PEMHIGUS AND PEMPHIGOID

天疱疮和类天疱疮

• 批准号: 3481558
• 负责人: Luis A. Diaz
• 金额: $ 23.06万
• 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 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3481558
• 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.

该申请是赠款“ Pemphigus和 幽灵“寻求支持有关这些免疫病理学的研究 疾病。 在上一个资金期间完成的项目包括 以下：在Pemphigus dulgaris（PV）和Pemphigus foliceus（PF）中，a）我们 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）的作用最小 在棘链解的发病机理中的补体激活； D）我们有 证明了PF IgG4自身抗体和PF Fab的致病性质 pf中的片段。 e）我们表征了人类的蛋白水解片段 表皮与PF和PV自身抗体特别反应。 在 大胆的幽灵（BP）我们已经证明：f）bp自动抗体 识别半底剂抗原。 g）BP患者的血清与 两个“主要” BP抗原（240 kD和180 kD）NAD其他下部M.W. “小” BP 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鉴定了两个cDNA克隆 对应于两个主要BP抗原（180和240 KD）的库。 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Hemidesmosmal多肽。 顺序 分析表明，180 kD BP抗原包含胶原蛋白样 域是一个潜在的地下膜结合位点。 自身抗体 - 这种相互作用的介导的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进步的研究 PV，PF和BP的免疫致病发生知识。 这将是 通过在分子级定义来完成：a）表位 被各自的自身抗体认可，b）性质和关系 “次要”和“主要” bp抗原，c）IgG的IgG子类 自身抗体系统呈现这些患者的血清，d） 来自PV和PF自身抗体引起的牙糖液的机制 通过损害其抗原的粘附功能），并通过开发e） BP的动物模型基于表位图研究的结果。 我们相信我们拥有专业知识和实验室设施 继续我们成功地促进我们对 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。