Ca ²⁺ signalling is critical for autoantibody?induced blistering of human epidermis in pemphigus*

Background Pemphigus is a severe bullous autoimmune skin disease. foliaceus (PF) characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering; mucosal pemphigus vulgaris (mPV) anti-Dsg3 inducing erosions in the mucosa; and mucocutaneous (PV) affecting both, with autoantibodies targeting Dsg1 Dsg3. Objectives To characterize Ca2+ flux pathway delineate its importance pathogenesis clinical phenotypes caused different antibody profiles. Methods Immunoprecipitation, analysis, Western blotting, immunofluorescence staining, dissociation assays human ex vivo model were used. Results PV PF IgG, but neither Dsg3-specific monoclonal (AK23) nor mPV influx primary keratinocytes. Phosphatidylinositol 4-kinase ? interacts not Its downstream target – phospholipase-C-?1 (PLC) was activated AK23 or IgG. PLC releases inositol 1,4,5-trisphosphate (IP3) IP3 receptor (IP3R) activation from endoplasmic reticulum into cytosol, which stimulates release-activated channels (CRAC)-mediated influx. Inhibitors against PLC, IP3R CRAC effectively blocked IgG-induced influx; ameliorated alterations of Dsg3 localization, reorganization keratin actin filaments; inhibited loss cell adhesion vitro. Finally, inhibiting protective blister formation redistribution vivo. Conclusions Ca2+-mediated signalling important for blistering dependent on autoantibody profile, indicates roles complexes organized Interfering may be promising approach to treat manifestations pemphigus.