Pemphigus foliaceus IgG causes dissociation of desmoglein 1–containing junctions without blocking desmoglein 1 transinteraction
Jens Waschke, Paola Bruggeman, Werner Baumgartner, Detlef Zillikens, Detlev Drenckhahn
Jens Waschke, Paola Bruggeman, Werner Baumgartner, Detlef Zillikens, Detlev Drenckhahn
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Research Article Dermatology

Pemphigus foliaceus IgG causes dissociation of desmoglein 1–containing junctions without blocking desmoglein 1 transinteraction

Abstract

Autoantibodies against the epidermal desmosomal cadherins desmoglein 1 (Dsg1) and Dsg3 have been shown to cause severe to lethal skin blistering clinically defined as pemphigus foliaceus (PF) and pemphigus vulgaris (PV). It is unknown whether antibody-induced dissociation of keratinocytes is caused by direct inhibition of Dsg1 transinteraction or by secondary cellular responses. Here we show in an in vitro system that IgGs purified from PF patient sera caused cellular dissociation of cultured human keratinocytes as well as significant release of Dsg1-coated microbeads attached to Dsg-containing sites on the keratinocyte cellular surface. However, cell dissociation and bead release induced by PF-IgGs was not caused by direct steric hindrance of Dsg1 transinteraction, as demonstrated by single molecule atomic force measurements and by laser trapping of surface-bound Dsg1-coated microbeads. Rather, our experiments strongly indicate that PF-IgG–mediated dissociation events must involve autoantibody-triggered cellular signaling pathways, resulting in destabilization of Dsg1-based adhesive sites and desmosomes.

Authors

Jens Waschke, Paola Bruggeman, Werner Baumgartner, Detlef Zillikens, Detlev Drenckhahn

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Figure 4

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Localization of Dsg1, Dsg3, and plakoglobin at cell-to-bead contacts. Ds...
Localization of Dsg1, Dsg3, and plakoglobin at cell-to-bead contacts. Dsg1-coated beads (A–D) and Fc-coated beads (E and F) were immunostained following settlement on HaCaT cells for 30 minutes. Immunostaining for Dsg1 (B) showed localization of Dsg1 at the cell surface underneath most Dsg1-coated beads, which are visualized in A by corresponding phase contrast microscopic image. Note halo-like accumulation of cellular Dsg1 and plakoglobin around the bead attachment sites (arrows in B and D). Similarly, Dsg3 (C) was detected at cell-bead contacts. In contrast, no immunoreactivity for Dsg1 was found underneath Fc-coated beads visualized in a corresponding phase contrast figure (E and F). Scale bar: 10 μm for all panels (n = 5).