PEMPHIGUS AND PEMPHIGOID

天疱疮和类天疱疮

• 批准号: 6286666
• 负责人: Luis A. Diaz
• 金额: $ 32.7万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6286666
• 关键词: Native Americans; autoantibody; autoantigens; autoimmune disorder; clinical research; disease /disorder model; enzyme linked immunosorbent assay; epidermolysis bullosa; epitope mapping; human subject; immunoglobulin G; immunopathology; intercellular connection; keratinocyte; keratosis; laboratory mouse; monoclonal antibody; neutrophil; orphan disease /drug; pemphigus; polymerase chain reaction; surface antigens; tissue /cell culture; vesicular skin disorder

This application represents the competitive continuation of the Merit Award R37-AR32081 that is funded until June 20, 2000. During the last 10 years of funding we have completed several relevant studies on pemphigus vulgaris (PV), non-endemic pemphigus foliaceus (PF), endemic PF [also known as Fogo Selvagem (FS)] and Bullous Pemphigoid (BP) that are summarized as follows: a) we have developed animals models of PV , PF, and FS by passive transfer of patients' IgG, b) we have developed affinity-chromatography procedures to purify autoantibodies from PF, PV, and BP sera, c) we have developed a highly sensitive and specific ELISA to detect PF, PV, and BP autoantibodies using recombinant proteins, d) we have characterized a human settlement with a high prevalence of endemic FS (3 percent) in a Brazilian Indian Reservation, e) we have studied in this reservation 5 FS cases in the pre-clinical stage and several normal controls that exhibit moderate titers of anti-dsg1 IgG autoantibodies, predominantly IgG1. These autoantibodies increased several fold when FS was fully established, and the predominant IgG isotype was IgG4, f) we have been able to clone antigen-specific T cells from peripheral blood of FS patients from this Indian reservation. In addition, g) we mapped the hemidesmosome as the target of BP autoantibodies, h) we discovered and characterized the BP180 antigen as a component of hemidesmosomes, i) we developed the first animal model of BP by passive transfer of anti-BP antibodies. In this grant we hypothesize that in FS anti-dsg1 autoantibodies of the IgG1 and IgG4 subclass may differ in their pathogenicity and epitope-specificity. To test this hypothesis we will isolate and study dsg1-specific IgG1 and IgG4 from FS sera, clone and sequence V genes from B cells of these patients by single cell RT-PCR, develop monoclonal anti-idiotypic antibodies, generate recombinant anti-dsg1 Fabs, and carry out dsg1 epitope mapping studies. Similar studies will be performed with anti-dsg3 autoantibodies in PV. These studies may lead to new therapies for these serious cutaneous autoimmune diseases.

该应用程序代表了竞争的延续 优异奖 R37-AR32081，资助截止日期为 2000 年 6 月 20 日。在过去 10 年中 经过多年的资助，我们已经完成了多项有关天疱疮的相关研究 寻常型天疱疮 (PV)、非地方性落叶型天疱疮 (PF)、地方性 PF [也称为 Fogo Selvagem (FS)] 和大疱性类天疱疮 (BP) 总结如下： a) 我们通过被动转移建立了 PV 、 PF 和 FS 的动物模型 患者的 IgG，b) 我们开发了亲和层析程序 从 PF、PV 和 BP 血清中纯化自身抗体，c) 我们开发了一种高度 使用灵敏且特异的 ELISA 检测 PF、PV 和 BP 自身抗体 重组蛋白，d）我们已经描述了一个具有高 巴西印第安保留地地方性 FS 的流行率（3%），e) 我们 在本保留中研究了 5 个临床前阶段的 FS 病例， 一些正常对照表现出中等滴度的抗 dsg1 IgG 自身抗体，主要是 IgG1。这些自身抗体增加了几倍 当 FS 完全建立且主要 IgG 同型为 IgG4 时，f) 我们 已经能够从 FS 的外周血中克隆抗原特异性 T 细胞 来自这个印第安保留地的病人。此外，g) 我们绘制了 半桥粒作为 BP 自身抗体的靶标，h) 我们发现并且 将 BP180 抗原表征为半桥粒的一个组成部分，i) 我们 通过被动转移抗BP药物，建立了第一个BP动物模型 抗体。 在这项拨款中，我们假设 FS 中 IgG1 的抗 dsg1 自身抗体 和 IgG4 亚类的致病性和表位特异性可能有所不同。到 为了验证这一假设，我们将从中分离并研究 dsg1 特异性 IgG1 和 IgG4 通过单一方法对这些患者的 B 细胞进行 FS 血清、克隆和 V 基因测序 细胞RT-PCR，开发单克隆抗独特型抗体，产生重组 anti-dsg1 Fabs，并进行 dsg1 表位作图研究。类似的研究 将在 PV 中使用抗 dsg3 自身抗体进行。这些研究可能会导致 针对这些严重皮肤自身免疫性疾病的新疗法。