The roles of Ca2+- influx and PLC for
pemphigus vulgaris pathogenesis
Ca2+ flux-dependent signalling plays an important role
in pemphigus pathogenesis. Inhibiting Ca2+ signalling
blocks PV-IgG-induced loss of keratinocyte adhesion in vitro and
blistering in human skin ex vivo (Figure 5). Binding of PV-IgG toDSG 1 [1], associated with PI4K and PLC ,
activates PLC and releases IP3 [2]. IP3 activates IP3Rthereby releasing Ca2+ from the ER into the cytosol
[3]. Low ER Ca2+ concentration activatesSTIM1 at the ER membrane. STIM1 contacts ORAI1 by
forming the CRAC and thereby causing Ca2+ influx from
the extracellular space [4]. With the IP3R still active, this
further increases the Ca2+ concentration in the
cytosol. Cytosolic Ca2+ finally activates PKC[5], which destabilizes the desmosome by keratin retraction and
depletion of DSG 1 and DSG 3 [6].
The complete mechanism of action of PKC is still unknown.
However, it presumably affects desmosome turn-over on several levels.
Upon PV-IgG treatment PKC has been proposed to translocate to the
desmosomal plaque . Cytoskeletal components such as keratin 8 and 18 are
substrates of PKC possibly inducing keratin filament retraction.
Similarly, PKC affects the actin cytoskeleton, mostly causing
disassembly and reduced anchorage and may also modulate desmosome
turn-over by modulating the actin-binding adducin . Moreover, PKCphosphorylates DP which is involved in destabilizing the
desmosome , and caused DSG 3 fragmentation and acantholysis in
pemphigus passive-immune-transfer mouse models which supports the
observations that inhibiting PKC ameliorated PV-IgG-induced loss
of adhesion in vitro .
Ca2+ has very profound effects on desmosome
regulation. The stability of newly formed desmosomes is dependent on
extracellular Ca2+ . After several days, desmosomes
become hyper-adhesive and independent of extracellular
Ca2+ . Hyper-adhesive desmosomes are also less
sensitive to PV-IgG . Inhibiting PKC causes a rapid
transformation from Ca2+-dependent to
Ca2+-independent desmosomes . Active PKC is
associated with DSG 1, which is known to be important for
regulation of epidermal differentiation . It is thus conceivable thatDSG 1 controls desmosome adhesion and skin differentiation at
least in part by controlling Ca2+ levels in
keratinocytes.
Loss of cell adhesion in response to AK23, which did not cause
Ca2+ influx and disrupts DSG 3 but notDSG 1 was ameliorated significantly by inhibiting PLC . This
indicates that PKC , which was observed to be involved inDSG 3 depletion in vivo and in vitro may be
activated independently of Ca2+ or baseline activity
is sufficient. It was reported, that PV-IgG against thyroid peroxidase
and other targets might also be able to activate Ca2+flux possibly via PLC . This indicates that these non-desmoglein
antibodies might play a crucial role for disease severity and relapse.
It is unlikely that PKC is the sole downstream pathway activated
by antibodies against DSG 1. In human epidermis, inhibition ofPKC alone under conditions which were effective in vitroand in mice in vivo, was not enough to block blistering in human
skin ex vivo . In contrast, inhibition of p38MAPK , was
protective in murine skin in vivo and human epidermis but not in
mucosa ex vivo . Since we observed that p38MAPK is
associated with both DSG 1 and DSG 3 , these data are
compatible with the hypothesis that antibodies against DSG 1 andDSG 3 or other targets are required for skin blistering.PLC might also modulate other events regulated by p38MAPKsuch as actin remodelling via RHOA .
This demonstrates that PV pathology is dependent on the antibody
profiles, different anti-DSG 1/DSG 3 ratios as well as
different target epitopes might play an important role . This might
influence the clinical phenotype by inducing specific signalling
responses in keratinocytes . More studies are required to delineate the
functional interplay between the complex mechanisms involved in
pemphigus pathogenesis. Nevertheless, the data presented here can
explain for the first time why autoantibodies against DSG 1 but
not DSG 3 are required for epidermal involvement in PV. SincePI4K upstream of Ca2+ signalling specifically
interacts with DSG 1 but not with DSG 3, this knowledge may
allow a new strategy to develop DSG 1-specific treatment options
in pemphigus.