Immunopathogenesis of Bullous Pemphigoid

描述(由申请者提供)：大疱性类天疱疮(BP)是一种危及生命的水疱性疾病，其特征是存在表皮下小泡和针对半桥粒蛋白BP180和BP230的补体激活自身抗体。BP自身抗体以Ig G和Ig E为主。人类BP和BP动物模型研究表明，这些疾病的关键致病因素包括对BP180、补体、肥大细胞和中性粒细胞/嗜酸性粒细胞的自身抗体反应。中性粒细胞弹性蛋白酶、基质金属蛋白酶-9和纤溶酶/纤溶酶原系统直接参与基底膜的组织损伤，导致真皮-表皮连接分离。这个项目的长期目标是增加我们对BP的病理生理学和自身免疫的了解，以及它与自身抗体和蛋白水解酶在炎症和自身免疫中的作用的关系。本应用的目的是利用兔抗mBP180抗体被动转移模型和我们新建立的人源化BP180NC16A小鼠模型，研究蛋白水解酶、致病性BP自身抗体的亚型和亚型的作用。目的1利用兔抗mBP180抗体被动转移模型，研究肥大细胞蛋白水解酶的作用。将致病性兔抗mBP180抗体注射到不同肥大细胞蛋白酶缺陷小鼠体内。将确定这些蛋白水解酶对BP180和其他关键细胞外基质成分的降解。目的2在人源化BP180NC16A小鼠中，用hBP180NC16A取代mBP180NC14A，直接检测BP患者血清中自身抗体的致病活性。人BP自身抗体的致病表位和免疫球蛋白亚类也将通过人源化小鼠进行鉴定。目的3是测试抗BP180 IgE自身抗体和嗜酸性粒细胞是否在疾病过程中发挥作用。目的4检测妊娠期疱疹患者抗BP180自身抗体的致病性。这些拟议研究的结果将大大增加我们对疾病机制的理解，并有助于为BP患者开发更具体、更有效、副作用更少的治疗方法。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。对疾病过程的更好理解将导致更有效的治疗。

DESCRIPTION (provided by applicatnt): Bullous pemphigoid (BP) are life-threatening blistering diseases that are characterized by the presence of sub-epidermal vesicles and complement-activating autoantibodies directed against the hemidesmosomal proteins, BP180 and BP230. BP autoantibodies are predominant IgG and IgE. Human BP and BP animal model studies have suggested that the key pathogenic elements of these diseases include autoantibody reactivity to BP180, complement, mast cells, and neutrophils/eosinophils. Neutrophil elastase, MMP-9, and plasmin/plasminogen system are directly involved in tissue injury at the basement membrane, resulting in dermal-epidermal junction separation. The long-term goal of this project is to increase our understanding of the pathophysiology and autoimmunity of BP and how it relates to the functions of autoantibodies and proteinases in inflammation and autoimmunity. The objective of this application is to study role of proteolytic enzymes, isotype and subclass of pathogenic BP autoantibodies using the rabbit anti-mBP180 IgG passive transfer model and our newly developed humanized BP180NC16A mouse model. Aim 1 is to study the role of mast cell proteinases using rabbit anti-mBP180 IgG passive transfer model. Pathogenic rabbit anti-mBP180 IgG antibodies will be injected into mice deficient in different mast cell proteinases. Degradation of BP180 and other key extracellular matrix components by these proteolytic enzymes will be determined. Aim 2 is to directly test the pathogenic activity of autoantibodies from BP patients' sera in humanized BP180NC16A mice, in which mBP180NC14A is replaced with hBP180NC16A. Pathogenic epitopes and IgG subclasses of human BP autoantibodies will also be identified by using the humanized mice. Aim 3 is to test whether anti-BP180 IgE autoantibodies and eosinophils play a part in the disease process. Aim 4 is to test pathogenicity of anti-BP180 autoantibodies from patients with herpes gestationis. Findings from these proposed studies will significantly increase our understanding of the disease mechanisms and help develop more specific and effective and less side-effect therapies for BP patients. Bullous pemphigoid (BP) is the most common and potentially fatal autoimmune blistering disease. Better understanding of the disease process will lead to more effective therapies.