Pemphigus pathogenesis: Insights from light and electron microscopy studies

Ena Sokol

    Research output: ThesisThesis fully internal (DIV)

    3385 Downloads (Pure)

    Abstract

    Pemphigus is a life-threatening autoimmune blistering disease caused by antibodies against proteins of desmosomes. Desmosomes are adhesion junctions that interconnect intermediate filament networks of neighboring cells. By targeting transmembrane proteins of desmosomes, desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3), pemphigus autoantibodies induce their clustering and loss of cell-cell adhesion (acantholysis) in the epidermis of the skin and epithelium of the mucosal membranes, which results in blistering. How pemphigus autoantibodies induce blisters is the main research question of this thesis. Skin and mucosa taken from pemphigus patients were analyzed using large scale electron microscopy, named ‘’nanotomy’’ and novel findings are described. The datasets are open source available at www.nanotomy.org. Pemphigus skin was further investigated using an overlay of light and electron microscopy showing that desmoglein clusters are interdigitations between cells in which the amount of Dsg1 in desmosomes is reduced. Lastly antibodies from pemphigus patients were applied to cultured human skin cells, revealing redistribution of the targeted desmogleins in specific patterns. This thesis suggests that loss of cell-cell adhesion in pemphigus occurs due to the depletion of the targeted desmogleins which then cannot be incorporated into the desmosomes. If other desmoglein isoform are not expressed, desmosomes will ‘melt’ away resulting in loss of cell-cell adhesion.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Jonkman, Marcellinus, Supervisor
    • Pas, Hendri, Co-supervisor
    • Giepmans, Ben, Co-supervisor
    • Peters, P.J., Assessment committee, External person
    • Ludwig, R., Assessment committee, External person
    • Heeringa, Peter, Assessment committee
    Award date6-Jan-2016
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-6259-982-6
    Publication statusPublished - 2016

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