@article{SchmittEguWalteretal.2021,
  author    = {Schmitt, T. and Egu, D.T. and Walter, E. and Sigmund, A.M. and Eichkorn, R. and Yazdi, A. and Schmidt, E. and S{\´a}rdy, M. and Eming, R. and Goebeler, M. and Waschke, J.},
  title     = {Ca\(^{2+}\) signalling is critical for autoantibody-induced blistering of human epidermis in pemphigus},
  series = {British Journal of Dermatology},
  volume    = {185},
  journal   = {British Journal of Dermatology},
  number    = {3},
  doi       = {10.1111/bjd.20091},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262810},
  pages     = {595 -- 604},
  year      = {2021},
  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 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.},
  language  = {en}
}
@article{ReckeKonitzerLemckeetal.2018,
  author    = {Recke, Andreas and Konitzer, Sarah and Lemcke, Susanne and Freitag, Miriam and Sommer, Nele Maxi and Abdelhady, Mohammad and Amoli, Mahsa M. and Benoit, Sandrine and El-Chennawy, Farha and Eldarouti, Mohammad and Eming, R{\"u}diger and Gl{\"a}ser, Regine and G{\"u}nther, Claudia and Hadaschik, Eva and Homey, Bernhard and Lieb, Wolfgang and Peitsch, Wiebke K. and Pf{\"o}hler, Claudia and Robati, Reza M. and Saeedi, Marjan and S{\´a}rdy, Mikl{\´o}s and Sticherling, Michael and Uzun, Soner and Worm, Margitta and Zillikens, Detlef and Ibrahim, Saleh and Vidarsson, Gestur and Schmidt, Enno},
  title     = {The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris-Analysis of Four Different Ethnic Cohorts},
  series = {frontiers in Immunology},
  volume    = {9},
  journal   = {frontiers in Immunology},
  doi       = {10.3389/fimmu.2018.01788},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225073},
  pages     = {1788, 1-8},
  year      = {2018},
  abstract  = {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.},
  subject      = {Diagnose},
  language  = {en}
}