Molecular regulation of hemidesmosome and pathogenesis of bullous and diskeratotic skin diseases

表皮角质形成细胞通过桥粒相互连接，并通过半桥粒与基底膜连接，从而形成片状结构。半桥粒由180-KD大疱性类天疱疮抗原（BPA）、230-KD BPA和整合素组成。本课题旨在阐明半桥粒分子组装和分解的调控机制，并在细胞连接调控紊乱的基础上阐明水疱和脱角化症的病理机制。1993年，大疱性类天疱疮抗体通过使用抗180-KD BPA、230-KD BPA和α 6、β 4整合素对半膜分子组装和分解的形态模式的影响。结果表明，180-KD BPA汇集在侧质膜上而不与角蛋白丝连接，抗体与抗原结合，所得免疫复合物被内化，从而抑制了半桥粒的分子组装（J Dermatol 21：838，1994，Dermatology 189，suupl 1：46，1994）。此外，我们首次发现佛波酯（TPA）可诱导180-KD BPA磷酸化，而不是230-KD BPA，使其分子量增加1 KD（皮肤病学电子显微镜：Bacic and Clinical Research pp111，1994，Elsevier Science）。研究了抗体与180-KDBPA和130-KDPVA细胞表面抗原结合激活的信号转导方式。天疱疮抗体与其抗原结合后，可通过激活磷脂酶C而使细胞内IP_3和Ca ~（++）含量一过性升高，而大疱性类天疱疮抗体与其抗原结合后则不产生这种效应。这表明两种跨膜连接分子在信号转导中起不同的作用，并且在天疱疮和大疱性类天疱疮之间存在刚毛机制的内在差异（J Invest Dermatol 104：33，1995）。

Epidermal keratinocytes are connected to each other with desmosomes and to basement membrane with hemidesmosomes so as to form a sheet structure. Hemidesmosomes connsist of 180-KD bullous pemphigoid antigen (BPA), 230-KD BPA and integrins. The purposes of this project are to clarity the regulatory mechanisms of assembly and disassembly of hemidesmosomal molecules and to elucidate the pathomechanisms of blistering and diskeratosis on the basis of regulatory disturbance of cell-jucntions. In 1993, effects of bullous pemphigoid antibody on the morphological mode of assembly and disassembly of hemidesmomal molecules by using anti-180-KD BPA,230-KD BPA and alpha6, beta4 integrins. It was shown that 180-KD BPA is pooled on the lateral plasma membrane without being connected to keratin filaments and the antibody binds to the antigen and the resultant immuncomplexes are internalized, so that molecular assembly of hemidesmosomes is in-hibited (J Dermatol 21 : 838,1994, Dermatology 189, suupl 1 : 46,1994). In addition, we revealed for the first time that phosphorylation of 180-KD BPA,but not of 230-KD BPA,can be induced by phorbol ester (TPA) to increase its molecular weight by 1 KD (Electron Microscopy in Dermatology : Bacic and Clinical Research pp111,1994, Elsevier Science).In 1994, the mode of signal transduction activated by the antibody-binding to the cell surface antigens of 180-KD BPA and 130-KD pemphigu s vulgar is antigen (PVA) was studied. The binding of pemphigus antibody to its antigen increased transiently the content of IP_3, and Ca^<++> by activating phospholipase C.However, this response was not exerted by the binding of bullous pemphigoid antibody to its antigen on the cell surface. These suggest that the two transmembrane junctional molecules play different roles in signal transduction and intrinsic differences in bristering mechanisms exist between pemhigus and bullous pemphigoid (J Invest Dermatol 104 : 33,1995).