In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases

Abstract

Pemphigoid diseases (PD) are a subgroup of rare acute or chronic autoimmune skin disorders characterized and caused by autoantibodies directed against distinct structural components of the dermal-epidermal junction. Binding of autoantibodies to their targets leads to the formation of blisters and erosions in patients. PDs comprise eight disorders for which the molecular target antigens have been identified. First, we review the available in vitro and ex vivo models for analysis of distinct aspects of the pathogenesis of PDs. This includes the binding of autoantibodies to skin sections, the analysis of blister formation capability and skin complement activation as well as investigation of neutrophil and keratinocyte activation. In addition to this, several animal models of PD have been developed during the last decades. These animal models have greatly contributed to our current understanding of the pathogenesis of PDs. We summarize spontaneously arising PD in animals and the induction of PD by transfer of (auto)antibodies, transfer of (auto)-antigen-specific lymphocytes and by immunization.In combined use, these models allow dissecting all aspects of PD pathogenesis, for example loss of tolerance, autoantibody production and inflammatory skin processes that lead to blister formation. Overall, we aimed to foster translational biomedical research, to deepen our understanding of PD pathogenesis and to develop novel treatments for patients suffering from these life-threatening and difficult-to-treat autoimmune diseases. K E Y W O R D Sanimal model, autoimmune bullous dermatoses, autoimmunity, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigoid disease, skin

Meta-analysis of the clinical and immunopathological characteristics and treatment outcomes in epidermolysis bullosa acquisita patients

“…This information, as mentioned above, has to be interpreted with caution, but may be useful to guide the planning of clinical trials in EBA patients. To establish the rationale for a controlled clinical trial in EBA patients, the therapeutic efficacy of “established” and emerging EBA treatments should be evaluated in parallel using animal models of the disease [10, 11, 68]. Use of these models has identified several compounds with therapeutic efficacy, including IVIG, as well as potential therapeutic targets [69–71].…”

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

“…121 Dimethyl fumarate Immune complex deposition at the dermal epidermal junction (DEJ) in pemphigoid underlies the subsequent complement activation, neutrophil extravasation and proteolytic destruction in experimental models of pemphigoid and EBA. 15,[125][126][127][128] Dimethyl fumarate (DMF) is a prodrug utilized in the treatment of autoimmune disorders psoriasis and multiple sclerosis. 129,130 Its therapeutic effect is realized through downregulation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase and activation of nuclear factor erythroid 2-related factor 2 (NRF2) which stimulates expression of cytoprotective and antioxidant genes.…”

New insights into pemphigoid diseases

“…The development and refinement of model systems, both in vitro and in vivo, have and still are a pillar for basic and translational research in PD. In this FTI, these model systems are described in great detail . Readers interested in utilizing these systems should pay special attention to the instructive supplement of this paper where the authors provide detailed protocols.…”