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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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Phenotype of the active disease model mice for pemphigus vulgaris. A. The recipient mice with Dsg3−/− splenocytes (upper) were smaller than controls with Dsg3+/− splenocytes (lower) because oral erosions inhibited food intake. B. Some recipient mice with Dsg3−/− splenocytes showed crusted erosions on the paws, where constant pressure is applied. C, D. Recipient mice with Dsg3−/− splenocytes showed in vivo mouse IgG deposition on keratinocyte cell surfaces (C) and suprabasilar acantholysis (D) as observed in patients with pemphigus vulgaris.
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fig07: Phenotype of the active disease model mice for pemphigus vulgaris. A. The recipient mice with Dsg3−/− splenocytes (upper) were smaller than controls with Dsg3+/− splenocytes (lower) because oral erosions inhibited food intake. B. Some recipient mice with Dsg3−/− splenocytes showed crusted erosions on the paws, where constant pressure is applied. C, D. Recipient mice with Dsg3−/− splenocytes showed in vivo mouse IgG deposition on keratinocyte cell surfaces (C) and suprabasilar acantholysis (D) as observed in patients with pemphigus vulgaris.

Mentions: In recipient mice with Dsg3−/− splenocytes, in vivo IgG deposition was found on keratinocyte cell surfaces in stratified squamous epithelia, including the skin and oral and esophageal mucous membranes, as seen in patients with pemphigus vulgaris (Fig. 7C). In these mice, no IgG deposition was found in other tissues, including heart, lung, liver, kidney, stomach, and the small and large intestine. These IgG binding sites correspond to the known tissue distribution of Dsg3. Histological examination of the recipient mice revealed intraepithelial loss of cell–cell adhesion just above the basal layers, i.e., suprabasilar acantholysis, in the buccal mucosa, hard palate, oropharyngeal areas, and the upper part of the esophagus, as seen in human patients (Fig. 7D). These oral erosions likely inhibited food intake, resulting in weight loss (Fig. 7A). Some of the recipient mice developed crusted erosions on the skin around the snout, an area that is normally traumatized by scratching, or paws, where constant pressure is applied (Fig. 7B). Close histological examination revealed that the recipient mice with Dsg3−/− splenocytes also exhibited eosinophilic spongiosis, which is often found in patients with early lesions.48) We also observed patchy hair loss in the recipient mice with Dsg3−/− splenocytes (Fig. 7A). Skin biopsy showed intense IgG deposition on the cell surface of keratinocytes surrounding the telogen hair club. Cleft formation was observed between the cells surrounding the telogen club and the basal layer of the outer root sheath epithelium. In contrast, no phenotypic or pathological changes were observed in recipient mice with Dsg3+/− splenocytes.


Autoimmune and infectious skin diseases that target desmogleins.

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

Phenotype of the active disease model mice for pemphigus vulgaris. A. The recipient mice with Dsg3−/− splenocytes (upper) were smaller than controls with Dsg3+/− splenocytes (lower) because oral erosions inhibited food intake. B. Some recipient mice with Dsg3−/− splenocytes showed crusted erosions on the paws, where constant pressure is applied. C, D. Recipient mice with Dsg3−/− splenocytes showed in vivo mouse IgG deposition on keratinocyte cell surfaces (C) and suprabasilar acantholysis (D) as observed in patients with pemphigus vulgaris.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig07: Phenotype of the active disease model mice for pemphigus vulgaris. A. The recipient mice with Dsg3−/− splenocytes (upper) were smaller than controls with Dsg3+/− splenocytes (lower) because oral erosions inhibited food intake. B. Some recipient mice with Dsg3−/− splenocytes showed crusted erosions on the paws, where constant pressure is applied. C, D. Recipient mice with Dsg3−/− splenocytes showed in vivo mouse IgG deposition on keratinocyte cell surfaces (C) and suprabasilar acantholysis (D) as observed in patients with pemphigus vulgaris.
Mentions: In recipient mice with Dsg3−/− splenocytes, in vivo IgG deposition was found on keratinocyte cell surfaces in stratified squamous epithelia, including the skin and oral and esophageal mucous membranes, as seen in patients with pemphigus vulgaris (Fig. 7C). In these mice, no IgG deposition was found in other tissues, including heart, lung, liver, kidney, stomach, and the small and large intestine. These IgG binding sites correspond to the known tissue distribution of Dsg3. Histological examination of the recipient mice revealed intraepithelial loss of cell–cell adhesion just above the basal layers, i.e., suprabasilar acantholysis, in the buccal mucosa, hard palate, oropharyngeal areas, and the upper part of the esophagus, as seen in human patients (Fig. 7D). These oral erosions likely inhibited food intake, resulting in weight loss (Fig. 7A). Some of the recipient mice developed crusted erosions on the skin around the snout, an area that is normally traumatized by scratching, or paws, where constant pressure is applied (Fig. 7B). Close histological examination revealed that the recipient mice with Dsg3−/− splenocytes also exhibited eosinophilic spongiosis, which is often found in patients with early lesions.48) We also observed patchy hair loss in the recipient mice with Dsg3−/− splenocytes (Fig. 7A). Skin biopsy showed intense IgG deposition on the cell surface of keratinocytes surrounding the telogen hair club. Cleft formation was observed between the cells surrounding the telogen club and the basal layer of the outer root sheath epithelium. In contrast, no phenotypic or pathological changes were observed in recipient mice with Dsg3+/− splenocytes.

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