Innate Immunity in Bullous Pemphigoid

描述（由申请人提供）：大疱性类天疱疮（BP）是一种自身免疫性表皮下起泡性疾病，以自身抗体和病变部位的炎症浸润为特征。BP自身抗体属于IgG和IgE同型，识别两种半染色体蛋白BP180和BP230。体外和体内研究表明，抗BP180自身抗体固定补体并具有致病性。NC16A是BP180的胞外结构域，是致病性自身抗体的主要靶点。嗜酸性粒细胞通常突出，真皮浸润也含有中性粒细胞、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然未知。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。我们的实验室目前开发了一种人源化BP180小鼠染色（称为NC16A小鼠），其中小鼠BP180NC14A结构域被人类BP180NC16A结构域取代。更重要的是，注射抗bp180自身抗体的新生NC16A小鼠会出现类似BP关键免疫学特征的皮肤病。本研究的目的是利用我们新开发的NC16A小鼠模型研究嗜酸性粒细胞和肥大细胞在BP中的作用。该项目的总体目标是增加我们对BP先天免疫的理解，以及它与炎症和自身免疫中先天免疫系统参与者的功能的关系。在目的1中，我们将确定BP是否需要肥大细胞。目的2是研究嗜酸性粒细胞的作用，并确定嗜酸性粒细胞和肥大细胞在BP中的功能相互作用。在Aim 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起泡中的作用。由于本提案将疾病机制研究和临床前试验相结合，研究结果有望对BP患者的治疗产生重大影响。

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.