Innate Immunity in Bullous Pemphigoid

大疱性类天疱疮的先天免疫

基本信息

批准号：
7987670
负责人：
Zhi Liu
金额：
$ 35.56万
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：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7987670
关键词：
Address Autoantibodies Autoimmune Process Autoimmunity BP180 autoantigen Binding Bulla Bullous Pemphigoid C5a anaphylatoxin receptor Cell Degranulation Chemotactic Factors Chymase Cleaved cell Complement Complement 5a Data Dermal Development Disease Eotaxin Event Extracellular Domain Extracellular Matrix Feedback Gelatinase B Goals Human IL8 gene IgE IgE Receptors IgG Receptors Immune Immune response Immune system Immunoglobulin G In Vitro Infiltration Inflammation Inflammatory Infiltrate Injection of therapeutic agent Injury Interleukin-5 Lesion Leukocyte Elastase Lymphocyte Mediating Mediator of activation protein Minor Modeling Mouse Strains Mus Natural Immunity Neonatal Neutrophil Infiltration Oryctolagus cuniculus Participant Pathway interactions Patients Peptide Hydrolases Positioning Attribute Process Proteins Recruitment Activity Research Resistance Role Site Skin Staining method Stains System Testing Tissues Widespread Disease Work anti-IgG crosslink disease mechanisms study disease phenotype effective therapy eosinophil human CCL26 protein in vivo keratinocyte mast cell mouse model neutrophil preclinical study public health relevance skin disorder

项目摘要

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.

描述（由申请人提供）：大胆的肺泡（BP）是一种自身免疫性下泡疾病，其特征是自身抗体和病行部位的炎症性浸润。 BP自身抗体属于IgG和IgE同种型，并识别两种Hemidesmosomal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且具有致病性。 NC16A是BP180的细胞外结构域，是致病自身抗体的主要目标。嗜酸性粒细胞通常是突出的，皮肤浸润还含有嗜中性粒细胞，肥大细胞和淋巴细胞。但是，这些关键的先天免疫玩家的角色仍然未知。缺乏可用的体内系统是使用患者衍生的自身抗体研究BP中先天免疫反应的主要障碍。我们的实验室目前开发了人源化的BP180小鼠染色（称为NC16A小鼠），其中小鼠BP180NC14A结构域被人体BP180NC16A域取代。更重要的是，注射抗BP180自身抗体的新生儿NC16A小鼠会形成皮肤疾病，这些皮肤疾病模仿了BP的关键免疫学特征。该建议的目的是使用我们新开发的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提高我们对BP先天免疫的理解，以及它与先天免疫系统参与者在炎症和自身免疫中的功能的关系。在AIM 1中，我们将确定BP是否需要肥大细胞。目标2是研究嗜酸性粒细胞的作用，并确定BP中嗜酸性粒细胞和肥大细胞之间的功能相互作用。在AIM 3中，我们将研究嗜酸性粒细胞和肥大细胞蛋白水解酶在BP泡中的作用。由于该提案既整合了疾病机制研究和临床前试验，因此这些发现预计将对BP患者的治疗产生重大影响。公共卫生相关性：大声疾呼（BP）是最常见和可能致命的自身免疫性疾病。我们将研究疾病发展的过程，并确定更有效疗法的新靶标。