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Autoimmune and infectious skin diseases that target desmogleins.

Amagai M - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Bottom Line: Dsg2 is expressed in all tissues possessing desmosomes, including simple epithelia and myocardia, and mutations in this gene are responsible for arrhythmogenic right ventricular cardiomyopathy/dysplasia.Dsg4 plays an important adhesive role mainly in hair follicles, and Dsg4 mutations cause abnormal hair development.Further investigation of desmoglein molecules will continue to provide insight into the unsolved pathophysiological mechanisms of diseases and aid in the development of novel therapeutic strategies with minimal side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan. amagai@sc.itc.keio.ac.jp

ABSTRACT
Desmosomes are intercellular adhesive junctions of epithelial cells that contain two major transmembrane components, the desmogleins (Dsg) and desmocollins (Dsc), which are cadherin-type cell-cell adhesion molecules and are anchored to intermediate filaments of keratin through interactions with plakoglobin and desmoplakin. Desmosomes play an important role in maintaining the proper structure and barrier function of the epidermis and mucous epithelia. Four Dsg isoforms have been identified to date, Dsg1-Dsg4, and are involved in several skin and heart diseases. Dsg1 and Dsg3 are the two major Dsg isoforms in the skin and mucous membranes, and are targeted by IgG autoantibodies in pemphigus, an autoimmune disease of the skin and mucous membranes. Dsg1 is also targeted by exfoliative toxin (ET) released by Staphylococcus aureus in the infectious skin diseases bullous impetigo and staphylococcal scalded skin syndrome (SSSS). ET is a unique serine protease that shows lock and key specificity to Dsg1. Dsg2 is expressed in all tissues possessing desmosomes, including simple epithelia and myocardia, and mutations in this gene are responsible for arrhythmogenic right ventricular cardiomyopathy/dysplasia. Dsg4 plays an important adhesive role mainly in hair follicles, and Dsg4 mutations cause abnormal hair development. Recently, an active disease model for pemphigus was generated by a unique approach using autoantigen-deficient mice that do not acquire tolerance against the defective autoantigen. Adoptive transfer of Dsg3(-/-) lymphocytes into mice expressing Dsg3 induces stable anti-Dsg3 IgG production with development of the pemphigus phenotype. This mouse model is a valuable tool with which to investigate immunological mechanisms of harmful IgG autoantibody production in pemphigus. Further investigation of desmoglein molecules will continue to provide insight into the unsolved pathophysiological mechanisms of diseases and aid in the development of novel therapeutic strategies with minimal side effects.

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Molecular structure of the pemphigus antigens. The extracellular (EC) region has four cadherin repeats, which have calcium-binding motifs. The intracellular cadherin-specific (ICS) domain is well conserved among cadherins and is responsible for interactions with β-catenin and plakoglobin. Desmogleins have their own unique sequences (repeating unit domain or RUD) of repeats of 29 ± 1 residues (arrowheads). Each desmocollin isotype has two products (a and b) derived from alternatively spliced transcripts of a single gene. Boxes with the same color have similarities in their amino acid sequences. IA, intracellular anchor domain; IPL, intracellular proline-rich linker; DTD, desmoglein-specific terminal domain.
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fig03: Molecular structure of the pemphigus antigens. The extracellular (EC) region has four cadherin repeats, which have calcium-binding motifs. The intracellular cadherin-specific (ICS) domain is well conserved among cadherins and is responsible for interactions with β-catenin and plakoglobin. Desmogleins have their own unique sequences (repeating unit domain or RUD) of repeats of 29 ± 1 residues (arrowheads). Each desmocollin isotype has two products (a and b) derived from alternatively spliced transcripts of a single gene. Boxes with the same color have similarities in their amino acid sequences. IA, intracellular anchor domain; IPL, intracellular proline-rich linker; DTD, desmoglein-specific terminal domain.

Mentions: Molecular cloning of cDNA encoding pemphigus antigens has indicated that IgG autoantibodies from patients recognize desmogleins (Dsg), which are cadherin-type cell–cell adhesion molecules found in the adhering junctions, the desmosomes6,7) (Fig. 3). Cadherins are a family of calcium-dependent cell–cell adhesion molecules that play important roles in the formation and maintenance of complex tissue integrity.12) The cadherins are divided into two major subgroups based on sequence similarity, i.e., the classic cadherins (e.g., E-, P-, N-cadherins) and the desmosomal cadherins (desmogleins and desmocollins). All members of the cadherin family contain conserved repeated amino-acid sequences (cadherin repeats) with calcium-binding motifs in their extracellular domains. When classic cadherins were introduced by gene transfection into nonadhesive mouse fibroblast L cells, the cells acquired strong cell adhesion activity.13) Furthermore, following transfection with different cadherins, cells expressing identical cadherin types bound to each other, indicating that the classic cadherins mediate homophilic-type interactions.14) Cadherins require their well-conserved cytoplasmic domains to associate with plaque proteins, α-catenin, β-catenin, and plakoglobin, which mediate and regulate binding to the cytoskeleton network. As a consequence of these interactions, cadherins achieve strong cell–cell adhesion with resultant morphological changes of the cells. In contrast, calcium-independent cell adhesion molecules, such as the immunoglobulin superfamily, mediate simple molecular interactions and do not involve morphological changes of cells. The “cell adhesion zipper” model has been proposed as a structural basis of cell adhesion mediated by classic cadherins.15) Cadherin molecules form a dimer as a functional unit, and each individual strand dimer interacts with opposing strand dimers on another cell through an adhesion interface of the N-terminal domain (EC1).


