Characterization and pharmacological inhibition of an adult antibody-transfer mouse model of pemphigus vulgaris (PV)

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease in which autoantibodies against the desmosomal adhesion molecules, desmoglein (Dsg) 1 and 3, ultimately lead to the formation of intraepithelial blisters and erosions of the skin and/or mucous membranes. Despite recent advances in PV treatment, there is still a high medical need for more effective, safer, and more specific therapies. Our preliminary data showed that AK47 anti-Dsg3 IgG1 mAb induces Dsg3 endocytosis and loss of cell cohesion in cultured keratinocytes. Repeated s.c. injections of AK47 in adult C57BL/6 mice resulted in oral and pharyngeal erosions and hair loss with suprabasal splitting. Concomitant i.p. injections of IVIg significantly reduced mucosal lesions and hair loss compared to vehicle-treated mice. Furthermore, IVIg-treated mice had significantly lower levels of circulating and tissue-bound autoantibodies. Similarly, disease severity was significantly abrogated by IVIg when administered to mice in which clinical lesions had already developed upon AK47 injection. Altogether, we generated a PV mouse model that reproduces key features of the human disease. We will employ this model to elucidate the pathomechanisms underlying blister induction and to evaluate novel therapeutic interventions, e.g., inhibitors of signaling pathways. To do so, we will focus on the following objectives: Aim 1: Identification of novel therapeutic targets for PV. AK47 stimulation leads to the upregulation of several kinases in cultured keratinocytes. Hence, we will administer selective kinase inhibitors to PV mice and assess their inhibitory efficacy on IgG-induced blistering in prophylactic and quasi-therapeutic settings. Aim 2: Omics-based cellular and molecular characterization of PV mice. We will employ a multi-pronged approach, including transcriptomics, kinomics, and proteomics, to investigate the cellular composition and molecular pathways in the PV model prior to and after the administration of selective kinase inhibitors. Aim 3: Unravelling the cellular and molecular basis of disease in PV patients. We will implement scRNA-seq to obtain a comprehensive visualization of the immunological hallmarks in perilesional biopsies from PV patients. Additionally, we will leverage cross-species comparative omics approaches to validate therapeutic targets and discover new disease biomarkers. By identifying phenotype-relevant cell subsets and molecular/metabolic networks, we will be able to determine disease-specific pathways in human and mouse species.