Pemphigus foliaceus IgG causes dissociation of desmoglein 1–containing junctions without blocking desmoglein 1 transinteraction
Jens Waschke, … , Detlef Zillikens, Detlev Drenckhahn
Jens Waschke, … , Detlef Zillikens, Detlev Drenckhahn
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3157-3165. https://doi.org/10.1172/JCI23475.
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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 2

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PF-IgG–induced cell dissociation in HaCaT monolayers. HaCaT cells double...
PF-IgG–induced cell dissociation in HaCaT monolayers. HaCaT cells double-stained for F-actin using Alexa-phalloidin (A, D, G, J, M, and P) and Dsg3 (B, E, H, K, N, and Q). In controls, F-actin and the desmosomal cadherin Dsg3 were distributed along cell junctions (A–C). Control IgGs (35 μg/ml, 24 hours) did not affect distribution of Dsg3 (E and F). In contrast, PF1-IgGs (35 μg/ml, 24 hours) induced intercellular gaps (arrows) best seen in the Alexa-phalloidin stain for F-actin (G and I). Note that Dsg3 is still present in cell processes spanning gaps (arrowheads in H). Following immunoabsorption of PF-IgGs by Dsg1-Fc–coated beads, PF2-IgGs (35 μg/ml, 24 hours) had no effect (J–L) whereas large gaps (arrows) were induced by incubation with PF2-IgGs when control absorption was performed with beads coated with VE-cadherin–Fc (VE-Fc) (M–O), indicating requirement of autoantibodies specific for Dsg1 for cell dissociation. Note that the inhibitory monoclonal antibody directed against the extracellular domain of Dsg1 did not induce gaps (P–R). Scale bar: 40 μm for all panels (n = 5). abs., immunoabsorption.