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Front. Immunol. | doi: 10.3389/fimmu.2018.00370

Soluble Fas Ligand is essential for blister formation in pemphigus

  • 1Dept. of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Italy
  • 2Molecular Genetics of Cancer Division, Walter and Eliza Hall Institute of Medical Research, Australia
  • 3Department of Medical Biology, University of Melbourne, Australia

Pemphigus is a blistering disease characterized by autoantibodies (PVIgG) directed mostly against desmogleins (Dsgs), resulting in loss of keratinocyte adhesion (acantholysis). Yet, the mechanisms underlying blister formation remain to be clarified. We have shown previously that anti-FasL antibody (Ab) prevents PVIgG-induced caspase-8 activation and Dsg cleavage in human keratinocytes, and that sera from pemphigus patients contain abnormally increased levels of FasL. Here, we demonstrate that recombinant FasL induces activation of caspases prior to Dsg degradation, and anti-FasL Ab prevents acantholysis in cultured keratinocytes. Moreover, silencing of FasL reduces PVIgG-induced caspase-8 activation and Dsg3 cleavage. Following injection of PVIgG into mice, FasL is up-regulated at 1-3 hrs and is followed by caspase-8-mediated keratinocyte apoptosis, before blister formation. Administration of anti-FasL antibody after PVIgG injection blocks blister formation in mice. Furthermore, we injected PVIgG into two different gene-targeted mutant mice that selectively lack either secreted soluble FasL (sFasL), FasLΔs/Δs mice, or the membrane-bound form of FasL (mFasL), FasLΔm/Δm mice. After PVIgG treatment, blisters are only visible in FasLΔm/Δm animals, lacking mFasL, but still producing sFasL, similar to WT (C57BL/6) animals. In contrast, a significant decrease in the relative acantholytic area is observed in the FasLΔs/Δs animals. These results demonstrate that soluble FasL plays a crucial role in the mechanisms of blister formation, and blockade of FasL could be an effective therapeutic approach for pemphigus.

Keywords: Pemphigus, Fas Ligand, Apoptosis, Keratinocytes, Autoantibodies, Cell Adhesion, mouse model

Received: 15 Dec 2017; Accepted: 09 Feb 2018.

Edited by:

Takayuki Yoshimoto, Tokyo Medical University, Japan

Reviewed by:

Hiroshi Koga, Department of Dermatology, Kurume University School of Medicine, Japan
Pedro A. Reche, Complutense University of Madrid, Spain  

Copyright: © 2018 Lotti, Shu, Petrachi, Marconi, Palazzo, Quadri, Lin, O'Reilly and Pincelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Carlo Pincelli, University of Modena and Reggio Emilia, Dept. of Surgical, Medical, Dental and Morphological Sciences, Modena, Italy,