TY  - JOUR
A1  - Schmitt, T.
A1  - Egu, D.T.
A1  - Walter, E.
A1  - Sigmund, A.M.
A1  - Eichkorn, R.
A1  - Yazdi, A.
A1  - Schmidt, E.
A1  - Sárdy, M.
A1  - Eming, R.
A1  - Goebeler, M.
A1  - Waschke, J.
T1  - Ca\(^{2+}\) signalling is critical for autoantibody‐induced blistering of human epidermis in pemphigus
JF  - British Journal of Dermatology
N2  - 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 Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ 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
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 Ca\(^{2+}\) signalling may be a promising approach to treat epidermal manifestations of pemphigus.
KW  - pemphigus
KW  - epidermis
KW  - Ca\(^{2+}\) signalling
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262810
VL  - 185
IS  - 3
SP  - 595
EP  - 604
ER  - 
TY  - JOUR
A1  - Recke, Andreas
A1  - Konitzer, Sarah
A1  - Lemcke, Susanne
A1  - Freitag, Miriam
A1  - Sommer, Nele Maxi
A1  - Abdelhady, Mohammad
A1  - Amoli, Mahsa M.
A1  - Benoit, Sandrine
A1  - El-Chennawy, Farha
A1  - Eldarouti, Mohammad
A1  - Eming, Rüdiger
A1  - Gläser, Regine
A1  - Günther, Claudia
A1  - Hadaschik, Eva
A1  - Homey, Bernhard
A1  - Lieb, Wolfgang
A1  - Peitsch, Wiebke K.
A1  - Pföhler, Claudia
A1  - Robati, Reza M.
A1  - Saeedi, Marjan
A1  - Sárdy, Miklós
A1  - Sticherling, Michael
A1  - Uzun, Soner
A1  - Worm, Margitta
A1  - Zillikens, Detlef
A1  - Ibrahim, Saleh
A1  - Vidarsson, Gestur
A1  - Schmidt, Enno
T1  - The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris-Analysis of Four Different Ethnic Cohorts
JF  - frontiers in Immunology
N2  - IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variation with PV risk, but not with BP risk. Our results suggest a hitherto unknown role for the function of IgG3 in the pathogenesis of PV.
KW  - immunology
KW  - dermatology
KW  - autoantibodies
KW  - allotype
KW  - pemphigus
KW  - Diagnose
KW  - pemphigoid
KW  - half-life
KW  - functional genetics
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225073
VL  - 9
ER  -