Super-Resolution Microscopy Reveals Altered Desmosomal Protein Organization in Tissue from Patients with Pemphigus Vulgaris

The Journal of Investigative Dermatology
Sara N StahleyAndrew P Kowalczyk

Abstract

Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease in which autoantibodies (IgG) are directed against the desmosomal cadherin desmoglein 3. To better understand how PV IgG alters desmosome morphology and function in vivo, biopsies from patients with PV were analyzed by structured illumination microscopy, a form of superresolution fluorescence microscopy. In patient tissue, desmosomal proteins were aberrantly clustered and patient IgG colocalized with markers for lipid rafts and endosomes. Additionally, steady-state levels of desmoglein 3 were decreased and desmosomes were reduced in size in patient tissue. Desmosomes at blister sites were occasionally split, with PV IgG decorating the extracellular faces of split desmosomes. Desmosome splitting was recapitulated in vitro by exposing cultured keratinocytes both to PV IgG and to mechanical stress, demonstrating that splitting at the blister interface in patient tissue is due to compromised desmosomal adhesive function. These findings indicate that desmoglein 3 clustering and endocytosis are associated with reduced desmosome size and adhesion defects in tissue of patients with PV. Further, this study reveals that superresolution optical imaging is a powerful app...Continue Reading

Citations

Jun 16, 2016·F1000Research·Eric A SheldenJonathan C R Jones
Apr 6, 2019·Cellular and Molecular Life Sciences : CMLS·Michael FuchsFranziska Vielmuth
Aug 10, 2016·Journal of Cell Science·Sara N StahleyAlexa L Mattheyses
May 12, 2017·Nature Reviews. Disease Primers·Michael KasperkiewiczMasayuki Amagai
Apr 13, 2018·Frontiers in Immunology·Franziska VielmuthJens Waschke
Apr 5, 2018·Frontiers in Immunology·Franziska VielmuthJens Waschke
Mar 23, 2019·Frontiers in Medicine·James M Pullman
Nov 30, 2019·Frontiers in Immunology·Dyah A M OktarinaHendri H Pas
Sep 15, 2020·Frontiers in Molecular Neuroscience·Michihiro IgarashiMotohiro Nozumi
Jul 13, 2018·ELife·Omer ShafrazSanjeevi Sivasankar
Feb 17, 2018·Frontiers in Immunology·Volker Spindler, Jens Waschke
Dec 24, 2019·Frontiers in Immunology·Desalegn Tadesse EguJens Waschke
Mar 24, 2020·The Journal of Investigative Dermatology·Christoph M Hammers, John R Stanley
Aug 6, 2021·The Journal of Investigative Dermatology·Stephanie E ZimmerAndrew P Kowalczyk
Aug 27, 2021·Frontiers in Medicine·Thomas Schmitt, Jens Waschke
Oct 13, 2021·Journal of Cell Science·Judith B FülleChristoph Ballestrem

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Methods Mentioned

BETA
electron microscopy
optical microscopy
super-resolution
light microscopy
ELISA
biopsies
biopsy
imaging techniques
dispase assay
fluorescence microscopy

Software Mentioned

Fiji
SIM
NIS
Elements
MATLAB
JACoP
ImageJ Fiji
ImageJ

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