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Tandem peptide blocks pemphigus vulgaris skin blistering in vivo and identifies a desmoglein receptor function leading to p38MAPK modulation
Author(s) -
Spindler Volker,
Kempf Bettina,
Waschke Jens
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.275.1
Subject(s) - desmoglein 3 , pemphigus , autoantibody , desmoglein 1 , pemphigus vulgaris , desmoglein , keratinocyte , acantholysis , pathogenesis , immunology , medicine , microbiology and biotechnology , chemistry , biology , in vitro , antibody , biochemistry
In the life‐threatening autoimmune disease pemphigus vulgaris, epidermal blisters are caused by autoantibodies primarily targeting the cadherin‐type cell adhesion molecules desmoglein (Dsg) 3 and Dsg1 leading to loss of keratinocyte cohesion. Due to limited deeper insights in disease pathogenesis current therapy is restricted to relatively unspecific long term immunosuppression. Both, direct inhibition of Dsg trans‐interaction as well as altered intracellular signaling likely contribute to loss of cell adhesion. Here, we applied a tandem‐peptide (TP) in vivo consisting of two connected peptide sequences each targeting the Dsg adhesive interface. TP was capable to block autoantibody‐mediated direct interference of Dsg3 transinteraction as revealed by atomic force microscopy and optical trapping. Importantly, it was effective to completely abrogate autoantibody‐mediated skin blistering in mice. Relevant for a possible therapeutic use in patients, TP was effective also when applied topically. In addition, TP blunted autoantibody‐induced activation of p38MAPK, a central signaling pathway in pemphigus pathogenesis. These data indicate that p38MAPK links autoantibody‐induced direct inhibition of Dsg binding to skin blistering. By limiting both loss of Dsg trans‐interaction and subsequent p38MAPK activation, TP may serve as promising treatment option in pemphigus vulgaris. DFG SFB487