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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.

项目摘要大疱性类天疱疮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以及病变部位的炎症浸润BP自身抗体属于IgG和IgE同种型，识别两种半桥粒蛋白，BP 180和BP 230。这些自身抗体主要靶向NC 16 A BP 180的胞外结构域。真皮浸润物含有嗜酸性粒细胞、中性粒细胞、肥大细胞、巨噬细胞和淋巴细胞，嗜酸性粒细胞是主要的细胞类型。抗BP 180 IgG自身抗体的作用 BP中的中性粒细胞已得到广泛研究。体外和体内研究表明，抗BP 180 NC 16 A IgG自身抗体固定补体，募集嗜中性粒细胞并引起BP样水疱。然而，抗BP 180 IgE和嗜酸性粒细胞在BP中的作用在很大程度上仍然未知。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IgE不能识别小鼠IgE 受体。我们的实验室目前开发了一种双重人源化小鼠染色剂（称为hFcεRI/NC 16 A小鼠），其中人NC 16 A结构域取代小鼠对应物NC 14 A结构域，并且人FcεRI是在嗜酸性粒细胞和肥大细胞上表达。更重要的是，成年hFcεRI/NC 16 A小鼠注射抗- 来自BP患者的NC 16 A IgE自身抗体发展为需要嗜酸性粒细胞和肥大细胞的BP皮肤病。本建议的目的是研究嗜酸性粒细胞和肥大细胞在BP中的作用，建立hFcεRI/NC 16 A小鼠模型。这个项目的总体目标是增加我们对 BP的先天免疫以及它如何与先天免疫系统参与者在炎症和自身免疫在这个拨款申请中，我们将确定嗜酸性粒细胞是如何被招募和功能性相互作用的。肥大细胞（目的1和2）。来自这些先天免疫细胞的蛋白水解酶对皮肤组织至关重要因此，我们将把我们的动物模型发现转化为人类BP（目标3）。由于这一提议整合了疾病机制研究和临床前试验，这些发现预计将具有重大意义。对BP患者的治疗有影响。