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    Soluble Fas Ligand Is Essential for Blister Formation in Pemphigus

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    Author
    Lotti, R; Shu, E; Petrachi, T; Marconi, A; Palazzo, E; Quadri, M; Lin, A; O'Reilly, LA; Pincelli, C
    Date
    2018-02-26
    Source Title
    Frontiers in Immunology
    Publisher
    FRONTIERS MEDIA SA
    University of Melbourne Author/s
    O'Reilly, Lorraine
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
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    Document Type
    Journal Article
    Citations
    Lotti, R., Shu, E., Petrachi, T., Marconi, A., Palazzo, E., Quadri, M., Lin, A., O'Reilly, L. A. & Pincelli, C. (2018). Soluble Fas Ligand Is Essential for Blister Formation in Pemphigus. FRONTIERS IN IMMUNOLOGY, 9 (FEB), https://doi.org/10.3389/fimmu.2018.00370.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/256082
    DOI
    10.3389/fimmu.2018.00370
    Abstract
    Pemphigus is a blistering disease characterized by pemphigus autoantibodies (PVIgG) directed mostly against desmogleins (Dsgs), resulting in the loss of keratinocyte adhesion (acantholysis). Yet, the mechanisms underlying blister formation remain to be clarified. We have shown previously that anti-Fas ligand (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 the activation of caspases prior to Dsg degradation, and anti-FasL Ab prevents acantholysis in cultured keratinocytes. Moreover, the silencing of FasL reduces PVIgG-induced caspase-8 activation and Dsg3 cleavage. Following injection of PVIgG into mice, FasL is upregulated at 1-3 h and is followed by caspase-8-mediated keratinocyte apoptosis, before blister formation. The administration of anti-FasL Ab 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 wild-type (C57BL/6) animals. By 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.

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