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Foto: Irina Nuhn
Group photo PEGASUS members 2019

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-specifc 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). With PEGASUS, a consortium of basic researchers and clinician-scientists with a long-standing interest in pemphigus and immunological research will aim at dissecting key events in the immunological induction and maintenance phase of PV. This approach will primarily focus on basic research of immunological and molecular events leading to the hallmark of PV, the loss of keratinocyte adhesion. Moreover, it has a strong translational approach with the aim to introduce therapeutic concepts originating from basic research in early phase clinical trials in PV.

Interplay of PEGASUS TPs: From cell biology (TP4, TP5, TP6new) and immunology (TP2 and TP3) over pre-clinical mouse model (TP1) to clinical phase 1 trial (TP8).
Graphic: Aaron Beller, Robert Pollmann

Interplay of PEGASUS TPs: From cell biology (TP4, TP5, TP6new) and immunology (TP2 and TP3) over pre-clinical mouse model (TP1) to clinical phase 1 trial (TP8). Click to enlarge figure

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 autoaggressive T cells (TP1, TP2, TP8), B cells (TP2, TP4) and innate immune mechanisms (TP3) in PV will be studied in vivo/ex vivo and in vitro, respectively. Major emphasis will be also put on dissecting critical events leading to loss of epidermal adhesion by IgG auto-ab against the target antigens of pemphigus (Dsg-poteins and flotillins) (TP4, TP5). Finally, a phase I trial in PV aimed at therapeutically targeting autoaggressive T cells will translate the concept of PV as a T cell driven disorder from ex vivo and in vivo 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 IgG auto-ab production but also novel clues how to translate the basic research findings into clinical reality. As PV is a model autoimmune disorder, the work of the research unit PEGASUS should provide novel, more specific treatment options for auto-ab-dependent autoimmune disorders in general.

Pegasus consortium:


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Joint work programme of Pegasus

Figure: Robert Pollmann

Overview of available immunological and molecular biologic methods at the different PEGASUS sites accesible to the whole consortium

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We have installed Core Units for special techniques which are critical for the work and the quality assurance of specific techniques of the PEGASUS consortium. The research methods applied in the different TPs of the PEGASUS consortium can be roughly divided into immunological methods and techniques in cellular and molecular biology, respectively. Those TPs that focuse on characterizing immune cells of the peripheral blood of patients or isolated cells from lymphoid organs of experimental animals rely on thorough phenotypical analyses by flow cytometry. PEGASUS enabled the performance of multi-parametric cell analysis by  flow cytometry. This allows a detailed characterization of immune cells (i.e. T and B cell subpopulations). By establishing standardized staining protocols, several TPs, such as TP1, TP2 and TP8 benefit from this core unit and the results can be compared with the work of other partners within PEGASUS. Another technique that is frequently applied by several TPs (e.g. TP1, TP4) is confocal microscopy and imaging in a broader sense. The imaging and microscopy core facility at the University of Giessen provides excellent opportunities to analyze immunofluorescent stainings of epithelial tissue. TP5 and TP6new provide a variety of cell-free systems and imaging facilities. Techniques such as atomic force microscopy (AFM)- and stimulated emission depletion (STED)-microscopy are well established in Munich and these methods are shared within the consortium. TP3 has established a 3D skin/mucosa model that is going to be available for all those TPs focusing on the effects of Dsg-reactive autoantibodies on cell adhesion, especially on desmosomal integrity.
In summary, PEGASUS realized the importance of standardized methods for the reproducibility of the data at different sites of the transregional Research Group and therefore, decided to establish decentral core units at the sites of the PEGASUS partners who are the experts in these procedures.