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

• Published in: British journal of dermatology (1951) Vol. 185; no. 3; pp. 595 - 604
• Main Authors: Schmitt, T., Egu, D.T., Walter, E., Sigmund, A.M., Eichkorn, R., Yazdi, A., Schmidt, E., Sárdy, M., Eming, R., Goebeler, M., Waschke, J.
• Format: Journal Article
• Language: English
• Published: England 01.09.2021
• ISSN: 0007-0963; 1365-2133
• DOI: 10.1111/bjd.20091

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 Ca flux pathway and delineate its importance for pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles. Immunoprecipitation, Ca 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 Ca 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 Ca flux from the endoplasmic reticulum into the cytosol, which stimulates Ca -release-activated-channels (CRAC)-mediated Ca influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV-IgG and PF-IgG-induced Ca 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. Ca -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 Ca signalling may be a promising approach to treat epidermal manifestations of pemphigus.