Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by anti-desmoglein(DSG)-1-IgG causing epidermal blistering, mucosal pemphigus vulgaris (mPV) by anti-DSG-3-IgG inducing erosions in the mucosa, and mucocutaneous pemphigus vulgaris (PV) by affecting both with autoantibodies targeting DSG1 and DSG3.Characterization of the Ca2+ flux pathway and delineate its importance for pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles.Immunoprecipitation, Ca2+ flux analysis, Western-blotting, Immunofluorescence staining, dissociation assays, human skin ex vivo model.PV-IgG and PF-IgG but neither DSG3-specific monoclonal antibody (AK23) nor mPV-IgG caused Ca2+ influx in primary human keratinocytes. Phosphatidyl-inositol-4-kinase-α (PI4K) interacts with DSG1 but not DSG3. Its downstream target Phospholipase-C-γ1 (PLC) was activated by PV-IgG and PF-IgG but not AK23 nor mPV-IgG. PLC releases Inositol-1,4,5-trisphosphate (IP3) causing IP3-receptor (IP3R) activation and Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ -release-activated-channels (CRAC)-mediated Ca2+ influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV-IgG and PF-IgG-induced Ca2+ influx, ameliorated alterations of DSG1 and DSG3 localization, reorganization of keratin and actin filaments and inhibited loss of cell adhesion in vitro. Finally, inhibiting PLC or IP3R was protective against PV-IgG-induced blister formation and redistribution of DSG1 and DSG3 in human skin ex vivo.Ca2+ -mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by DSG1 and DSG3. Interfering with PLC and Ca2+ signalling may be a promising approach to treat epidermal manifestations of pemphigus.
T Schmitt, D T Egu, E Walter, A M Sigmund, R Eichkorn, A Yazdi, E Schmidt, M Sárdy, R Eming, M Goebeler, J Waschke