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 .