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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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Serological diagnosis of pemphigus with ELISA. Patients with pemphigus foliaceus (PF) have only anti-Dsg1 IgG autoantibodies, but not anti-Dsg3 IgG autoantibodies. Patients with mucosal dominant-type pemphigus vulgaris (PV) have only anti-Dsg3 IgG autoantibodies, but not anti-Dsg1 IgG autoantibodies. PV patients with mucocutaneous lesions have both anti-Dsg1 and anti-Dsg3 IgG autoantibodies. Normal individuals do not have any IgG autoantibodies against Dsg1 or Dsg3.
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fig04: Serological diagnosis of pemphigus with ELISA. Patients with pemphigus foliaceus (PF) have only anti-Dsg1 IgG autoantibodies, but not anti-Dsg3 IgG autoantibodies. Patients with mucosal dominant-type pemphigus vulgaris (PV) have only anti-Dsg3 IgG autoantibodies, but not anti-Dsg1 IgG autoantibodies. PV patients with mucocutaneous lesions have both anti-Dsg1 and anti-Dsg3 IgG autoantibodies. Normal individuals do not have any IgG autoantibodies against Dsg1 or Dsg3.

Mentions: With a diagnosis of suspected pemphigus based on clinical findings, it is important to perform serum tests to identify IgG autoantibodies against cell-surface antigens of keratinocytes or desmogleins. In the diagnosis of pemphigus, ELISA provides a specific, sensitive, and quantitative means of detecting and measuring circulating IgG autoantibodies.28,29) The patient’s serum is tested on ELISA plates precoated with recombinant Dsg1 or Dsg3 proteins produced in the baculovirus expression system. ELISA enables us to serologically distinguish subtypes of pemphigus vulgaris and foliaceus (Fig. 4). In general, if serum is positive against Dsg1 but negative against Dsg3, this suggests a diagnosis of pemphigus foliaceus. Conversely, serum negative against Dsg1 but positive against Dsg3 suggests a diagnosis of mucosal-dominant-type pemphigus vulgaris. Serum positivity against both Dsg1 and Dsg3 suggests a diagnosis of mucocutaneous-type pemphigus vulgaris. Furthermore, ELISA scores show parallel fluctuation with disease activity.22) Thus, ELISA is also useful for monitoring disease activity to plan tapering schedules of corticosteroids and to predict flares or relapses before clinical evidence is noted.


Autoimmune and infectious skin diseases that target desmogleins.

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

Serological diagnosis of pemphigus with ELISA. Patients with pemphigus foliaceus (PF) have only anti-Dsg1 IgG autoantibodies, but not anti-Dsg3 IgG autoantibodies. Patients with mucosal dominant-type pemphigus vulgaris (PV) have only anti-Dsg3 IgG autoantibodies, but not anti-Dsg1 IgG autoantibodies. PV patients with mucocutaneous lesions have both anti-Dsg1 and anti-Dsg3 IgG autoantibodies. Normal individuals do not have any IgG autoantibodies against Dsg1 or Dsg3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Serological diagnosis of pemphigus with ELISA. Patients with pemphigus foliaceus (PF) have only anti-Dsg1 IgG autoantibodies, but not anti-Dsg3 IgG autoantibodies. Patients with mucosal dominant-type pemphigus vulgaris (PV) have only anti-Dsg3 IgG autoantibodies, but not anti-Dsg1 IgG autoantibodies. PV patients with mucocutaneous lesions have both anti-Dsg1 and anti-Dsg3 IgG autoantibodies. Normal individuals do not have any IgG autoantibodies against Dsg1 or Dsg3.
Mentions: With a diagnosis of suspected pemphigus based on clinical findings, it is important to perform serum tests to identify IgG autoantibodies against cell-surface antigens of keratinocytes or desmogleins. In the diagnosis of pemphigus, ELISA provides a specific, sensitive, and quantitative means of detecting and measuring circulating IgG autoantibodies.28,29) The patient’s serum is tested on ELISA plates precoated with recombinant Dsg1 or Dsg3 proteins produced in the baculovirus expression system. ELISA enables us to serologically distinguish subtypes of pemphigus vulgaris and foliaceus (Fig. 4). In general, if serum is positive against Dsg1 but negative against Dsg3, this suggests a diagnosis of pemphigus foliaceus. Conversely, serum negative against Dsg1 but positive against Dsg3 suggests a diagnosis of mucosal-dominant-type pemphigus vulgaris. Serum positivity against both Dsg1 and Dsg3 suggests a diagnosis of mucocutaneous-type pemphigus vulgaris. Furthermore, ELISA scores show parallel fluctuation with disease activity.22) Thus, ELISA is also useful for monitoring disease activity to plan tapering schedules of corticosteroids and to predict flares or relapses before clinical evidence is noted.

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