Abstract
Background
The Desmoglein 3 (Dsg3) knockout mouse and pemphigus vulgaris (PV) mouse model present
a similar type of supra-basal acantholysis, even though the subcellular mechanism
is considered to be completely different.
Objectives
To detect changes in the desmosomal molecular composition in Dsg3−/− mice and PV model
mice to highlight the precise mechanism for acantholysis at an ultrastructural level.
Methods
Using epithelia from Dsg3−/− mice, PV model mice, and their respective control mice,
the desmosomal components were immunostained using a post-embedding immunogold labeling
method, and their precise localization and the labeling density were statistically
analyzed in the desmosomes before the occurrence of acantholysis.
Results
Positive findings were detected in desmoplakin and plakoglobin. In the Dsg3−/− mice,
the localization of desmoplakin shifted 12.6 nm toward the cytoplasm and the plakoglobin labeling density per desmosome decreased
31% in the desmosomes. In the PV model mice Desmoplakin shifted 22.7 nm more distantly from the plasma membrane but the labeling density per desmosome
showed no significant difference, including plakoglobin. Similar results were obtained
when analyzing the desmosomes of spinous cells in the mid-epidermis.
Conclusion
These results showed the functional blocking of Dsg3 by autoantibody binding and the
genetic defect of Dsg3 to induce different changes in the cytoplasmic desmosomal plaque
proteins. A decrease in the level of plakoglobin is therefore not involved in the
acantholysis in the PV model mice. The desmoplakin shift from the desmosomal plaque,
which is induced by autoantibody binding under in vivo conditions in the PV model mouse, could be an early molecular change before the occurrence
of acantholysis.
Keywords
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References
- Auto antibodies against a novel epithelial adhering in pemphigus vulgaris, a disease of cell adhesion.Cell. 1991; 67: 869-877
- Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic.J Clin Invest. 1992; 90: 919-926
- Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris.J Cell Biol. 1997; 137: 1091-1102
- Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.J Clin Invest. 2000; 105: 625-631
- Immunologic and histopathologic characterization of active disease mouse model for pemphigus vulgaris.J Invest Dermatol. 2002; 118: 199-204
- Ultrastructural changes in mice actively producing antibodies to desmoglein 3 parallel those in patients with pemphigus vulgaris.Arch Dermatol Res. 2002; 294: 318-323
- A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris.J Cell Biol. 2001; 153: 823-834
- IgG binds to desmoglein 3 in desmosomes and causes a desmosomal split without keratin retraction in a pemphigus mouse model.J Invest Dermatol. 2004; 122: 1145-1153
- Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies.J Biol Chem. 2006; 281: 7623-7634
- Development of CD4-CD8- abTCR + NK1.1 + T lymphocytes: thymic selection by self antigen.J Immunol. 1996; 157: 4379-4389
- Assessment of splice variant-specific functions of desmocollin 1 in the skin.Mol Cell Biol. 2004; 24: 154-163
- Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3.J Immunol. 2003; 170: 2170-2178
- Demonstration of intra- and extracellular localization of bullous pemphigoid antigen using cryofixation and freeze substitution for postembedding immunoelectron microscopy.Arch Dermatol Res. 1989; 281: 443-448
- The use of silver-enhanced 1-nm gold probes for light and electron microscopic localization of intra- and extracellular antigens in skin.J Histochem Cytochem. 1992; 40: 883-888
- In vivo ultrastructural localization of the desmoglein 3 adhesive interface to the desmosome mid-line.J Invest Dermatol. 2005; 124: 984-989
- Desmoplakin I and desmoplakin II. Purification and characterization.J Biol Chem. 1989; 264: 8310-8318
- The desmoplakin carboxyl terminus coaligns with and specifically disrupts intermediate filament networks when expressed in cultured cells.J Cell Biol. 1992; 116: 1197-1209
- Defining the interactions between intermediate filaments and desmosomes.J Cell Biol. 1998; 141: 1229-1241
- The amino-terminal domain of desmoplakin binds to plakoglobin clusters desmosomal cadherin-plakoglobin complexes.J Cell Biol. 1997; 139: 773-784
- Are desmosomes more then tethers for intermediate filaments?.Nat Rev. 2000; 1: 208-216
- Transmembrane signaling for adhesive regulation of desmosomes and hemidesmosomes, and for cell-cell detachment induced by pemphigus IgG in cultured keratinocytes: involvement of protein kinase C.J Invest Dermatol Symp Proc. 1999; 4: 137-144
- Pemphigus vulgaris-IgG causes a rapid detection of desmoglein 3(Dsg3) from the Triton X-100 soluble pools, leading to the formation of Dsg3-depleted desmosomes in a human squamous carcinoma cell line, DJM-1 cells.J Invest Dermatol. 1999; 112: 67-71
- A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes.Eur J Immunol. 1999; 29: 2233-2240
- A possible role of catenin dyslocalization in pemphigus vulgaris pathogenesis.J Cutan Pathol. 2001; 28: 460-469
- Pemphigus antibody induced phosphorylation of keratinocyte proteins.Autoimmunity (England). 2006; 39: 577-586
- Pemphigus vulgaris IgG directly inhibit desmoglein 3-mediated transinteraction.J Immunol. 2008; 181: 1825-1834
Article info
Publication history
Published online: July 12, 2010
Accepted:
May 17,
2009
Received in revised form:
March 2,
2009
Received:
July 31,
2008
Identification
Copyright
© 2009 Japanese Society for Investigative Dermatology. Published by Elsevier Inc. All rights reserved.
