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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）：天疱疮是一组潜在致命的水疱性疾病，其特征是针对天疱疮的自身抗体桥粒芯糖蛋白 (Dsg) 细胞粘附蛋白。目前的治疗需要全身免疫抑制，这存在风险致命的感染和继发性癌症。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体设计合理的、有针对性的疗法的长期目标。我们率先使用抗体克隆天疱疮技术可识别患者自身抗体可变区和恒定区的特征引起疾病。我们已经确定了致病性自身抗体可变区基因的使用模式，即使在不同的患者之间也是共享的。定义了抗 Dsg 可变区的子集就足够了对于皮肤起泡，我们现在处于独特的位置，可以解决抗体恒定区 (Fc) 在天疱疮发病机制。我们假设 IgG4、IgA 和 IgE 是关键的致病同种型。天疱疮，占疾病的完整临床和组织学谱。抗 Dsg IgG1 存在于缓解期患者及其健康亲属，而活动性疾病患者则表现出 IgG4 自身抗体。在 IgA 天疱疮中，中性粒细胞性皮肤脓肿是由抗 Dsg IgA 与白细胞 Fc 受体结合引起的，类推抗Dsg IgE可能引起嗜酸性粒细胞型天疱疮。由于慢性抗原刺激促进从 IgG1 到 IgG4、IgA 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，后者对于提供更重要的信息免受感染的免疫力。在目标 1 中，我们将从中克隆 IgG1 和 IgG4 抗 Dsg 单克隆抗体 (mAb) 天疱疮患者以确定是否在 IgG1、IgG4 或两种同种型中发现致病性抗体。如果在 IgG1 和 IgG4 中均发现，我们将确定抗 Dsg IgG4 是否是由 IgG1 或 IgG1 类别转换引起的来自不同的 B 细胞群，有助于深入了解天疱疮中 IgG4 类别转换的机制。在目标 2 和 3 中，我们将从中性粒细胞和嗜酸性粒细胞形式的患者中克隆抗 Dsg IgA 和 IgE mAb 分别为天疱疮。我们将评估抗 Dsg IgA 和 IgE 是否会重现炎症性水疱在针对相关 Fc 受体进行人源化的小鼠中进行疾病研究，并证明了水疱的 Fc 依赖性和/或通过用 Fc 效应子功能抑制剂治疗小鼠来治疗炎症。通过系统地表征天疱疮单克隆抗体同种型的可变区和恒定区的致病性，我们可以定义哪些结构特征导致疾病。这些研究将创建一个合理的框架来预测不同的反应形式的天疱疮的治疗，描述了用于评估 Fc 介导的疾病的新型小鼠模型，并且可能确定新的治疗策略，例如同种型特异性靶向。由于类似的同种型分布出现在类天疱疮、获得性大疱性表皮松解症和其他慢性自身免疫性疾病，我们的研究可能有与广泛的自身抗体介导的疾病的治疗相关性。