A Dsg3-specific pemphigus autoantibody induces formation of immature desmosomes associated with impaired adhesion.

Authors

Julia Huber, Michael Fuchs, Jens Waschke, Christoph Hudemann, Lukas F Reissig, Thomas Schmitt

Published in

Tissue barriers. Pages 2700483. Jul 10, 2026. Epub Jul 10, 2026.

Abstract

Pemphigus is a severe blistering autoimmune disease in which autoantibodies against the desmosomal cadherins Dsg1 and Dsg3 cause loss of desmosome adhesion. It is hypothesized that this loss of adhesion results from a combination of direct inhibition of cadherin interaction and subsequent downstream signaling events impairing desmosome turnover and maturation. In this study, we combined dissociation assays with super-resolution STED microscopy to investigate desmosome ultrastructural features as markers for turnover and maturation. Immunostaining, super-resolution STimulated Emission Depletion (STED) microscopy, SUper resolution SHadow Imaging (SUSHI), Ca²⁺-depletion-repletion, dispase-based dissociation assay, Western blot analysis. We found that desmosome number, plaque distance, plaque thickness and intercellular widening are reliable parameters correlating with adhesive strength. These parameters, as well as accumulation of Dsg1 at cell borders, also appear to be good delineators for desmosome maturation. E-Cadherin and EGFR incorporation on the other hand occur only at very early stages of desmosome recovery or dependent on other factors and therefore appear to be less reliable indicators. We further show that the Dsg3-specific pemphigus antibody AK23 or AK23 Fab also partially reverted desmosomes to an immature stage. Lastly, we observed that cAMP accelerates whereas Src slows desmosome recovery. This study supports the hypothesis that autoantibodies in pemphigus interfere with desmosome recovery and maturation, which can be reliably investigated using super-resolution microscopy. Considering the current state of the art, detailed investigation of pathways involved in the regulation of desmosome turnover and maturation may provide valuable insights for future treatment strategies.

PMID:
42430447
Bibliographic data and abstract were imported from PubMed on 11 Jul 2026.

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