Document Detail


Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering.
MedLine Citation:
PMID:  23298835     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In pemphigus vulgaris, a life-threatening autoimmune skin disease, epidermal blisters are caused by autoantibodies primarily targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion. Due to limited insights into disease pathogenesis, current therapy relies primarily on nonspecific long-term immunosuppression. Both direct inhibition of DSG transinteraction and altered intracellular signaling by p38 MAPK likely contribute to the loss of cell adhesion. Here, we applied a tandem peptide (TP) consisting of 2 connected peptide sequences targeting the DSG adhesive interface that was capable of blocking autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force microscopy and optical trapping. Importantly, TP abrogated autoantibody-mediated skin blistering in mice and was effective when applied topically. Mechanistically, TP inhibited both autoantibody-induced p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retraction, and promoted desmosomal DSG3 oligomerization. These data indicate that p38 MAPK links autoantibody-mediated inhibition of DSG3 binding to skin blistering. By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin filament retraction, which are hallmarks of pemphigus pathogenesis, TP may serve as a promising treatment option.
Authors:
Volker Spindler; Vera Rötzer; Carina Dehner; Bettina Kempf; Martin Gliem; Mariya Radeva; Eva Hartlieb; Gregory S Harms; Enno Schmidt; Jens Waschke
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-09
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  800-11     Citation Subset:  AIM; IM    
Affiliation:
Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität, Munich, Germany.
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MeSH Terms
Descriptor/Qualifier:
Acantholysis / immunology,  pathology,  prevention & control
Administration, Topical
Animals
Animals, Newborn
Autoantibodies / administration & dosage
Cross-Linking Reagents
Desmoglein 3 / administration & dosage,  chemistry*,  immunology*
Humans
Mice
Mice, Inbred BALB C
Microscopy, Atomic Force
Pemphigus / immunology,  metabolism,  pathology,  prevention & control*
Recombinant Proteins / administration & dosage,  chemistry,  immunology
p38 Mitogen-Activated Protein Kinases / metabolism
Chemical
Reg. No./Substance:
0/Autoantibodies; 0/Cross-Linking Reagents; 0/DSG3 protein, human; 0/Desmoglein 3; 0/Recombinant Proteins; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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