KFO 303:  Pemphigoid Diseases - Molecular Pathways and their Therapeutic Potential

• Subject Area: Medicine
• Term: from 2015 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269234613

Pemphigoid diseases (PD) are a group of severe, closely related, chronic, autoantibody (AAb)-induced, subepidermal blistering skin diseases caused by an immune response directed to defined autoantigens serving as adhesion molecules within in the hemidesmosomal anchoring complex at the dermal-epithelial junction (DEJ) of squamous epithelia, including the skin. In the effector phase of this immune response, inflammatory cells are recruited into the dermis and release mediators, including proteases, compromising dermal-epidermal adhesion. Consequently, skin blisters and erosions develop.PDs mainly affect elderly and are associated with a high mortality. With their incidence rising, they constitute a growing health concern. Treatment options are limited and often elicit severe adverse effects. Development of novel therapeutic strategies takes sound understanding of PD pathogenesis. The molecular mechanisms driving PDs, however, are only incompletely understood. The mere presence of AAbs alone, although a prerequisite for skin inflammation, is not sufficient to initiate the effector phase. A pivotal question therefore is how immune effector cell recruitment into the dermis is initiated, amplified, and finally perpetuated. Effectively and specifically blunting effector cell recruitment in a therapeutic effort is presumably key to control PD. The Department of Dermatology at the University of Lübeck is one of few academic centers worldwide specialized in both research and treatment of PDs. We have developed unique mouse models of PDs and have established a significant PD patient cohort. This has allowed us to shed some light on the pathogenesis of PDs, which has turned out to be more complex than previously anticipated. Recently, we have made new exciting discoveries, specifically on the effector phase of PDs, now kindling this Clinical Research Unit (CRU) proposal. Our goal is to uncover the factors triggering and driving skin inflammation and to provide a comprehensive model for the effector phase of PDs. We will particularly elucidate the mechanisms initiating, amplifying, and perpetuating effector cell recruitment, and we will translate these new insights into novel therapeutics, preventive strategies, and biomarkers. In this context, PDs will serve as paradigm for the elucidation of the effector phase of AAb-driven autoimmune diseases in general. Unlike in PDs, the autoantigens in the majority of autoimmune diseases are unknown, thus complicating the elucidation of the effector phase of most autoimmune diseases, especially its early stage when tissue inflammation is just emerging.By this CRU, we will establish a permanent translational research unit at the University of Lübeck and will train particularly physician scientists. The CRU will further strengthen the major research focus ¿Infection and Inflammation¿ of the University of Lübeck.

• DFG Programme: Clinical Research Units

Projects

• Administrative unit (Applicant Sadik, Christian David )
• Biostatistics and Systems Medicine Core Unit (Z2-Project) (Applicants Busch, Hauke ;  Erdmann, Jeanette ;  Koenig, Inke Regina ;  Sadik, Christian David )
• Central Clinical Infrastructure (Z1-Project) (Applicants van Beek, Nina ;  Sadik, Christian David ;  Schmidt, Enno ;  Zillikens, Detlef )
• Cutaneous complement C3 as key driver of pemphigoid disease pathogenesis (Applicants Ludwig, Ralf Joachim ;  Verschoor, Ph.D., Admar )
• Functional characterization and directed modulation of the skin microbiome in pemphigoid diseases (Applicants Baines, John F. ;  Schmidt, Enno )
• HCA2 activation in Pemphigoid Diseases - therapeutic effect and mode of action (Applicants Schwaninger, Markus ;  Zillikens, Detlef )
• Lipid Mediator-orchestrated molecular Mechanisms resolving Skin Inflammation in Pemphigoid Diseases (Applicant Sadik, Christian David )
• “Mitochondrial” Regulation of Pemphigoid Diseases (Applicants Hirose, Misa ;  Ibrahim, Saleh M. )
• The C5a/C5aR1 axis as a regulator of autoreactive IgG antibody glycosylation in pemphigoid diseases (Applicant Köhl, Jörg )
• The role of C5aR2 in the pathogenesis of pemphigoid diseases (Applicants Karsten, Christian ;  Schmidt, Enno )
• The Role of Lymphocyte-derived Factors in the Effector Phase of Pemphigoid Diseases (Applicants Bieber, Katja ;  Manz, Rudolf )
• The Role of Monocyte-derived Cells and the molecular Mechanisms of their Recruitment in the Pathogenesis of Pemphigoid Diseases (Applicants König, Peter ;  Sadik, Christian David )
• Therapeutic potential of sialylated Pemphigoid Disease autoantibodies (Applicants Ehlers, Marc ;  Hirose, Misa )

• Spokesperson: Professor Dr. Detlef Zillikens (†)
• Leader: Professor Dr. Christian David Sadik
• Project Heads: Professor Dr. John F. Baines; Dr. Nina van Beek; Privatdozentin Dr. Katja Bieber; Professor Dr. Hauke Busch; Professorin Dr. Jeanette Erdmann (†); Dr. Misa Hirose; Professor Dr. Saleh M. Ibrahim; Professor Dr. Christian Karsten; Professorin Dr. Inke Regina Koenig; Professor Dr. Jörg Köhl; Professor Dr. Peter König; Professor Dr. Ralf Joachim Ludwig; Professor Dr. Rudolf Manz; Professor Dr. Thomas F. Münte; Professor Dr. Enno Schmidt; Professor Dr. Markus Schwaninger; Professor Admar Verschoor, Ph.D.