Immunopathogenesis of Bullous Pemphigoid

描述（由申请人提供）：大疱性类天疱疮（BP）是一种危及生命的水疱性疾病，其特征是表皮下小囊泡的存在和针对半粒染色体蛋白BP180和BP230的补体激活自身抗体。BP自身抗体主要是IgG和IgE。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性。中性粒细胞弹性酶、MMP-9和纤溶酶/纤溶酶原系统直接参与基底膜组织损伤，导致真皮-表皮交界处分离。该项目的长期目标是增加我们对BP的病理生理和自身免疫的理解，以及它与自身抗体和蛋白酶在炎症和自身免疫中的作用的关系。本申请的目的是利用兔抗mbp180 IgG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自身抗体同型和亚类的作用。目的1：利用兔抗mbp180 IgG被动转移模型，研究肥大细胞蛋白酶的作用。将致病性兔抗mbp180 IgG抗体注射到不同肥大细胞蛋白酶缺乏的小鼠体内。这些蛋白水解酶降解BP180和其他关键的细胞外基质成分将被确定。目的2：用hBP180NC16A替代mBP180NC14A，直接检测BP患者血清自身抗体对人源化BP180NC16A小鼠的致病活性。人BP自身抗体的致病表位和IgG亚类也将通过人源化小鼠进行鉴定。目的3是检测抗bp180 IgE自身抗体和嗜酸性粒细胞是否在疾病过程中起作用。目的4：检测妊娠疱疹患者抗bp180自身抗体的致病性。这些研究的发现将大大增加我们对疾病机制的理解，并有助于为BP患者开发更特异性、更有效、副作用更小的治疗方法。大疱性类天疱疮（BP）是最常见和潜在致命的自身免疫性水疱疾病。更好地了解疾病过程将导致更有效的治疗方法。

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.