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Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering
Volker Spindler, … , Enno Schmidt, Jens Waschke
Volker Spindler, … , Enno Schmidt, Jens Waschke
Published January 9, 2013
Citation Information: J Clin Invest. 2013;123(2):800-811. https://doi.org/10.1172/JCI60139.
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Research Article Dermatology

Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering

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Abstract

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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Figure 1

TP blocked acantholysis in vivo.

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TP blocked acantholysis in vivo.
TP blocked macroscopic blistering (arro...
TP blocked macroscopic blistering (arrows) when injected into the back skin of neonatal mice (A) or applied topically (B). Processing of cryosections revealed typical suprabasal blistering under conditions of AK23 and PV1-IgG injections, but absence or minor blistering (arrows) under conditions of topical TP treatment (C, upper panels). Lower panels demonstrate proper IgG deposition within the epidermis following injection of AK23 or PV-IgG and absence of staining in control-IgG–injected animals. Dashed lines represent dermal-epidermal junction. Scale bar: 50 μm (inserts, ×2 magnification). Evaluation of blister size in serial sections under conditions of TP application 2 hours prior to Ab injection (D) and 6 hours after Ab injection (E). Serial sections of skin samples were evaluated for cleft length and sorted into a score ranging from 0 to 4 as detailed in Methods. Every data point represents 1 injected animal; higher values indicate stronger blistering. *P < 0.05 Ab injection vs. respective Ab injection + TP.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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