Role of autoantibody isotype in pemphigus pathogenesis

自身抗体同种型在天疱疮发病机制中的作用

基本信息

批准号：
8243476
负责人：
Aimee S Payne
金额：
$ 34.21万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8243476
关键词：
Abscess Accounting Address Antibodies Antigens Autoantibodies Autoimmune Process Autoimmunity B-Lymphocytes Binding Bulla Bullous Pemphigoid Cell Adhesion Molecules Cells Chemotaxis Chronic Chronic Disease Clinical Clinical Markers Cloning Dapsone Defect Dependence Disease Disease remission Epidermolysis Bullosa Acquisita Exhibits Fc Receptor Fc(alpha) receptor Goals Histologic Human IgE IgE Receptors IgG1 IgG4 Immune Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin Constant Region Immunoglobulin G Immunoglobulin Variable Region Immunosuppression Infection Inflammation Inflammatory Lesion Leukocytes Link Mediating Monoclonal Antibodies Mus Neonatal Pathogenesis Pathogenicity Patients Pattern Pemphigus Pemphigus Vulgaris Phage Display Population Relative (related person)Research Risk Role Second Primary Cancers Skin Technology Therapeutic Transgenic Mice anti-IgA anti-IgE design desmoglein eosinophil eosinophilic inflammation frontier inhibitor/antagonist insight mouse model neutrophil novel novel strategies novel therapeutics omalizumab response skin abscess skin disorder variable region gene

项目摘要

Project summary (30 lines maximum): Pemphigus is a group of potentially fatal blistering diseases characterized by autoantibodies against desmoglein (Dsg) cell adhesion proteins. Current therapy requires general immune suppression, which risks fatal infection and secondary cancers. A major frontier for autoimmunity research is to target only disease- causing antibodies. Our overall aim is to better define this pathogenic antibody population in pemphigus, with the long term goal of designing rational, targeted therapies. We have pioneered the use of antibody cloning technology in pemphigus to identify features of variable and constant regions of patient autoantibodies that cause disease. We have identified a pattern of variable region gene usage for pathogenic autoantibodies, which is shared even among different patients. Having defined a subset of anti-Dsg variable regions sufficient for skin blistering, we are now uniquely situated to address the role of the antibody constant region (Fc) in pemphigus pathogenesis. We hypothesize that IgG4, IgA and IgE are the critical pathogenic isotypes in pemphigus, accounting for the full clinical and histologic spectrum of disease. Anti-Dsg IgG1 is found in patients in remission and their healthy relatives, while patients with active disease exhibit IgG4 autoantibodies. In IgA pemphigus, neutrophilic skin abscesses are caused by anti-Dsg IgA binding to leukocyte Fc receptors, and anti-Dsg IgE may cause eosinophilic forms of pemphigus by analogy. Because chronic antigen stimulation promotes class switching from IgG1 to IgG4, IgA, and IgE, these isotypes may serve as clinical markers to distinguish disease-specific antibodies from the other IgG subclasses that are more important for providing immunity from infection. In Aim 1 we will clone IgG1 and IgG4 anti-Dsg monoclonal antibodies (mAbs) from pemphigus patients to determine whether pathogenic antibodies are found in IgG1, IgG4, or both isotypes. If found in both IgG1 and IgG4, we will determine whether anti-Dsg IgG4 result from class switching from IgG1 or arise from separate B cell populations, lending insight into mechanisms of IgG4 class switching in pemphigus. In Aims 2 and 3 we will clone anti-Dsg IgA and IgE mAbs from patients with neutrophilic and eosinophilic forms of pemphigus, respectively. We will evaluate whether anti-Dsg IgA and IgE reproduce inflammatory blistering disease in mice humanized for the relevant Fc receptor and demonstrate the Fc-dependence of blistering and/or inflammation by treating mice with inhibitors of Fc effector function. By systematically characterizing the pathogenicity of the variable and constant regions of pemphigus mAb isotypes, we can define which structural features cause disease. These studies will create a rational framework for predicting the response of different forms of pemphigus to therapy, describe novel mouse models for evaluating Fc-mediated disease, and may identify novel therapeutic strategies, such as isotype-specific targeting. As similar isotype profiles occur in pemphigoid, epidermolysis bullosa acquisita, and other chronic autoimmune conditions, our studies may have therapeutic relevance for a broad range of autoantibody-mediated diseases.

项目摘要（最多30行）： Pemphigus是一组潜在的致命起泡疾病，其特征是自身抗体 Desmoglein（DSG）细胞粘附蛋白。当前的治疗需要一般的免疫抑制，这有风险致命感染和继发性癌症。自身免疫研究的主要领域是仅针对疾病 - 引起抗体。我们的总体目的是更好地定义Pemphigus中的病原抗体种群，并具有设计理性的，有针对性疗法的长期目标。我们开创了抗体克隆的使用 Pemphigus的技术以识别患者自身抗体的可变和恒定区域的特征引起疾病。我们已经确定了一种可变区域基因使用模式，用于致病自身抗体，即使在不同的患者中也共享。定义了抗DSG变量区域的子集足够对于皮肤起泡，我们现在处于独特的位置，可以解决抗体常数区域（FC）在 Pemphigus发病机理。我们假设IgG4，IgA和IgE是关键的致病性同种型 Pemphigus，考虑了疾病的完整临床和组织学谱。抗DSG IgG1在缓解患者及其健康的亲戚，而患有活性疾病的患者表现出IgG4自身抗体。在Iga pemphigus中，中性粒细胞皮肤脓肿是由抗DSG IgA与白细胞FC受体结合引起的，和抗DSG IgE可能会通过类比引起嗜酸性形式的Pemphigus。因为慢性抗原刺激促进从IgG1转换为IgG4，IgA和IgE的类别的类别，这些同种型可以用作临床标记将疾病特异性抗体与其他IgG亚类区分开免疫感染。在AIM 1中，我们将克隆IgG1和IgG4抗DSG单克隆抗体（mAb） Pemphigus患者确定在IgG1，IgG4或两种同种型中发现致病性抗体。如果在IgG1和IgG4中都发现，我们将确定抗DSG IgG4是由IgG1或IgG1切换而引起的由单独的B细胞群体产生，借鉴Pemphigus中IgG4类切换的机制。在AIM 2和3中，我们将来自具有嗜中性粒细胞和嗜酸性形式的患者的抗DSG IgA和IgE mAb。分别是Pemphigus。我们将评估抗DSG IgA和IgE是否会繁殖炎症起泡相关FC受体人性化的小鼠疾病，并证明了泡沫的FC依赖性和/或通过使用FC效应功能抑制剂治疗小鼠来炎症。通过系统地表征 Pemphigus mab同种型的变量和恒定区域的致病性，我们可以定义哪个结构特征引起疾病。这些研究将创建一个合理的框架来预测不同的响应 pemphigus进行治疗的形式，描述用于评估FC介导疾病的新型小鼠模型，并可能确定新颖的治疗策略，例如特定于同种型的靶向。由于类似的同种型轮廓发生在肺炎，表皮溶解Bullosa Accuisita和其他慢性自身免疫性条件，我们的研究可能具有与各种自身抗体介导的疾病的治疗相关性。