Autoimmune and infectious skin diseases that target desmogleins.

Amagai M - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Molecular structure of the pemphigus antigens. The extracellular (EC) region has four cadherin repeats, which have calcium-binding motifs. The intracellular cadherin-specific (ICS) domain is well conserved among cadherins and is responsible for interactions with β-catenin and plakoglobin. Desmogleins have their own unique sequences (repeating unit domain or RUD) of repeats of 29 ± 1 residues (arrowheads). Each desmocollin isotype has two products (a and b) derived from alternatively spliced transcripts of a single gene. Boxes with the same color have similarities in their amino acid sequences. IA, intracellular anchor domain; IPL, intracellular proline-rich linker; DTD, desmoglein-specific terminal domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108298&req=5

fig03: Molecular structure of the pemphigus antigens. The extracellular (EC) region has four cadherin repeats, which have calcium-binding motifs. The intracellular cadherin-specific (ICS) domain is well conserved among cadherins and is responsible for interactions with β-catenin and plakoglobin. Desmogleins have their own unique sequences (repeating unit domain or RUD) of repeats of 29 ± 1 residues (arrowheads). Each desmocollin isotype has two products (a and b) derived from alternatively spliced transcripts of a single gene. Boxes with the same color have similarities in their amino acid sequences. IA, intracellular anchor domain; IPL, intracellular proline-rich linker; DTD, desmoglein-specific terminal domain.
Mentions: Molecular cloning of cDNA encoding pemphigus antigens has indicated that IgG autoantibodies from patients recognize desmogleins (Dsg), which are cadherin-type cell–cell adhesion molecules found in the adhering junctions, the desmosomes6,7) (Fig. 3). Cadherins are a family of calcium-dependent cell–cell adhesion molecules that play important roles in the formation and maintenance of complex tissue integrity.12) The cadherins are divided into two major subgroups based on sequence similarity, i.e., the classic cadherins (e.g., E-, P-, N-cadherins) and the desmosomal cadherins (desmogleins and desmocollins). All members of the cadherin family contain conserved repeated amino-acid sequences (cadherin repeats) with calcium-binding motifs in their extracellular domains. When classic cadherins were introduced by gene transfection into nonadhesive mouse fibroblast L cells, the cells acquired strong cell adhesion activity.13) Furthermore, following transfection with different cadherins, cells expressing identical cadherin types bound to each other, indicating that the classic cadherins mediate homophilic-type interactions.14) Cadherins require their well-conserved cytoplasmic domains to associate with plaque proteins, α-catenin, β-catenin, and plakoglobin, which mediate and regulate binding to the cytoskeleton network. As a consequence of these interactions, cadherins achieve strong cell–cell adhesion with resultant morphological changes of the cells. In contrast, calcium-independent cell adhesion molecules, such as the immunoglobulin superfamily, mediate simple molecular interactions and do not involve morphological changes of cells. The “cell adhesion zipper” model has been proposed as a structural basis of cell adhesion mediated by classic cadherins.15) Cadherin molecules form a dimer as a functional unit, and each individual strand dimer interacts with opposing strand dimers on another cell through an adhesion interface of the N-terminal domain (EC1).

Bottom Line: Dsg2 is expressed in all tissues possessing desmosomes, including simple epithelia and myocardia, and mutations in this gene are responsible for arrhythmogenic right ventricular cardiomyopathy/dysplasia.Dsg4 plays an important adhesive role mainly in hair follicles, and Dsg4 mutations cause abnormal hair development.Further investigation of desmoglein molecules will continue to provide insight into the unsolved pathophysiological mechanisms of diseases and aid in the development of novel therapeutic strategies with minimal side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan. amagai@sc.itc.keio.ac.jp

ABSTRACT
Desmosomes are intercellular adhesive junctions of epithelial cells that contain two major transmembrane components, the desmogleins (Dsg) and desmocollins (Dsc), which are cadherin-type cell-cell adhesion molecules and are anchored to intermediate filaments of keratin through interactions with plakoglobin and desmoplakin. Desmosomes play an important role in maintaining the proper structure and barrier function of the epidermis and mucous epithelia. Four Dsg isoforms have been identified to date, Dsg1-Dsg4, and are involved in several skin and heart diseases. Dsg1 and Dsg3 are the two major Dsg isoforms in the skin and mucous membranes, and are targeted by IgG autoantibodies in pemphigus, an autoimmune disease of the skin and mucous membranes. Dsg1 is also targeted by exfoliative toxin (ET) released by Staphylococcus aureus in the infectious skin diseases bullous impetigo and staphylococcal scalded skin syndrome (SSSS). ET is a unique serine protease that shows lock and key specificity to Dsg1. Dsg2 is expressed in all tissues possessing desmosomes, including simple epithelia and myocardia, and mutations in this gene are responsible for arrhythmogenic right ventricular cardiomyopathy/dysplasia. Dsg4 plays an important adhesive role mainly in hair follicles, and Dsg4 mutations cause abnormal hair development. Recently, an active disease model for pemphigus was generated by a unique approach using autoantigen-deficient mice that do not acquire tolerance against the defective autoantigen. Adoptive transfer of Dsg3(-/-) lymphocytes into mice expressing Dsg3 induces stable anti-Dsg3 IgG production with development of the pemphigus phenotype. This mouse model is a valuable tool with which to investigate immunological mechanisms of harmful IgG autoantibody production in pemphigus. Further investigation of desmoglein molecules will continue to provide insight into the unsolved pathophysiological mechanisms of diseases and aid in the development of novel therapeutic strategies with minimal side effects.

Show MeSH
Related in: MedlinePlus