期刊
BRITISH JOURNAL OF DERMATOLOGY
卷 185, 期 3, 页码 595-604出版社
WILEY
DOI: 10.1111/bjd.20091
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类别
资金
- Projekt DEAL
- [249-12]
The study investigates the role of the Ca2+ flux pathway in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles, finding that Ca2+-mediated signaling is important for epidermal blistering and depends on the autoantibody profile. Interfering with PLC and Ca2+ signaling may be a promising approach to treat epidermal manifestations of pemphigus.
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.
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