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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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Related in: MedlinePlus

History of pemphigus research. In 1964 Beutner and Jordon discovered that patients with pemphigus have IgG autoantibodies against keratinocytes. In 1991, their target antigens were discovered to be desmogleins (Dsg1 and Dsg3), cadherin-type cell–cell adhesion molecules in desmosomes. Further studies will reveal how T cells and B cells begin to produce harmful autoantibodies in pemphigus patients.
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fig01: History of pemphigus research. In 1964 Beutner and Jordon discovered that patients with pemphigus have IgG autoantibodies against keratinocytes. In 1991, their target antigens were discovered to be desmogleins (Dsg1 and Dsg3), cadherin-type cell–cell adhesion molecules in desmosomes. Further studies will reveal how T cells and B cells begin to produce harmful autoantibodies in pemphigus patients.

Mentions: The term pemphigus stems from the Greek pemphix, meaning blister or bubble, and describes a group of chronic blistering skin diseases in which autoantibodies are directed against the cell surface of keratinocytes, resulting in the loss of cell–cell adhesion of keratinocytes through a process called acantholysis. In 1964, Beutner and Jordon discovered that sera from patients with pemphigus contain circulating IgG autoantibodies directed against the cell surface of keratinocytes.1) The modern history of pemphigus as an autoimmune disease began with this finding (Fig. 1). In the late 1970s to early 1980s, pemphigus autoantibodies were shown to have pathogenic activity in the induction of blister formation in skin organ culture systems as well as by passive transfer of patients’ IgG into neonatal mice.2,3) In the mid- to late 1980s, the target antigens of pemphigus were characterized by immunochemical methods, such as immunoprecipitation and immunoblotting.4,5) In the early 1990s, isolation of cDNA for pemphigus antigens demonstrated that the target antigens in pemphigus are desmogleins.6,7)


Autoimmune and infectious skin diseases that target desmogleins.

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

History of pemphigus research. In 1964 Beutner and Jordon discovered that patients with pemphigus have IgG autoantibodies against keratinocytes. In 1991, their target antigens were discovered to be desmogleins (Dsg1 and Dsg3), cadherin-type cell–cell adhesion molecules in desmosomes. Further studies will reveal how T cells and B cells begin to produce harmful autoantibodies in pemphigus patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: History of pemphigus research. In 1964 Beutner and Jordon discovered that patients with pemphigus have IgG autoantibodies against keratinocytes. In 1991, their target antigens were discovered to be desmogleins (Dsg1 and Dsg3), cadherin-type cell–cell adhesion molecules in desmosomes. Further studies will reveal how T cells and B cells begin to produce harmful autoantibodies in pemphigus patients.
Mentions: The term pemphigus stems from the Greek pemphix, meaning blister or bubble, and describes a group of chronic blistering skin diseases in which autoantibodies are directed against the cell surface of keratinocytes, resulting in the loss of cell–cell adhesion of keratinocytes through a process called acantholysis. In 1964, Beutner and Jordon discovered that sera from patients with pemphigus contain circulating IgG autoantibodies directed against the cell surface of keratinocytes.1) The modern history of pemphigus as an autoimmune disease began with this finding (Fig. 1). In the late 1970s to early 1980s, pemphigus autoantibodies were shown to have pathogenic activity in the induction of blister formation in skin organ culture systems as well as by passive transfer of patients’ IgG into neonatal mice.2,3) In the mid- to late 1980s, the target antigens of pemphigus were characterized by immunochemical methods, such as immunoprecipitation and immunoblotting.4,5) In the early 1990s, isolation of cDNA for pemphigus antigens demonstrated that the target antigens in pemphigus are desmogleins.6,7)

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