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

• 批准号: 8449190
• 负责人: Aimee S Payne
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/8449190
• 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

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.

项目总结(最多30行)： 天疱疮是一组具有潜在致命性的水疱性疾病，以自身抗体为特征。 桥粒芯糖蛋白(DSG)细胞黏附蛋白。目前的治疗方法需要全面的免疫抑制，这有风险 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只针对疾病- 引起抗体。我们的总体目标是更好地确定天疱疮中的致病抗体群体， 设计合理的、有针对性的疗法的长期目标。我们已率先使用抗体克隆 天疱疮中识别患者自身抗体可变区和恒定区特征的技术 引发疾病。我们已经确定了致病性自身抗体的可变区基因使用模式， 即使在不同的患者之间也是共享的。定义了足够的反DSG可变区的子集 对于皮肤水泡，我们现在唯一的位置是解决抗体恒定区(Fc)在 天疱疮发病机制。我们推测，IgG4、IgA和IgE是猪瘟的关键致病亚型。 天疱疮，占疾病的全部临床和组织学谱系。抗DSG IgG1抗体存在于 缓解期患者和他们的健康亲属，而活动期患者表现出IgG4自身抗体。 在IgA天疱疮中，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。 类推，抗DSG IgE抗体可引起嗜酸性天疱疮。因为慢性抗原刺激 促进类从IgG1到IgG4、IgA和IgE的转换，这些亚型可作为临床标志物 将疾病特异性抗体与其他更重要的免疫球蛋白亚类区分开来 对感染有免疫力。在目标1中，我们将克隆抗DSG的IgG1和IgG4单抗 天疱疮患者以确定是否在IgG1和/或IgG4中发现致病抗体。如果 在IgG1和IgG4中都发现，我们将确定抗DSG IgG4是由于从IgG1或 来自不同的B细胞群，有助于深入了解天疱疮中IgG4类转换的机制。 在目标2和目标3中，我们将从中性粒细胞和嗜酸性粒细胞患者中克隆抗DSG IgA和IgE单抗 分别为天疱疮。我们将评估抗DSG IgA和IgE是否复制炎性水泡 在人源化的小鼠疾病中寻找相关的Fc受体，并证明水泡对Fc的依赖 和/或炎症，通过用Fc效应功能的抑制剂治疗小鼠。通过系统地描述 天疱疮mAb亚型可变区和恒定区的致病性，我们可以定义哪种结构 容貌导致疾病。这些研究将创建一个合理的框架来预测不同 天疱疮的治疗形式，描述了用于评估FC介导的疾病的新的小鼠模型，并可能 确定新的治疗策略，例如针对同种类型的靶向。当相似的同型图谱出现在 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 对广泛的自身抗体介导性疾病的治疗相关性。