INTRODUCTION
The skin as the main outer barrier against pathogens, chemicals and other hazards is an important organ. The autoimmune disease pemphigus vulgaris (PV) affects the mucosa and epidermis . Disruption of the skin barrier, caused by often extensive blisters, can lead to severe complications and high mortality if untreated . Current first-line treatments are systemic high-dose long term corticosteroids with or without further immunosuppressants or rituximab combined with rapidly tapered corticosteroids, both associated with high rates of severe adverse events . Other treatment options such as intravenous-immunoglobulin G (IV-IgG) or immuno-adsorption also have drawbacks, including availability of donor IgG , immunosuppressive effects and short-term effectiveness . Understanding the mechanisms of PV pathology and finding specific treatment options are thus the main goals of current research.
PV is caused by autoantibodies (PV-IgG) including IgG against the desmosomal proteins desmoglein (DSG )1 and 3 and autoantibodies against other target proteins . Desmosomes are adhesive cell-cell contacts in the epidermis , in which DSG s are connected to plaque proteins including desmoplakin (DP ) which links them to the keratin cytoskeleton .
Desmosomes provide mechanical stability, but also partake in cellular signalling . In pemphigus, loss of desmosomal adhesion is caused by both direct inhibition of DSG binding and cellular signalling mechanisms .
It is well-known that the clinical phenotype of PV correlates with the autoantibody profile and anti-DSG 1-IgG are believed to be required for epidermal blistering . It is thus possible that anti-DSG 1-IgGs modulate specific signalling pathways involved in loss of desmosomal adhesion . Indeed, Ca2+ influx in human keratinocytes was shown to be induced by PV-IgG including autoantibodies against DSG 1 but not by AK23, aDSG 3-specific IgG . PV-IgG is known to lead to activation of phospholipase-C γ1 (PLC ) generating inositol-1,4,5-trisphosphat (IP3) and increasing the intracellular Ca2+concentration . In line with this, an interaction between DSG 1 and PI4K (phosphoinositole-4-kinase α), upstream of PLC , was predicted .
Further downstream, IP3 activates IP3R(Inositol-trisphosphate-receptor), releasing Ca2+ from the endoplasmic reticulum (ER) into the cytosol . Ca2+flux from the ER into the cytosol stimulates Ca2+-release-activated-channels (CRAC) causing further Ca2+ influx . Ca2+ activates protein kinase-C α (PKC ) , which was shown to also be important for PV-IgG-induced loss of keratinocyte adhesion and skin blistering by mechanisms including depletion of DSG 3 , keratin retraction and loss of cell adhesion in vitro and in mice in vivo .