Molecular medicine of autoimmune bullous diseases in terms of the signal transduction to regulate the cell adhesion molecules and cytoskeletons

天疱疮（Pemphigus，P）是一种自身免疫性大疱性疾病，由抗桥粒粘附分子（Desmosomal adhesion molecules，Dsg 1）的自身抗体引起，其中Dsg 1代表落叶型天疱疮（Pemphiaceus foliaceus，PF），Dsg 3代表寻常型天疱疮（Pemphigus vulgaris，PV）。这些抗体与Dsgs的结合如何导致细胞-细胞分离的机制仍然未知。角质形成细胞和其他细胞一样，也能对细胞外信号作出反应，控制细胞-细胞和细胞-基质的连接。在这方面，我们一直专注于由PV-IgG与Dsg 3结合引起的由外向内信号传导。通过该项目，我们取得了以下成果。我们发现PV-IgG依赖性激活蛋白激酶C（PKC）介导纤溶酶原激活物的分泌（Arch Dermatol Res 135：1556-1557，1999），纤溶酶原激活物受体的表达（J Invest Dermatol Symp Proc 4：137-144，1999），Dsg 3的PKC非依赖性磷酸化与其降解和从斑珠蛋白解离有关（Eur J Immunol 29：2233-2240，1999）和Dsg 3缺陷桥粒的形成（J Invest Dermatol 112：67-71，1999）。此外，我们显示在桥粒形成之前形成Dsg 3聚集体和半桥粒，并且PV-IgG与这些聚集体的结合引起PV-IgG-Dsg 3免疫复合物的内吞作用（Lab Invest 80：1583-1592，2000）。我们还在临床上使用Dsg 1，3 ELISA来跟踪PV和PF的临床过程（Eur J Dermatol 10：18-21，2000）。

Pemphigus (P) is an autoimmune bullous disease caused by autoantibodies against desmosomal adhesion molecules, desmoglein 1 (Dsg1) for P foliaceus (PF) or Dsg3 for P vulgaris (PV). The mechanisms how the binding of these antibodies to Dsgs leads to cell-cell detachment are still unknown. Keratinocytes are thought to response to the extracellular signals to control cell-cell and cell-matrix junctions as other cells. In this respect, we have been focusing on the outside-in signaling caused by PV-IgG binding to Dsg3. Through this project, we have obtained the following results. We showed PV-IgG-dependent activation of protein kinase C (PKC) mediating the secretion of plasminogen activator (Arch Dermatol Res 135 : 1556-1557, 1999), expression of plasminogen activator receptor (J Invest Dermatol Symp Proc 4 : 137-144, 1999), PKC-independent phosphorylation of Dsg3 associated with its degradation and dissociation from plakoglobin (Eur J Immunol 29 : 2233-2240, 1999), and the formation of Dsg3-deficient desmosomes (J Invest Dermatol 112 : 67-71, 1999). Furthermore, we showed the formation of Dsg3 aggregation and half-desmosomes before desmosome formation and the binding of PV-IgG to these aggregations caused endocytosis of PV-IgG-Dsg3 immune complexes (Lab Invest 80 : 1583-1592, 2000). We also used clinically Dsg1, 3 ELISA to follow the clinical course of PV and PF (Eur J Dermatol 10 : 18-21, 2000).