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

天疱疮(P)是一种自身免疫性大疱性疾病，由抗桥粒黏附分子自身抗体引起，桥粒蛋白1(DSG1)用于叶状天疱疮(PF)或Dsg3用于寻常型天疱疮(PV)。这些抗体如何与双链抗体结合导致细胞-细胞分离的机制尚不清楚。角质形成细胞被认为是对细胞外信号的反应，以控制细胞-细胞和细胞-基质连接，就像其他细胞一样。在这方面，我们一直在关注PV-IgG与Dsg3结合所引起的由外向内的信号转导。通过这个项目，我们取得了以下成果。我们发现依赖PV-Ig G激活的蛋白激酶C(PKC)介导纤溶酶原激活剂的分泌(Arch dermatol res 135：1556-1557,1999)，纤溶酶原激活剂受体的表达(J Invest Dermatol symp Proc 4：137-144,1999)，Dsg3的非PKC磷酸化与其降解和与白蛋白的解离相关(EUR免疫29：2233-2240,1999)，以及Dsg3缺陷桥粒的形成(J Invest Dermatol 112：67-71,1999)。此外，我们还发现在桥粒形成之前Dsg3聚集和半桥粒的形成，以及PV-Ig G与这些聚集体的结合导致了PV-Ig G-Dsg3免疫复合体的内吞(Lab Invest 80：1583-1592,2000)。临床应用DSG1，3-EL ISA跟踪PV和PF的临床病程(欧洲皮肤科杂志，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).