Innate Immunity in Bullous Pemphigoid

描述(申请人提供)：大疱性类天疱疮(BP)是一种自身免疫性真皮下水泡病，其特征是皮损部位有自身抗体和炎性浸润物。BP自身抗体属于Ig G和Ig E亚型，识别BP180和BP230两种半染色体蛋白。体外和体内研究已经证明，抗BP180自身抗体可以固定补体并具有致病性。NC16A是BP180的胞外区，是致病自身抗体的主要靶点。嗜酸性粒细胞通常很突出，真皮渗出物中还含有中性粒细胞、肥大细胞和淋巴细胞。然而，这些关键的先天免疫参与者的作用仍不清楚。缺乏可用的体内系统是使用患者来源的自身抗体研究BP先天免疫反应的主要障碍。我们实验室目前开发了人源化的BP180小鼠染色(称为NC16A小鼠)，其中小鼠的BP180NC14A结构域被人的BP180NC16A结构域取代。更重要的是，注射了抗BP180自身抗体的新生NC16A小鼠患上了模仿BP关键免疫学特征的皮肤病。这项建议的目的是利用我们新开发的NC16A小鼠模型来研究嗜酸性粒细胞和肥大细胞在BP中的作用。这个项目的总体目标是增加我们对BP先天免疫的了解，以及它如何与先天免疫系统玩家在炎症和自身免疫中的功能有关。在目标1中，我们将确定BP是否需要肥大细胞。目的2研究嗜酸性粒细胞在BP中的作用及与肥大细胞的功能相互作用。在目标3中，我们将研究嗜酸性粒细胞和肥大细胞的蛋白水解酶在BP水泡中的作用。由于这项建议整合了疾病机制研究和临床前试验，预计研究结果将对BP患者的治疗产生重大影响。 公共卫生相关性：大疱性类天疱疮(BP)是最常见且可能致命的自身免疫性水疱病。我们将研究疾病的发展过程，并为更有效的治疗寻找新的靶点。

DESCRIPTION (provided by applicant): Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by autoantibodies and an inflammatory infiltrate at the lesional site. BP autoantibodies belong to IgG and IgE isotypes and recognize two hemidesmosomal proteins, BP180 and BP230. In vitro and in vivo studies have demonstrated that anti- BP180 autoantibodies fix complement and are pathogenic. NC16A, an extracellular domain of BP180, is the primary target of pathogenic autoantibodies. Eosinophils are usually prominent, and the dermal infiltrate also contains neutrophils, mast cells and lymphocytes. However, roles of these key innate immune players remain unknown. Lack of a usable in vivo system is a major obstacle for studies of innate immune responses in BP using patient-derived autoantibodies. Our lab currently developed a humanized BP180 mouse stain (termed NC16A mice), in which the mouse BP180NC14A domain is replaced by the human BP180NC16A domain. More significantly, neonatal NC16A mice injected with anti-BP180 autoantibodies develop skin disease that mimics key immunological features of BP. The objective of this proposal is to study the role of eosinophils and mast cells in BP using our newly developed NC16A mouse model. The overall goal of this project is to increase our understanding of the innate immunity of BP and how it relates to the functions of innate immune system players in inflammation and autoimmunity. In Aim 1, we will determine whether mast cells are required for BP. Aim 2 is to study the role of eosinophils and to determine functional interaction between eosinophils and mast cells in BP. In Aim 3, we will study the role of proteolytic enzymes of eosinophils and mast cells in BP blistering. Since this proposal integrates both disease mechanism studies and preclinical trials, the findings are expected to have a significant impact on the treatment of patients with BP. PUBLIC HEALTH RELEVANCE: Bullous pemphigoid (BP) is the most common and potentially fatal autoimmune blistering disease. We will study the process of the disease development and identify new targets for more effective therapies.