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，该病的分子基础和病理生理学被定义如下。IgG类自身抗体靶向钙粘蛋白超基因家族分子。在叶状天疱疮（PF）中，自身抗原是粘粒蛋白1 （Dsg1）。在寻常型天疱疮（PV）中，自身抗体在单纯口腔疾病患者中识别desmoglin 3 (Dsg3)1，在粘膜皮肤受损伤患者中识别Dsg3和Dsg1 2。我们已经证实，在新生小鼠的被动转移模型中，自身抗体在水疱形成中起主要致病作用3。当Dsg3基因被靶向破坏的基因工程小鼠出现寻常型天疱疮典型的皮肤粘膜病变时，Dsg3作为粘附分子的重要性得到了证实。疾病易感性与HLA DR4和DR6基因的强关联也已被确立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启动，疾病的自然过程或潜在的免疫干预。我们的研究目的是通过三种不同的策略，通过打破小鼠易感品系的免疫耐受，建立PV的主动自身免疫模型：目的：通过重组人Dsg3免疫破坏表达人HLA- DR4基因（HLA- drb1 *0402）的转基因小鼠的免疫耐受。2. 目的：通过注射具有相同遗传背景的小鼠胚胎的原始抗原提呈细胞（APC），并以重组人Dsg3脉冲来打破小鼠的免疫耐受。3. 通过稳定转染全长鼠主要组织相容性复合体（MHC） II类分子和鼠Dsg3细胞外部分的鼠成纤维细胞免疫小鼠，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来发展活动性疾病模型。

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.