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Egu, Desalegn Tadesse
Fuchs, Michael Tobias
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AbstractAutoantibodies against desmoglein (Dsg) 1 and Dsg3 primarily cause blister formation in the autoimmune disease pemphigus vulgaris (PV). Src was proposed to contribute to loss of keratinocyte cohesion. However, the role and underlying mechanisms are unclear and were studied here. In keratinocytes, cell cohesion in response to autoantibodies was reduced in Src-dependent manner by two patient-derived PV-IgG fractions as well as by AK23 but not by a third PV-IgG fraction, although Src was activated by all autoantibodies. Loss of cell cohesion was progredient in a timeframe of 24 h and AK23, similar to PV-IgG, interfered with reconstitution of cell cohesion after Ca2+-switch, indicating that the autoantibodies also interfered with desmosome assembly. Dsg3 co-localized along cell contacts and interacted with the Src substrate cortactin. In keratinocytes isolated from cortactin-deficient mice, cell adhesion was impaired and Src-mediated inhibition of AK23-induced loss of cell cohesion for 24 h was significantly reduced compared to wild-type (wt) cells. Similarly, AK23 impaired reconstitution of cell adhesion was Src-dependent only in the presence of cortactin. Likewise, Src inhibition significantly reduced AK23-induced skin blistering in wt but not cortactin-deficient mice. These data suggest that the Src-mediated long-term effects of AK23 on loss of cell cohesion and skin blistering are dependent on cortactin-mediated desmosome assembly. However, in human epidermis PV-IgG-induced skin blistering and ultrastructural alterations of desmosomes were not affected by Src inhibition, indicating that Src may not be critical for skin blistering in intact human skin, at least when high levels of autoantibodies targeting Dsg1 are present.
CitationFront Immunol. 2019 Apr 4;10:626. doi: 10.3389/fimmu.2019.00626. eCollection 2019.
AffiliationHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
JournalFrontiers in Immunology
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- Creative Commons
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- Inhibition of p38MAPK signalling prevents epidermal blistering and alterations of desmosome structure induced by pemphigus autoantibodies in human epidermis.
- Authors: Egu DT, Walter E, Spindler V, Waschke J
- Issue date: 2017 Dec
- Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus.
- Authors: Walter E, Vielmuth F, Rotkopf L, Sárdy M, Horváth ON, Goebeler M, Schmidt E, Eming R, Hertl M, Spindler V, Waschke J
- Issue date: 2017 Jun 15
- A new ex vivo human oral mucosa model reveals that p38MAPK inhibition is not effective in preventing autoantibody-induced mucosal blistering in pemphigus.
- Authors: Egu DT, Sigmund AM, Schmidt E, Spindler V, Walter E, Waschke J
- Issue date: 2020 Apr
- Keratin Retraction and Desmoglein3 Internalization Independently Contribute to Autoantibody-Induced Cell Dissociation in Pemphigus Vulgaris.
- Authors: Schlögl E, Radeva MY, Vielmuth F, Schinner C, Waschke J, Spindler V
- Issue date: 2018
- ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation.
- Authors: Radeva MY, Walter E, Stach RA, Yazdi AS, Schlegel N, Sarig O, Sprecher E, Waschke J
- Issue date: 2019