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ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune blistering disease in which antibodies against the desmosomal cadherin, DSG3 (desmoglein-3), cause acantholysis. It has become increasingly clear that loss of cell-cell adhesion in PV is a complex and active process involving multiple signaling events such as activation of p38MAPK. It has also been demonstrated that incubating keratinocytes with PV IgG causes a redistribution of DSG3 from the cell surface to endosomes, which target these proteins for degradation. This study was undertaken to determine the relationship between p38MAPK and DSG3 endocytosis in pemphigus. In this work, we confirm that PV IgG causes internalization of cell-surface DSG3 into endosomes (as early as 4 h), which are then depleted from both detergent-soluble and detergent-insoluble pools. Cell-surface DSG3 internalization and depletion from both the detergent-soluble and detergent-insoluble fractions were blocked by the p38MAPK inhibitor SB202190. These data suggest that p38MAPK is capable of regulating PV IgG-mediated DSG3 internalization and that previously isolated mechanistic observations may be linked to a common pathway by which pemphigus autoantibodies lead to acantholysis.
Journal of Biological Chemistry 03/2010; 285(12):8936-41. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune blistering disease in which antibodies against the desmosomal cadherin, DSG3 (desmoglein-3),
cause acantholysis. It has become increasingly clear that loss of cell-cell adhesion in PV is a complex and active process
involving multiple signaling events such as activation of p38MAPK. It has also been demonstrated that incubating keratinocytes
with PV IgG causes a redistribution of DSG3 from the cell surface to endosomes, which target these proteins for degradation.
This study was undertaken to determine the relationship between p38MAPK and DSG3 endocytosis in pemphigus. In this work, we
confirm that PV IgG causes internalization of cell-surface DSG3 into endosomes (as early as 4 h), which are then depleted
from both detergent-soluble and detergent-insoluble pools. Cell-surface DSG3 internalization and depletion from both the detergent-soluble
and detergent-insoluble fractions were blocked by the p38MAPK inhibitor SB202190. These data suggest that p38MAPK is capable
of regulating PV IgG-mediated DSG3 internalization and that previously isolated mechanistic observations may be linked to
a common pathway by which pemphigus autoantibodies lead to acantholysis.
Journal of Biological Chemistry 03/2010; 285(12):8936-8941. · 4.77 Impact Factor
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ABSTRACT: In pemphigus vulgaris and pemphigus foliaceus (PF), autoantibodies against desmoglein-3 and desmoglein-1 induce epidermal cell detachment (acantholysis) and blistering. Activation of keratinocyte intracellular signaling pathways is emerging as an important component of pemphigus IgG-mediated acantholysis. We previously reported activation of p38 mitogen-activated protein kinase (MAPK) in response to pathogenic pemphigus vulgaris and PF IgG. Inhibition of p38MAPK blocked pemphigus IgG-induced cytoskeletal reorganization in tissue culture and blistering in pemphigus mouse models. We now extend these observations by demonstrating two peaks of p38MAPK activation in pemphigus tissue culture and mouse models. Administration of the p38MAPK inhibitor SB202190 before PF IgG injection blocked both peaks of p38MAPK phosphorylation and blister formation, consistent with our previous findings; however, administration of the inhibitor 4 h after PF IgG injection blocked only the later peak of p38MAPK activation but failed to block blistering. Examination of the temporal relationship of p38MAPK phosphorylation and apoptosis showed that apoptosis occurs at or after the second peak of p38MAPK activation. The time course of p38MAPK activation and apoptotic markers, as well as the ability of inhibitors of p38MAPK to block activation of the proapoptotic proteinase caspase-3, suggest that activation of apoptosis is downstream to, and a consequence of, p38MAPK activation in pemphigus acantholysis. Furthermore, these observations suggest that the earlier peak of p38MAPK activation is part of the mechanism leading to acantholysis, whereas the later peak of p38MAPK and apoptosis may not be essential for acantholysis.
Journal of Biological Chemistry 04/2009; 284(18):12524-32. · 4.77 Impact Factor
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International journal of dermatology 04/2008; 47(3):305-7. · 1.18 Impact Factor
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ABSTRACT: Punch incision has been introduced as an alternative method to surgical excision for troublesome epidermal inclusion cysts. To date, there is no randomized study directly comparing the long-term results of these two methods.
To compare the surgical outcomes of these two procedures and to identify the characteristics of a lesion most suitable for the punch incision technique.
In a 16-month period, 60 patients with noninfected epidermal inclusion cysts were randomly treated with either punch incision or elliptical excision. Demographic data, size, and location of lesion, length of wound, operative time, complications, recurrence, and patient satisfaction were compared statistically.
The mean lengths of the wounds in the punch incision and elliptical excision groups were 0.73 and 2.34 cm, respectively (p<.001). Mean operative time was significantly shorter in the punch group (12.7 minutes) as compared with the surgical group (21.6 minutes) (p<.001). No complication occurred in the punch incision group. There was no significant difference in the recurrence rate.
Punch incision produces a superior cosmetic result while keeping a low recurrence rate of cysts. Epidermal inclusion cysts measuring 1 to 2 cm that are located on the face or in an area of cosmetic concern are best treated with punch incision.
Dermatologic Surgery 04/2006; 32(4):520-5. · 1.80 Impact Factor
