Preclinical studies identify non-apoptotic low-level caspase-3 as therapeutic target in pemphigus vulgaris

PloS One
Camille LuyetArnaud Galichet

Abstract

The majority of pemphigus vulgaris (PV) patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis). The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg) 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG), PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice) as well as PV patients' biopsies (n=6). A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP) and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-lev...Continue Reading

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Citations

Nov 26, 2015·Seminars in Immunopathology·Giovanni Di ZenzoLuca Borradori
Apr 10, 2017·The Journal of Investigative Dermatology·Enno SchmidtJens Waschke
Feb 17, 2018·Frontiers in Immunology·Volker Spindler, Jens Waschke
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Aug 31, 2016·Experimental Dermatology·Giovanni Di ZenzoEliane J Muller
Aug 27, 2021·Frontiers in Medicine·Thomas Schmitt, Jens Waschke

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Methods Mentioned

BETA
electron microscopy
biopsy
biopsies
immunoprecipitation
electrophoresis
FACS
flow cytometry

Software Mentioned

ImageJ
NCSS

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