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Ca 2+ signalling is critical for autoantibody‐induced blistering of human epidermis in pemphigus *
Author(s) -
Schmitt T.,
Egu D.T.,
Walter E.,
Sigmund A.M.,
Eichkorn R.,
Yazdi A.,
Schmidt E.,
Sárdy M.,
Eming R.,
Goebeler M.,
Waschke J.
Publication year - 2021
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.20091
Subject(s) - pemphigus vulgaris , pemphigus , desmoglein 3 , acantholysis , desmoglein , desmosome , chemistry , autoantibody , antibody , microbiology and biotechnology , immunology , biology , cell , biochemistry
Summary 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 Ca 2+ flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles. Methods Immunoprecipitation, Ca 2+ 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 Ca 2+ influx in primary human keratinocytes. Phosphatidylinositol 4‐kinase α interacts with Dsg1 but not with Dsg3. Its downstream target – phospholipase‐C‐γ1 (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 Ca 2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca 2+ release‐activated channels (CRAC)‐mediated Ca 2+ influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV IgG and PF IgG‐induced Ca 2+ 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 Ca 2+ ‐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 2+ signalling may be a promising approach to treat epidermal manifestations of pemphigus.