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）已被证明可有效治疗多种免疫介导的炎症性疾病。已经提出了许多机制来解释IVIG的作用模式。在本申请中，我们建议研究IVIG在自身免疫性起泡性疾病天疱疮和类天疱疮中的保护特性的分子基础。天疱疮和类天疱疮是一组潜在致命的器官特异性自身免疫性疾病。天疱疮的特征在于表皮内水疱和表皮特异性IgG自身抗体。类天疱疮的特征是表皮下水疱和抗基底膜区（BMZ）半桥粒和细胞外基质成分的自身抗体。在这个建议中，我们将集中在三个临床实体：落叶型天疱疮（PF），寻常型天疱疮（PV），大疱性类天疱疮（BP）。我们将使用充分表征的IgG被动转移和这些疾病的主动动物模型来测试一个假设，即输注的WIG通过结合和阻断FcRn（IgG catalysts的保护受体）来预防IgG抗体介导的水疱疾病，这导致加速病原性IgG的清除。在目的1中，我们将确定治疗剂量的IVIG是否阻断实验性PF、PV、BP和MMP中的水泡。在目的2中，我们将确定IVIG在这些疾病模型中的保护性质是否取决于FcRn。我们将用IVIG治疗在FcRn缺陷小鼠中诱导皮肤病。在目的3中，我们将确定IgG Fc片段是否可以替代IVIG和FcRn抑制肽是否具有治疗性。该项目的总体目标是研究WIG在自身抗体介导的疾病中的作用机制，并开发新的疗法来取代目前的免疫抑制治疗，这些治疗会产生严重的副作用。

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.