FOR 2497:  Pemphigus - from Pathogenesis to Therapeutics (Pegasus)

• Subject Area: Medicine
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289113135

Pemphigus is a rare, potentially devastating autoimmune disease of the skin and mucous membranes with high morbidity and mortality. Based on its well-characterized immune pathogenesis, pemphigus can be considered as a paradigm of an organ-specific autoimmune disease and will be used as such in the proposed DFG Research Unit PEGASUS. The major clinical variant, pemphigus vulgaris (PV) is caused by a loss of adhesion of epidermal keratinocytes which is induced by IgG autoantibodies (auto-ab) against components of desmosomes, i.e. desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). There is a close immunogenetic association of PV with the human leukocyte antigen (HLA) class II alleles, HLA-DRB1*04:02 and HLA-DQB1*05:03. Both HLA class II alleles are critical for the presentation of immunodominant peptides to autoreactive CD4+ Th cells which are considered as the key players in the induction and regulation of auto-ab formation. The importance of autoreactive T-B cell interaction in the induction of pathogenic, anti-Dsg IgG auto-ab has been demonstrated both clinically (by the use of the anti-CD20 monoclonal antibody, rituximab), and, experimentally, in PV mouse models. The strong association of clinically active pemphigus with auto-ab of the IgG4 and IgE subclasses as well as the preferential detection of autoreactive Th2 cells in PV patients underscores the importance of Th2 cells in the immune pathogenesis of this disorder. Currently, there is only limited insight into the molecular mechanisms that occur after binding of pathogenic IgG auto-ab to their desmosomal targets. There is ongoing debate whether anti-Dsg IgG auto-ab act via steric hindrance of desmosomal cell-cell adhesion, altered signaling of the targeted proteins, or interference with non-Dsg adhesion molecules and target antigens without known adhesive function. Specifically, PEGASUS will address the following aspects of the PV pathogenesis: Utilizing a pre-clinical animal model of PV (TP1), skin biopsies and peripheral blood lymphocytes from PV patients, the relative role of autoreactive T cells (TP1, TP2, TP8), B cells (TP2, TP4, TP6) and innate immune mechanisms (TP3) in PV will be studied in vivo and ex vivo/in vitro, respectively. Major emphasis will also be put on dissecting critical events leading to loss of epidermal adhesion by anti-desmosomal (TP4, TP5, TP6) and non-desmosomal IgG auto-ab (TP7). Finally, a phase Ib trial aimed at targeting autoreactive T cells will translate the concept of PV as a T cell driven disorder from pre-clinical models into clinical reality (TP8). Based on the broad expertise of the PEGASUS consortium, we not only expect a deepened understanding of the immunological regulation of auto-ab production but also novel clues how to translate the basic research findings into clinical reality. The work of the Research Unit PEGASUS should provide novel, more specific treatment options not only for PV but also for auto-ab-dependent autoimmune disorders in general.

• DFG Programme: Research Units
• International Connection: Switzerland

Projects

• Autoimmunity against desmocollins in pemphigus (Applicant Sitaru, Cassian )
• Coordination Funds (Applicant Hertl, Michael )
• Desmoglein-dependent signaling complexes in pemphigus (Applicant Waschke, Jens )
• Desmosomal hyper-adhesion and heterophilic desmoglein interactions in pemphigus (Applicant Vielmuth, Franziska )
• Epitope spreading in Pemphigus (Applicants Borradori, Ph.D., Luca ;  Schmidt, Ansgar )
• Flotillins in the regulation of desmosomal adhesion in pemphigus (Applicant Tikkanen, Ritva )
• Human leukocyte antigen (HLA)-transgenic mice as a pre-clinical model of pemphigus vulgaris (Applicants Garn, Holger ;  Hertl, Michael )
• Impact of innate immunity on pemphigus vulgaris disease manifestation (Applicants Baron, Jens Malte ;  Yazdi, Amir Sadegh )
• Monitoring of autoreactive T cells responses in active and remittent pemphigus vulgaris (Applicant Hertl, Michael )
• T-cell-dependent regulation of autoreactive B cells in pemphigus (Applicants Ghoreschi, Kamran ;  Möbs, Christian )

• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Spokesperson: Professor Dr. Michael Hertl