Impact of innate immunity on pemphigus vulgaris disease manifestation

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As shown for psoriasis, innate immunity can serve an important role in T cell mediated diseases. Therefore, we aim to investigate the impact of the innate immune system on the antibody mediated autoimmune disease pemphigus vulgaris. Even though PV relies on the development of anti-Dsg3-specific antibodies, disease manifestation requires additional factors. One of these factors might be the innate immune system. Previous findings in pemphigus mouse models and ex vivo findings in pemphigus patients suggest that IL-1 and IL-6 which is induced by IL-1 are critical for auto-ab-induced intraepidermal loss of adhesion. After having shown that cytokines of innate immunity are induced by PV antibodies, by mechanical stress, and by UV, we use 3D-skin models to treat keratinocytes and fibroblasts with PV IgG and add cofactors either topically on the epidermis or to the liquid phase of the 3D-skin equivalents. In addition, we will include macrophages and neutrophils in the system to mimic cellular innate infiltration. Using genetically modified keratinocytes or pharmacological inhibition, the functional dependency of acantholysis on the presence of NFκB, IL-1, NLRs or caspases will be evaluated. This approach can elucidate the responsible innate pathway for blister formation and dismantle the mechanism of suprabasal acantholysis. Furthermore, a loss of desmoglein-1 or mutations in Dsg1, the structure against which antibodies are generated in pemphigus foliaceus, are associated with SAM-syndrome. This rare disease is associated with severe wasting, transepidermal water-loss and the production of IL-1 cytokines. A further aim besides the impact of innate immunity on blister formation ist to decipher the impact of Dsg1 on the inflammatory response in keratinocytes and in particular in PV. We will use 3D-skin models to either treat them with anti-Dsg1 or with Dsg1-deficient or mutated keratinocytes. Then we aim to investigate a different inflammatory pattern which might explain the different phenotypes in SAM-syndrome and PF. As the presence of Dsg1 protects from anti-Dsg3 induced acantholysis, we will then investigte the impact of the inflammatory signature in Dsg-1 deficiency on PV. Here, we utilize a recently established mucous membrane 3D-skin model as the mucosal epithelia do not carry significant amounts of Dsg1. The proposed experiments will clarify the role of the innate immune and of Dsg1 in acantholysis and PV manifestation. As both the IL-1 and IL-6 pathways are pharmacologically targetable, this might lead to the identification of new targets that could be used as effective therapy.