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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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Bullous impetigo and staphylococcal scalded skin syndrome in humans and mice. A. Patients with bullous impetigo develop superficial flaccid blisters and shiny erosions with scaly crusts. B. Patients with staphylococcal scalded skin syndrome show widespread erosions with characteristic wet-tissue-paper-like wrinkling due to the formation of flaccid blisters. C. Neonatal mice injected with staphylococcal exfoliative toxin develop extensive superficial blisters with a wet-tissue-paper-like wrinkled appearance. D. Histology of the mice shows acantholysis due to loss of cell–cell adhesion in the upper layers of the epidermis. The bar indicates 50 µm.
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fig05: Bullous impetigo and staphylococcal scalded skin syndrome in humans and mice. A. Patients with bullous impetigo develop superficial flaccid blisters and shiny erosions with scaly crusts. B. Patients with staphylococcal scalded skin syndrome show widespread erosions with characteristic wet-tissue-paper-like wrinkling due to the formation of flaccid blisters. C. Neonatal mice injected with staphylococcal exfoliative toxin develop extensive superficial blisters with a wet-tissue-paper-like wrinkled appearance. D. Histology of the mice shows acantholysis due to loss of cell–cell adhesion in the upper layers of the epidermis. The bar indicates 50 µm.

Mentions: Clinically, bullous impetigo commonly begins on any part of the body as small vesicles that enlarge rapidly into superficial flaccid bullae filled with cloudy fluid surrounded by an erythematous rim (Fig. 5A). These bullae rupture easily, leaving shiny erosions with scaly crusts. SSSS begins as erythema, frequently with a prodrome of malaise, low-grade fever, irritability, and tenderness of the skin. The rash progresses to a characteristic wet-tissue-paper-like wrinkling due to the formation of flaccid blisters within 24 to 48 h (Fig. 5B). Subsequent generalized involvement elsewhere on the body occurs, but spares the mucous membranes. Histologically, both bullous impetigo and SSSS are characterized by intraepidermal cleavage in the upper layers of the epidermis, i.e., beneath or within the granular layers. In SSSS, the remainder of the epidermis appears unremarkable without keratinocyte necrosis and the dermis contains no inflammatory cell infiltrates in the fresh lesions. In bullous impetigo, however, the blister cavities become filled with neutrophils and the underlying dermis contains mixed infiltrates of neutrophils and lymphocytes in response to the inflammatory reaction to S. aureus.


Autoimmune and infectious skin diseases that target desmogleins.

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

Bullous impetigo and staphylococcal scalded skin syndrome in humans and mice. A. Patients with bullous impetigo develop superficial flaccid blisters and shiny erosions with scaly crusts. B. Patients with staphylococcal scalded skin syndrome show widespread erosions with characteristic wet-tissue-paper-like wrinkling due to the formation of flaccid blisters. C. Neonatal mice injected with staphylococcal exfoliative toxin develop extensive superficial blisters with a wet-tissue-paper-like wrinkled appearance. D. Histology of the mice shows acantholysis due to loss of cell–cell adhesion in the upper layers of the epidermis. The bar indicates 50 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Bullous impetigo and staphylococcal scalded skin syndrome in humans and mice. A. Patients with bullous impetigo develop superficial flaccid blisters and shiny erosions with scaly crusts. B. Patients with staphylococcal scalded skin syndrome show widespread erosions with characteristic wet-tissue-paper-like wrinkling due to the formation of flaccid blisters. C. Neonatal mice injected with staphylococcal exfoliative toxin develop extensive superficial blisters with a wet-tissue-paper-like wrinkled appearance. D. Histology of the mice shows acantholysis due to loss of cell–cell adhesion in the upper layers of the epidermis. The bar indicates 50 µm.
Mentions: Clinically, bullous impetigo commonly begins on any part of the body as small vesicles that enlarge rapidly into superficial flaccid bullae filled with cloudy fluid surrounded by an erythematous rim (Fig. 5A). These bullae rupture easily, leaving shiny erosions with scaly crusts. SSSS begins as erythema, frequently with a prodrome of malaise, low-grade fever, irritability, and tenderness of the skin. The rash progresses to a characteristic wet-tissue-paper-like wrinkling due to the formation of flaccid blisters within 24 to 48 h (Fig. 5B). Subsequent generalized involvement elsewhere on the body occurs, but spares the mucous membranes. Histologically, both bullous impetigo and SSSS are characterized by intraepidermal cleavage in the upper layers of the epidermis, i.e., beneath or within the granular layers. In SSSS, the remainder of the epidermis appears unremarkable without keratinocyte necrosis and the dermis contains no inflammatory cell infiltrates in the fresh lesions. In bullous impetigo, however, the blister cavities become filled with neutrophils and the underlying dermis contains mixed infiltrates of neutrophils and lymphocytes in response to the inflammatory reaction to S. aureus.

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