Epitope spreading in Pemphigus

• Applicants: Professor Dr. Luca Borradori, Ph.D.; Dr. Ansgar Schmidt
• Subject Area: Dermatology ; Immunology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289113135

Epitope spreading has been linked to the chronic course and severity of distinct autoimmune disorders. Paraneoplastic pemphigus (PNP), a tumor-associated clinical variant of pemphigus is characterized by a mostly lethal outcome and a broad range of auto-antigens targeted by IgG auto-antibodies. The experiments include the generation of human monoclonal antibodies derived by immortalization of memory B-cells from PNP-patients. Subsequently, it is planned to analyse the repertoire of these immortalized memory B cells against several target antigens specific to PNP, i.e. alpha 2 macroglobulin-like 1 (A2ML1), a protease inhibitor of unknown function, the intracellular desmosomal adhesion molecules, desmoplakin, envoplakin, and periplakin, as well as plakophilin 3 (PKP3), an armadillo protein predominately expressed in skin. Specifically, we want to elucidate the relevance of the autoantigens A2ML1 and PKP3 for the loss of cellular adhesion in epithelia during the pemphigus disease as well as the molecular mechanisms that are associated with these proteins in the pathogenesis of pemphigus. Based on our findings, we expect crucial insights into epitope spreading in pemphigus and the functional relevance of auto-antigens which do not possess adhesive function, such as A2ML1.

• DFG Programme: Research Units
• Subproject of: FOR 2497: Pemphigus - from Pathogenesis to Therapeutics (Pegasus)
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Co-Investigator: Dr. Bertrand Favre