PEMPHIGUS AND PEMPHIGOID

天疱疮和类天疱疮

• 批准号: 2442790
• 负责人: Luis A. Diaz
• 金额: $ 26.94万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442790
• 关键词: autoantibody; autoantigens; autoimmune disorder; basement membrane; chimeric proteins; complement; complement pathway; complementary DNA; disease /disorder model; epidermolysis bullosa; epitope mapping; guinea pigs; hairless mouse; human subject; hybridomas; immunochemistry; immunoglobulin G; keratinocyte; laboratory mouse; laboratory rabbit; monoclonal antibody; neutrophil; orphan disease /drug; pemphigus; plasminogen activator; surface antigens; tissue /cell culture; vesicular skin disorder

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.

该申请是“天疱疮和 类天疱疮”寻求对这些疾病的免疫病理学研究的支持 疾病。 上一资助期间完成的项目包括 以下：对于寻常型天疱疮 (PV) 和落叶型天疱疮 (PF)，a) 我们 完整定义了PV和PF的动物模型。 使用这些模型我们 已证明 b) 纤溶酶原激活剂和 c) 的作用最小 棘层松解症发病机制中的补体激活； d) 我们有 证明了 PF IgG4 自身抗体和 PF Fab' 的致病性质 PF 中的碎片。 e) 我们已经表征了来自人类的蛋白水解片段 表皮与 PF 和 PV 自身抗体发生特异性反应。 在 大疱性类天疱疮 (BP) 我们已经证明： f) BP 自身抗体 识别半桥粒抗原。 g) BP患者的血清与 两种“主要”BP 抗原（240 kD 和 180 kD）以及其他较低分子量。 “轻微”血压 抗原； h) 妊娠疱疹血清与 180 kD BP 抗原反应。 i) 我们最近从角质形成细胞 cDNA 中鉴定出两个 cDNA 克隆 对应于两种主要 BP 抗原（180 和 240 kD）的文库。 对 cDNA 编码的融合蛋白的分析表明，180 和 240 kD BP抗原确实是不同的半桥粒多肽。 顺序 分析表明 180 kD BP 抗原含有胶原蛋白样 结构域是一个潜在的基底膜结合位点。 自身抗体- 这种相互作用的介导破坏可能与水泡有关 BP患者的形成。 本申请包括旨在继续和推进的研究 PV、PF 和 BP 免疫发病机制的知识。 这将是 通过在分子水平上定义来完成：a) 表位 被各自的自身抗体识别，b) 性质和关系 “次要”和“主要”BP 抗原，c) IgG 的 IgG 亚类 这些患者的血清中存在自身抗体系统，d) PV 和 PF 自身抗体中的 Fab' 引起棘层松解的机制 通过损害其抗原的粘附功能），以及 e）通过开发 基于表位作图研究结果的BP动物模型。 我们相信我们拥有专业知识和实验室设施 继续成功地增进我们对 这些疾病的免疫病理学。 生成的数据将是新颖的并且 相关的。