1- and Dsg3-IgG autoantibodies and perform a chip-based kinome analysis. Based on the kinases that are involved in Dsg1- and Dsg3-IgG autoantibody stimulation we will select inhibitors to investigate their potential to block keratinocyte acantholysis, the key event in pemphigus pathogenesis. The functional relevance of these inhibitors will be proven using the Keratinocyte Dissociation Assay.