Waschke Jens, Spindler Volker, Bruggeman Paola, Zillikens Detlef, Schmidt Gudula, Drenckhahn Detlev
Institute of Anatomy and Cell Biology, University of Würzburg, D-97070 Würzburg, Germany.
J Cell Biol. 2006 Dec 4;175(5):721-7. doi: 10.1083/jcb.200605125. Epub 2006 Nov 27.
The autoimmune blistering skin diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are mainly caused by autoantibodies against desmosomal cadherins. In this study, we provide evidence that PV-immunoglobulin G (IgG) and PF-IgG induce skin blistering by interference with Rho A signaling. In vitro, pemphigus IgG caused typical hallmarks of pemphigus pathogenesis such as epidermal blistering in human skin, cell dissociation, and loss of desmoglein 1 (Dsg 1)-mediated binding probed by laser tweezers. These changes were accompanied by interference with Rho A activation and reduction of Rho A activity. Pemphigus IgG-triggered keratinocyte dissociation and Rho A inactivation were p38 mitogen-activated protein kinase dependent. Specific activation of Rho A by cytotoxic necrotizing factor-y abolished all pemphigus-triggered effects, including keratin retraction and release of Dsg 3 from the cytoskeleton. These data demonstrate that Rho A is involved in the regulation of desmosomal adhesion, at least in part by maintaining the cytoskeletal anchorage of desmosomal proteins. This may open the possibility of pemphigus treatment with the epidermal application of Rho A agonists.
自身免疫性水疱性皮肤病寻常型天疱疮（PV）和落叶型天疱疮（PF）主要由针对桥粒钙黏蛋白的自身抗体引起。在本研究中，我们提供证据表明PV免疫球蛋白G（IgG）和PF-IgG通过干扰Rho A信号传导诱导皮肤水疱形成。在体外，天疱疮IgG导致天疱疮发病的典型特征，如人皮肤中的表皮水疱形成、细胞解离以及通过激光镊子检测的桥粒芯糖蛋白1（Dsg 1）介导的结合丧失。这些变化伴随着对Rho A激活的干扰和Rho A活性的降低。天疱疮IgG触发的角质形成细胞解离和Rho A失活依赖于p38丝裂原活化蛋白激酶。细胞毒性坏死因子-y对Rho A的特异性激活消除了所有天疱疮触发的效应，包括角蛋白回缩和桥粒芯糖蛋白3从细胞骨架的释放。这些数据表明，Rho A参与桥粒黏附的调节，至少部分是通过维持桥粒蛋白的细胞骨架锚定。这可能为通过在表皮应用Rho A激动剂治疗天疱疮开辟可能性。
