Eosinophils in Bullous Pemphigoid

大疱性类天疱疮中的嗜酸性粒细胞

基本信息

批准号：
10198769
负责人：
Zhi Liu
金额：
$ 36.76万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-24 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198769
关键词：
Adult Animal Model Applications Grants Autoantibodies Autoimmune Autoimmunity Binding Biological Markers Bulla Bullous Pemphigoid CC chemokine receptor 3 Cells Characteristics Chemotactic Factors Chymase Complement Data Dermal Development Disease Eotaxin Extracellular Domain Gelatinase B Goals Homologous Gene Human IgE IgE Receptors IgG autoantibodies Immune Immunoglobulin G In Vitro Infiltration Inflammation Inflammatory Infiltrate Innate Immune System Lesion Liquid substance Lymphocyte Mediating Modeling Mouse Strains Mus Natural Immunity Neutrophil Infiltration Participant Patients Peptide Hydrolases Positioning Attribute Proteins Research Resistance Role Serum Site Skin Skin Tissue Stains Study models Testing Translating cell type disease mechanisms study effective therapy eosinophil eotaxin receptor humanized mouse in vivo innate immune function keratinocyte macrophage mast cell mouse model neutrophil preclinical study preclinical trial recruit skin disorder tissue injury

项目摘要

Project Summary 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. These autoantibodies mainly target the NC16A extracellular domain of BP180. The dermal infiltrate contains eosinophils, neutrophils, mast cells, macrophage and lymphocytes, with eosinophils being the predominant cell type. The roles of anti-BP180 IgG autoantibodies and neutrophils in BP have been extensively investigated. In vitro and in vivo studies have demonstrated that anti-BP180 NC16A IgG autoantibodies fix complement, recruit neutrophils and cause BP-like blisters. However, roles of anti-BP180 IgE and eosinophils in BP remain largely unknown. Lack of a suitable animal model is a major obstacle for studies of IgE and eosinophils because human IgE do not recognize mouse IgE receptors. Our lab currently developed a double humanized mouse stain (termed hFcεRI/NC16A mice), in which the human NC16A domain replaced the mouse counterpart NC14A domain and human FcεRI are expressed on eosinophils and mast cells. More significantly, adult hFcεRI/NC16A mice injected with anti- NC16A IgE autoantibodies from BP patients develop BP skin disease that required eosinophils and mast cells. The objective of this proposal is to study the role of eosinophils and mast cells in BP using our newly developed hFcεRI/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 this grant proposal, we will determine how eosinophils are recruited and functionally interact with mast cells (Aims 1 and 2). Proteolytic enzymes from these innate immune cells are critical for skin tissue injury, therefore, we will translate our animal model findings to human BP (Aim 3). 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.

项目概要大疱性类天疱疮（BP）是一种以自身抗体为特征的自身免疫性表皮下水疱性疾病病变部位有炎症浸润，BP 自身抗体属于 IgG 和 IgE 同种型。识别两种半桥粒蛋白 BP180 和 BP230 这些自身抗体主要针对 NC16A。 BP180 的细胞外结构域含有嗜酸性粒细胞、中性粒细胞、肥大细胞、巨噬细胞。和淋巴细胞，其中嗜酸性粒细胞是主要细胞类型。抗 BP180 IgG 自身抗体的作用。 BP 中的中性粒细胞经过专门研究，体外和体内研究证明了这一点。抗 BP180 NC16A IgG 自身抗体可修复补体、募集中性粒细胞并引起 BP 样水疱。然而，抗 BP180 IgE 和嗜酸性粒细胞在 BP 中的作用仍然很大程度上未知。缺乏合适的动物。模型是 IgE 和嗜酸性粒细胞研究的主要障碍，因为人类 IgE 不能识别小鼠 IgE 我们的实验室目前开发了一种双人源化小鼠染色剂（称为 hFcεRI/NC16A 小鼠），其中人 NC16A 结构域取代了小鼠对应的 NC14A 结构域，而人 FcεRI 是更显着的是，注射抗-的成年 hFcεRI/NC16A 小鼠在嗜酸性粒细胞和肥大细胞上表达。 BP 患者的 NC16A IgE 自身抗体会导致 BP 皮肤病，需要嗜酸性粒细胞和肥大细胞。本提案的目的是利用我们最新的方法研究嗜酸性粒细胞和肥大细胞在血压中的作用开发了 hFcεRI/NC16A 小鼠模型该项目的总体目标是增加我们对 hFcεRI/NC16A 小鼠模型的了解。 BP 的先天免疫及其与炎症和先天免疫系统参与者功能的关系在这项拨款提案中，我们将确定嗜酸性粒细胞如何招募和功能相互作用。肥大细胞（目标 1 和 2）来自这些先天免疫细胞的蛋白水解酶对于皮肤组织至关重要。因此，我们将把我们的动物模型研究结果转化为人类血压（目标 3）。结合疾病机制研究和临床前试验，研究结果预计将具有重大意义对 BP 患者治疗的影响。