Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

University of Würzburg, Institute of Anatomy and Cell Biology, Würzburg, Germany.
American Journal Of Pathology (Impact Factor: 4.59). 10/2007; 171(3):906-16. DOI: 10.2353/ajpath.2007.070028
Source: PubMed


According to the desmoglein (Dsg) compensation concept, different epidermal cleavage planes observed in pemphigus vulgaris and pemphigus foliaceus have been proposed to be caused by different autoantibody profiles against the desmosomal proteins Dsg 1 and Dsg 3. According to this model, Dsg 1 autoantibodies would only lead to epidermal splitting in those epidermal layers in which no Dsg 3 is present to compensate for the functional loss of Dsg 1. We provide evidence that both pemphigus foliaceus-IgG containing Dsg 1- but not Dsg 3-specific antibodies and pemphigus vulgaris-IgG with antibodies to Dsg 1 and Dsg 3 were equally effective in causing epidermal splitting in human skin and keratinocyte dissociation in vitro. These effects were present where keratinocytes expressed both Dsg 1 and Dsg 3, demonstrating that Dsg 3 does not compensate for Dsg 1 inactivation. Rather, the cleavage plane in intact human skin caused by pemphigus autoantibodies was similar to the plane of keratinocyte dissociation in response to toxin B-mediated inactivation of Rho GTPases. Because we recently demonstrated that pemphigus-IgG causes epidermal splitting by inhibition of Rho A, we propose that Rho GTPase inactivation contributes to the mechanisms accounting for the cleavage plane in pemphigus skin splitting.

