PATHOPHYSIOLOGY OF PEMPHIGUS IN VIVO

天疱疮体内病理生理学

• 批准号: 6191052
• 负责人: GRANT J ANHALT
• 金额: $ 28.69万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6191052
• 关键词: antigen presenting cell; autoantibody; autoantigens; cadherins; cell adhesion molecules; genetically modified animals; immune tolerance /unresponsiveness; immunopathology; intercellular connection; laboratory mouse; major histocompatibility complex; pathologic process; pemphigus

Pemphigus is an organ specific autoimmune disease. Over the last two decades, the molecular basis and pathophysiology of the disease has been defined as follows. IgG class autoantibodies target molecules of the cadherin supergene family. In pemphigus foliaceus, (PF), the autoantigen is Desmoglein 1 (Dsg1). In pemphigus vulgaris (PV), autoantibodies recognize Desmoglein 3 (Dsg3)1 in patients with just oral disease, and both Dsg3 and Dsg1 in those with mucocutaneous invovlement2. The autoantibodies have been proven by us to play a primary pathogenic role in the blister formation by a passive transfer model in neonatal mice 3. The importance of Dsg3 as an adhesion molecule was confirmed when genetically engineered mice with a targeted disruption of Dsg3 gene developed mucocutaneous lesions typical of pemphigus vulgaris4. The strong linkage of disease susceptibility to HLA DR4 and DR6 genes has also been established5,6,7. However, current models do not allow us to examine the initiation of autoimmunity against these antigens, the natural course of the disease or potential immunologic interventions. The goal of our study is to develop an active autoimmune model of PV by breaking immune tolerance in susceptible strains of mice using three different strategies: 1. To break immune tolerance in transgenic mice expressing the human HLA DR4 gene (HLA-DRB1*0402) by immunization with recombinant human Dsg3. 2. To break immune tolerance in mice by injection with naive antigen presenting cells (APC), derived from murine fetuses of the same genetic background, and pulsed with recombinant human Dsg3. 3. To break immune tolerance in mice by immunizing with murine fibroblasts, stably transfected with full length of murine major histocompatibility complex (MHC) class II molecule and the extracellular portion of murine Dsg3. Pemphigus is a "clean" model of autoimmunity, and is an ideal candidate disease that could allow us to study fundamental mechanisms of autoimmunity, potential immune manipulation and immunologic therapies. This cannot occur in the absence of an active disease model, which we propose to develop by these studies.

天疱疮是一种器官特异性自身免疫性疾病。 在过去的二十年中，该疾病的分子基础和病理生理学定义如下。 IgG 类自身抗体靶向钙粘蛋白超基因家族的分子。 在落叶型天疱疮 (PF) 中，自身抗原是桥粒芯糖蛋白 1 (Dsg1)。 在寻常型天疱疮 (PV) 中，仅患有口腔疾病的患者自身抗体可识别桥粒芯糖蛋白 3 (Dsg3)1，而皮肤粘膜受累患者的自身抗体可识别 Dsg3 和 Dsg12。 我们已通过新生小鼠的被动转移模型证明，自身抗体在水疱形成中发挥主要致病作用3。当靶向破坏Dsg3基因的基因工程小鼠出现寻常型天疱疮4典型的皮肤粘膜病变时，证实了Dsg3作为粘附分子的重要性。 疾病易感性与 HLA DR4 和 DR6 基因之间的紧密联系也已被证实5,6,7。然而，目前的模型不允许我们检查针对这些抗原的自身免疫的启动、疾病的自然病程或潜在的免疫干预措施。 我们研究的目标是通过使用三种不同的策略破坏易感品系小鼠的免疫耐受来开发PV的主动自身免疫模型： 1.通过用重组人Dsg3免疫来破坏表达人HLA DR4基因（HLA-DRB1*0402）的转基因小鼠的免疫耐受。 2. 通过注射来自相同遗传背景的小鼠胎儿的初始抗原呈递细胞 (APC)，并用重组人 Dsg3 进行脉冲，打破小鼠的免疫耐受。 3.通过用稳定转染有全长的鼠主要组织相容性复合物(MHC)II类分子和鼠Dsg3的胞外部分的鼠成纤维细胞进行免疫来打破小鼠的免疫耐受。天疱疮是一种“干净”的自身免疫模型，是一种理想的候选疾病，可以让我们研究自身免疫的基本机制、潜在的免疫操作和免疫疗法。 如果没有活跃的疾病模型，这种情况就不可能发生，我们建议通过这些研究开发该模型。