PEMPHIGUS AND PEMPHIGOID

这项申请是“天鹅座和天鹅座”项目的竞争性延续 “类天疱疮”寻求对这些疾病的免疫病理研究的支持 疾病。在上一个资助期完成的项目包括 在寻常型天疱疮(Pv)和叶天疱疮(Pf)中，a) 已经完全定义了PV和PF的动物模型。使用这些模型，我们 已经证明了b)纤溶酶原激活剂和c) 补体激活在棘层松解症发病机制中的作用；d)我们有 证明了PF-IgG4自身抗体和PF Fab‘的致病本质 PF中的片段。E)我们已经鉴定了人类的蛋白质降解片段 与PF和PV自身抗体发生特异性反应的表皮。在……里面 大疱性类天疱疮(BP)我们已经证明：F)BP自身抗体 识别半染色体抗原。G)BP患者的血清与 两个主要的BP抗原(240kD和180kD)和其他较低的相对分子质量。“次要”BP 和h)妊娠疱疹病毒血清与180kD碱基的抗原发生反应。 I)我们最近从角质形成细胞的cDNA中鉴定了两个cdna克隆 与两个主要的BP抗原(180和240kD)相对应的文库。 对编码的融合蛋白的分析表明，180和240kD的融合蛋白 BP抗原确实是不同的半桥粒多肽。数列 分析表明，180kD碱基的抗原含有类胶原蛋白 结构域是一个潜在的基底膜结合部位。自身抗体- 这种相互作用的中介中断可能与水泡有关 在BP患者中形成。 本申请包括旨在继续和推进的研究 对PV、PF和BP免疫发病机制的认识。这将是 通过在分子水平上定义：a)表位 由各自的自身抗体识别，b)性质和关系 “次要”和“主要”BP抗原，c)免疫球蛋白的免疫球蛋白亚类 这些患者的血清中存在自身抗体系统，d) PV和PF自身抗体Fab‘引起棘层松解的机制 通过损害其抗原的黏附功能)，以及e)通过发展 根据表位定位研究结果建立BP动物模型。 我们有信心我们拥有专业知识和实验室设施 继续我们的成功，推动我们对 这些疾病的免疫病理学。产生的数据将是新颖的和 切合实际。

This application is a competitive continuation of the grant "Pemphigus and Pemphigoid" seeking support for studies on the immunopathology of these diseases. Projects accomplished in the previous funding period include the following: In Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF), a) we have fully defined the animal models of PV and PF. Using these models we have demonstrated the minimal role of b) plasminogen activator and c) complement activation in the pathogenesis of acantholysis; d) we have demonstrated the pathogenic nature of PF IgG4 autoantibodies and PF Fab' fragments in PF. e) We have characterized proteolytic fragments from human epidermis which react specifically with PF and PV autoantibodies. In Bullous Pemphigoid (BP) we have demonstrated that: f) BP autoantibodies recognize hemidesmosomal antigens. g) the sera of BP patients react with two "major" BP antigens (240 kD and 180 kD) nad other lower m.w. "minor" BP antigens; and h) herpes gestationis sera react with the 180 kD BP antigen. i) We have recently identified two cDNA clones from a keratinocyte cDNA library corresponding to the two major BP antigens (180 and 240 kD). Analyses of the cDNA-encoded fusion proteins showed that the 180 and 240 kD BP antigens are indeed distinct hemidesmosomal polypeptides. Sequence analysis has revealed that the 180 kD BP antigen contains a collagen-like domain which is a potential basement membrane binding site. Autoantibody- mediated disruption of such an interaction may be relevant to blister formation in BP patients. The present application includes studies designed to continue and advance the knowledge in immunopathogenesis of PV, PF and BP. This will be accomplished by defining at the molecular level: a) the epitopes recognized by the respective autoantibodies, b) the nature and relationship of the "minor" and "major" BP antigens, c) the IgG subclass of the IgG autoantibody systems present int he sera of these patients, d) the mechanisms by which Fab' from PV and PF autoantibodies cause acantholysis by impairing the adhesive function of its antigen), and e) by developing the animal model of BP based on the results of epitope mapping studies. We are confident that we have the expertise and the laboratory facilities to continue our success in advancing our understanding of the immunopathology of these diseases. The data generated will be novel and relevant.