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    • "At 48 hours after transfections, the cells were incubated with 30 mmol l –1 SB202190, a specific inhibitor of p38MAPK for 6 hours. Next, cells were fixed with 2% formalin (freshly prepared from paraformaldehyde) for 10 minutes and subjected to immunostaining procedures as described in detail elsewhere (Spindler et al., 2007). Mouse monoclonal Pg Ab (Progen), rabbit polyclonal DP Ab (NW6, a kind gift of Dr Kathleen Green, Northwestern University, Chicago, IL), FITC-conjugated pancytokeratin mAb (Sigma-Aldrich), or pan-cytokeratin E605 mAb (Ebioscience, San Diego, CA) was used as the primary Ab. "
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    ABSTRACT: Plakoglobin (Pg) and desmoplakin (DP) are adapter proteins within the desmosome, providing a mechanical link between desmosomal cadherins as transmembrane adhesion molecules and the intermediate filament cytoskeleton. Because in the severe skin blistering disease pemphigus autoantibodies against desmosomal adhesion molecules induce loss of keratinocyte cohesion at least in part via p38MAPK activation and depletion of desmosomal components, we evaluated the roles of Pg and DP in p38MAPK-dependent loss of cell adhesion. Silencing of either Pg or DP reduced cohesion of cultured human keratinocytes in dissociation assays. However, Pg but not DP silencing caused activation of p38MAPK-dependent keratin filament collapse and cell dissociation. Interestingly, extranuclear but not nuclear Pg rescued loss of cell adhesion and keratin retraction. In line with this, Pg regulated the levels of the desmosomal adhesion molecule desmoglein 3 and tethered p38MAPK to desmosomal complexes. Our data demonstrate a role of extranuclear Pg in controlling cell adhesion via p38MAPK-dependent regulation of keratin filament organization.Journal of Investigative Dermatology accepted article preview online, 17 January 2014. doi:10.1038/jid.2014.21.
    Full-text · Article · Jan 2014 · Journal of Investigative Dermatology
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    • "To reconcile these on first sight conflicting findings it has to be considered that, dependent on the differentiation status, keratinocytes usually express a large set of Dsg and Dsc isoforms that can serve as potential compensation partners for the disrupted intercellular Dsg2 binding, whereas in Caco-2 cells Dsg2 and Dsc2 are the only desmosomal cadherins expressed. Under conditions used for our study, HaCaT cells express Dsg2, Dsg3, Dsc2 (Fig. 4 C) and Dsc3 [16] whereas Dsg1 (and putatively Dsg4 and Dsc1) was found in significant amounts only when cells were further differentiated [1], [14], [28]. In the field of pemphigus research the so-called “desmoglein compensation hypothesis” was established to explain that some Dsg isoforms can compensate for each other: when autoantibodies are present in pemphigus patients targeting both Dsg1 and Dsg3, they may bind as an initial event to the extracellular domain of desmosomal cadherins, disrupt intercellular binding and lead to epidermal blister formation. "
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    ABSTRACT: Desmosomes provide intercellular adhesive strength required for integrity of epithelial and some non-epithelial tissues. Within the epidermis, the cadherin-type adhesion molecules desmoglein (Dsg) 1-4 and desmocollin (Dsc) 1-3 build the adhesive core of desmosomes. In keratinocytes, several isoforms of these proteins are co-expressed. However, the contribution of specific isoforms to overall cell cohesion is unclear. Therefore, in this study we investigated the roles of Dsg2 and Dsg3, the latter of which is known to be essential for keratinocyte adhesion based on its autoantibody-induced loss of function in the autoimmune blistering skin disease pemphigus vulgaris (PV). The pathogenic PV antibody AK23, targeting the Dsg3 adhesive domain, led to profound loss of cell cohesion in human keratinocytes as revealed by the dispase-based dissociation assays. In contrast, an antibody against Dsg2 had no effect on cell cohesion although the Dsg2 antibody was demonstrated to interfere with Dsg2 transinteraction by single molecule atomic force microscopy and was effective to reduce cell cohesion in intestinal epithelial Caco-2 cells which express Dsg2 as the only Dsg isoform. To substantiate these findings, siRNA-mediated silencing of Dsg2 or Dsg3 was performed in keratinocytes. In contrast to Dsg3-depleted cells, Dsg2 knockdown reduced cell cohesion only under conditions of increased shear. These experiments indicate that specific desmosomal cadherins contribute differently to keratinocyte cohesion and that Dsg2 compared to Dsg3 is less important in this context.
    Preview · Article · Jan 2013 · PLoS ONE
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    • "Thus, as a positive control we stained sections of normal human skin with the Dsg1 antibody used to detect its expression in pancreatic tissues (Additional file 1). Consistent with previous findings [42], Dsg1 was detected throughout the epidermis from superficial to basal layers. In recent studies in mice, the presence of DSG1 and DSG3 mRNAs have been reported in many epithelial organs [41]. "
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    ABSTRACT: In a previous report we have demonstrated that the chymotryptic-like serine protease kallikrein 7 (KLK7/hK7) is overexpressed in pancreatic cancer. In normal skin, hK7 is thought to participate in skin desquamation by contributing in the degradation of desmosomal components, such as desmogleins. Thus, the ability of hK7 to degrade desmogleins was assessed and the effect of hK7 expression on desmoglein 2 was examined in cultured pancreatic cancer cells. The expression of Dsg1, Dsg2, and Dsg3 in pancreatic tissues was examined by immunohistochemistry and their expression in two pancreatic cancer cell lines, BxPC-3 and Panc-1, was determined by western blot analysis. The ability of hK7 to degrade Dsg1 and Dsg2 was investigated using in vitro degradation assays. BxPC-3 cells stably transfected to overexpress hK7 were used to examine the effect of hK7 on cell-surface resident Dsg2. The levels of immunoreactive Dsg1 and Dsg2 were reduced in pancreatic adenocarcinomas compared with both normal pancreatic and chronic pancreatitis tissues. Among the desmosomal proteins examined, Dsg2 exhibited robust expression on the surface of BxPC-3 cells. When hK7 was overexpressed in this cell line, there was a significant increase in the amount of soluble Dsg2 released into the culture medium compared with vector-transfected control cells. A reduction in the amount of the cell adhesion components Dsg1 and Dsg2 in pancreatic tumors suggests that loss of these desmosomal proteins may play a role in pancreatic cancer invasion. Using in vitro degradation assays, both Dsg1 and Dsg2 could be readily proteolyzed by hK7, which is overexpressed in pancreatic adenocarcinomas. The enforced expression of hK7 in BxPC-3 cells that express significant amounts of Dsg2 resulted in a marked increase in the shedding of soluble Dsg2, which is consistent with the notion that aberrant expression of hK7 in pancreatic tumors may result in diminished cell-cell adhesion and facilitate tumor cell invasion.
    Full-text · Article · Jan 2009 · BMC Cancer
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