Ca2+ signalling is critical for autoantibody-induced blistering of human epidermis in pemphigus

Schmitt, T.; Egu, D. T.; Walter, E.; Sigmund, A. M.; Eichkorn, R.; Yazdi, A.; Schmidt, E.; Sardy, M.; Eming, R.; Goebeler, M. und Waschke, J. (2021): Ca2+ signalling is critical for autoantibody-induced blistering of human epidermis in pemphigus. In: British Journal of Dermatology, Bd. 185, Nr. 3: S. 595-604

Abstract

Background Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering;mucosal pemphigus vulgaris (mPV) by anti-Dsg3 IgG inducing erosions in the mucosa;and mucocutaneous pemphigus vulgaris (PV) by affecting both, with autoantibodies targeting Dsg1 and Dsg3. Objectives To characterize the Ca2+ flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles. Methods Immunoprecipitation, Ca2+ flux analysis, Western blotting, immunofluorescence staining, dissociation assays and a human skin ex vivo model were used. Results PV IgG and PF IgG, but neither Dsg3-specific monoclonal antibody (AK23) nor mPV IgG, caused Ca2+ influx in primary human keratinocytes. Phosphatidylinositol 4-kinase alpha interacts with Dsg1 but not with Dsg3. Its downstream target - phospholipase-C-gamma 1 (PLC) - was activated by PV IgG and PF IgG but not AK23 or 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, and 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. Conclusions 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0007-0963
• Sprache: Englisch