PATHOPHYSIOLOGY OF PEMPHIGUS IN VIVO

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（Dsg 1）。 在寻常型天疱疮（PV）中，自身抗体在仅患有口腔疾病的患者中识别桥粒芯糖蛋白3（Dsg 3）1，在皮肤粘膜受累的患者中识别Dsg 3和Dsg 1 2。 我们已经通过新生小鼠被动转移模型证明了自身抗体在水疱形成中起主要致病作用3。 Dsg 3作为一种粘附分子的重要性得到了证实，当基因工程小鼠与Dsg 3基因的靶向破坏发展典型的寻常天疱疮粘膜皮肤病变4。 疾病易感性与HLADR 4和DR 6基因的强连锁也已建立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起始、疾病的自然病程或潜在的免疫干预。 本研究的目的是通过使用三种不同的策略打破敏感品系小鼠的免疫耐受来建立PV的主动自身免疫模型：1。 目的通过重组人Dsg 3免疫表达人HLA-DRB 1 *0402基因的转基因小鼠，打破免疫耐受。 2. 通过注射来自相同遗传背景的鼠胎儿的幼稚抗原呈递细胞（APC）并用重组人Dsg 3脉冲来破坏小鼠中的免疫耐受。 3. 通过用鼠成纤维细胞免疫来破坏小鼠中的免疫耐受，所述鼠成纤维细胞用全长鼠主要组织相容性复合物（MHC）II类分子和鼠Dsg 3的细胞外部分稳定转染。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，潜在的免疫操纵和免疫治疗。 这在没有活动性疾病模型的情况下是不可能发生的，我们建议通过这些研究开发这种疾病模型。

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.