The Mechanism of IVIG Action in Pemphigus

描述(由申请人提供)： 大剂量静脉注射免疫球蛋白(IVIG)已被证明是治疗各种免疫介导性炎症性疾病的有效药物。已经提出了许多机制来解释静脉注射免疫球蛋白的作用模式。在这一应用中，我们建议研究IVIG在自身免疫性水泡性疾病天疱疮和类天疱疮中保护作用的分子基础。天疱疮和类天疱疮是一组潜在的致命性器官特异性自身免疫性疾病。天疱疮的特征是表皮内水泡和表皮特异性免疫球蛋白抗体。类天疱疮的特征是基底膜区域(BMZ)的真皮下水泡和自身抗体抗半染色体和细胞外基质成分。在这个方案中，我们将集中在三个临床实体：叶天疱疮(PF)，寻常型天疱疮(PV)和大疱性类天疱疮(BP)。我们将使用针对这些疾病的成熟的免疫球蛋白被动转移和主动动物模型来检验一种假说，即注射假发通过结合和阻断免疫球蛋白分解代谢的保护受体FcRN来预防免疫球蛋白抗体介导的水泡性疾病，从而加速致病免疫球蛋白的清除。在目标1中，我们将确定IVlG的治疗剂量是否能阻断实验性PF、PV、BP和MMP中的水泡。在目标2中，我们将确定IVlG在这些疾病模型中的保护作用是否依赖于FcRN。我们将通过静脉注射免疫球蛋白治疗FcRN基因缺陷的小鼠来诱发皮肤病。在目标3中，我们将确定Ig G Fc片段是否可以替代IVIG，以及FcRN抑制肽是否具有治疗作用。该项目的总体目标是研究假发在自身抗体介导的疾病中的作用机制，并开发新的治疗方法来取代目前具有严重副作用的免疫抑制治疗。

DESCRIPTION (provided by applicant): High-dose intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of a variety of immune-mediated inflammatory diseases. Numerous mechanisms have been proposed to explain the mode of action of IVIG. In this application, we propose to investigate the molecular basis for the protective property of IVIG in the autoimmune blistering diseases pemphigus and pemphigoid. Pemphigus and pemphigoid are a group of potentially fatal organ specific autoimmune diseases. Pemphigus is characterized by intraepidermal blisters and epidermal-specific IgG autoantibodies. Pemphigoid is characterized by subepidermal blisters and autoantibodies against hemidesmosomal and extracellular matrix components in the basement membrane zone (BMZ). In this proposal, we will focus on three clinical entities: pemphigus foliaceus (PF), pemphigus vulgaris (PV), and bullous pemphigoid (BP). We will use well-characterized IgG passive transfer and active animal models for these diseases to test a hypothesis that infused WIG prevents IgG antibody-mediated blistering diseases by binding and blocking FcRn, the protection receptor for IgG catabolism, which leads to accelerated clearance of pathogenic IgG. In Aim 1, we will determine whether therapeutic doses of IVlG block blisters in experimental PF, PV, BP, and MMP. In Aim 2, we will determine whether the protective property of IVlG in these disease models depends on FcRn. We will induce skin disease in FcRn-deficient mice with IVIG treatment. In Aim 3, we will determine whether IgG Fc fragments can replace IVIG and FcRn inhibitory peptides are therapeutic. The overall goal of this project is to study the mechanisms of WIG action in autoantibody-mediated diseases and develop novel therapies to replace current immunosuppressive treatments, which confer severe side effects.