Identification of novel therapeutic targets for the treatment of autoantibody-induced tissue pathology in pemphigus

Pemphigus is an organ-specific autoimmune disease of the skin and/or mucus membranes. In the majority of cases, pemphigus is caused by autoantibodies targeting desmoglein (Dsg) 1 and/or Dsg 3. Mechanistically, autoantibodies induce skin pathology by several mechanisms -among these, induction of aberrant signaling in keratinocytes. Before the use of corticosteroid treatment, pemphigus was a lethal disease. More recently, the CD20 antibody rituximab (RTX) in combination with corticosteroids has been established as standard treatment. Overall, this has dramatically improved the prognosis of patients being affected with pemphigus. However, under combined RTX/corticosteroid therapy, it requires at least 180 days to achieve remission, and 20% of patients do not respond properly. We thus hypothesize that topical treatment of pemphigus targeting autoantibody-induced aberrant signaling could be used to induce rapid remission – thus closing the therapeutic gap until RTX becomes effective. In project-related previous work based on chemical library screening, we identified and validated four cell signaling molecules as potential therapeutic targets in pemphigus. Pharmacological inhibition using selective kinase inhibitors demonstrated therapeutic efficacy in a human skin organ culture model of pemphigus. In parallel, we recently established the Pamgene technology in the laboratory, allowing unbiased and comprehensive insights into kinase activation in tissues. Herein we now propose to apply this technology in pemphigus to obtain comprehensive insights into Dsg1/3 autoantibody induced signaling in skin and mucosal keratinocytes. Identified kinases will be validated across several model systems including human skin/mucosa organ culture models. Ultimately, aiming at translation into clinical use, we will contrast the kinase activity in pemphigus patient skin to those of healthy controls. Overall, we expect to obtain detailed insights into the (differential) Dsg1/3 autoantibody-induced signaling in both skin and mucosal keratinocytes. In addition to these biological insights, we here will also identify novel therapeutic targets for the treatment of pemphigus that have the potential to significantly shorten the time to remission.