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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）：天疱疮是一组潜在的致命性水疱性疾病，其特征在于抗桥粒芯糖蛋白（Dsg）细胞粘附蛋白。目前的治疗需要全身免疫抑制，致命感染和继发性癌症。自身免疫研究的一个主要前沿是仅针对疾病- 引起抗体。我们的总体目标是更好地定义天疱疮中的致病性抗体群，设计合理的靶向治疗的长期目标。我们率先使用抗体克隆天疱疮中鉴定患者自身抗体可变区和恒定区特征的技术，导致疾病。我们已经确定了致病性自身抗体的可变区基因使用模式，甚至在不同的病人之间共享。已经定义了足够的抗Dsg可变区的子集，对于皮肤起泡，我们现在处于独特的位置，以解决抗体恒定区（Fc）在皮肤起泡中的作用。天疱疮发病机制。我们假设IgG 4、伊加和IgE是大肠癌的关键致病同种型，天疱疮，占疾病的全部临床和组织学谱。抗Dsg IgG 1存在于缓解期患者及其健康亲属，而活动性疾病患者表现出IgG 4自身抗体。在伊加天疱疮中，嗜中性粒细胞皮肤炎是由抗Dsg伊加与白细胞Fc受体结合引起的，与此类似，抗Dsg IgE可引起嗜酸性形式的天疱疮。因为慢性抗原刺激促进从IgG 1到IgG 4、伊加和IgE的类别转换，这些同种型可以作为临床标志物，将疾病特异性抗体与其他IgG亚类区分开来，这些亚类对提供对感染的免疫力。在目的1中，我们将从小鼠中克隆IgG 1和IgG 4抗Dsg单克隆抗体（mAb），天疱疮患者，以确定致病性抗体是否存在于IgG 1、IgG 4或两种同种型中。如果在IgG 1和IgG 4中均发现，我们将确定抗Dsg IgG 4是否由IgG 1的类别转换产生，来自不同的B细胞群，有助于了解天疱疮中IgG 4类别转换的机制。在目标2和3中，我们将从嗜酸性和嗜酸性形式的患者中克隆抗Dsg伊加和IgE mAb 天疱疮，分别。我们将评估抗Dsg伊加和IgE是否能复制炎性水疱在小鼠中对相关Fc受体进行人源化，并证明水疱的Fc依赖性和/或炎症。通过系统地描述天疱疮mAb同种型的可变区和恒定区的致病性，我们可以确定特征导致疾病。这些研究将建立一个合理的框架来预测不同的反应，天疱疮形式的治疗，描述了用于评估Fc介导的疾病的新的小鼠模型，并且可以确定新的治疗策略，如同种型特异性靶向。由于类似的同种型分布发生在类天疱疮，获得性大疱性表皮炎和其他慢性自身免疫性疾病，我们的研究可能有广泛的自身抗体介导的疾病的治疗相关性。