Molecular function and signaling in regulation of desmosomal adhesion : effects of pemphigus IgG

天疱疮(P)是一种自身免疫性大疱性疾病，由于抗桥粒黏附分子自身抗体引起桥粒破坏，寻常型天疱疮(PV)的桥粒蛋白3(Dsg3)或寻常型天疱疮(PV)的DSG1。Pf)。目前尚不清楚PV-Ig G与桥粒蛋白结合后是如何诱发水泡的。本研究的目的是从PV-Ig G结合引起的外向内信号转导和控制桥粒粘连的角度，阐明PV-Ig G诱导水泡形成的机制。我们先前已经证明，PV-Ig G引起蛋白激酶C的激活，介导纤溶酶原激活物(UPA)的分泌、uPA受体(UPAR)的表达，以及与其降解和解离相关的Dsg3的磷酸化。在本研究中，我们通过使用uPAR抑制剂(Gun Exp Dermatol 26：289-295,2001)的抑制实验揭示了uPAR在水泡中的作用，并证明PV-IgG结合不会引起桥粒粘连的空间障碍(J Invest Dermatol 117：406,2001)。此外，我们还发现，在Dsg3-ELISA滴度降至正常范围之前，临床症状就消失了(2003年大疱性疾病研究俱乐部第23届年会)。我们还介绍了PV-IgG对其他桥粒分子(桥粒、桥粒)影响的实验结果(Clin.Exp Dermatol 27：684-690,2002，Arch dermatol res 295：S17-123,2003)，并展示了乙酰胆碱受体在角质形成细胞的细胞-细胞黏附中的作用(Life Science 72：208 1-2085,2003，Exp Cell RES 2004，出版中)。最近，我们发表了PV-Ig G和甲基强的松林对角质形成细胞的相互作用的新结果(J Biol Chem279：2132-2146,2004)。关于角蛋白细胞骨架和大疱性表皮松解症，我们发现了两种新的突变类型和一种新的临床类型，这种疾病是由一种新的移码和延迟终止密码子突变引起的(J Dermatol 29：136-145,2002，J Invest Dermatol 121：482-485,2003)。

Pemphigus (P) is an autoimmune bullous disease caused by disruption of desmosomes due to autoantibodies against desmosomal adhesion molecules, desmoglein 3 (Dsg3) for P vulgaris (PV) or Dsg1 for. P foliaceus (PF). It is yet unknown how blisters are induced after PV-IgG bound to desmogleins. The aim of this study is to elucidate the mechanisms of PV-IgG-induced blistering in terms of outside-in signaling caused by PV-IgG binding and control desmosome adhesion. We have previously showed that PV-IgG causes activation of protein kinase C, mediating the secretion of plasminogen activator (uPA), expression of uPA receptor (uPAR), and phosphorylation of Dsg3 associated with its degradation and dissociation from plakoglobin. In the present study, we revealed the involvement of uPAR in blistering by inhibition experiments using uPAR inhibitors (Gun Exp Dermatol 26: 289-295, 2001), and demonstrated that PV-IgG-binding did not cause steric hindrance of desmosome adhesion (J Invest Dermatol 117: 406, 2001). In addition, we showed that clinical symptoms disappear before the titers of Dsg3-ELISA decreased down to normal range (The 23^<rd> Annual Meeting of Bullous Disease Research Club, 2003). We also presented experimental results on the effects of PV-IgG on the other desmosomal molecules (desmocollins, desmoplakins) (Clin.Exp Dermatol 27 : 684-690, 2002, Arch Dermatol Res 295 : s17-123, 2003), and showed the involvement of acetylcholine receptor function in cell-cell adhesion in keratinocytes (Life Science 72 : 208 1-2085, 2003, Exp Cell Res 2004, in press). Recently, we published new results that PV-IgG and methylprednisoline exhibit reciprocal effects on keratinocytes (J Biol Chem279 : 2132-2146, 2004). Regarding the keratin cytoskeleton and epidermolysis bullosa, we found two new types of mutation and a new clinical type of this diseases caused by a new frame-shift and delayed termination codon mutation (J Dermatol 29 : 136-145, 2002, J Invest Dermatol 121: 482-485, 2003).