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: 8032485
• 负责人: Aimee S Payne
• 金额: $ 34.48万
• 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/8032485
• 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; public health relevance; response; skin abscess; skin disorder; variable region gene

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We propose to use antibody cloning technology as a novel approach to identify features within patient autoantibodies that cause pemphigus, a potentially fatal autoimmune blistering skin disorder. We hypothesize that IgG4, IgA, and IgE are the critical pathogenic antibody isotypes in pemphigus, and as such may serve as clinical markers to distinguish disease-specific antibodies from the other IgG subclasses that are important for providing immunity from infection. Our studies will create a rational framework for predicting the response of different forms of pemphigus to therapy, describe novel mouse models for evaluating disease, and may suggest novel and potentially safer therapeutic strategies, such as isotype-specific targeting.

描述（由申请人提供）：天疱疮是一组以抗桥粒芯糖蛋白（Dsg）细胞粘附蛋白的自身抗体为特征的潜在致命性起泡疾病。目前的治疗需要全身免疫抑制，这有致命感染和继发性癌症的风险。自身免疫研究的一个主要前沿是只针对致病抗体。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，长期目标是设计合理的靶向治疗。我们率先在天疱疮中使用抗体克隆技术，以确定导致疾病的患者自身抗体的可变区和恒定区的特征。我们已经确定了致病性自身抗体的可变区基因使用模式，甚至在不同的患者中也是共享的。在定义了足以引起皮肤起泡的抗Dsg可变区的子集后，我们现在独特地定位于解决抗体恒定区（Fc）在天疱疮发病机制中的作用。我们假设IgG 4、伊加和IgE是天疱疮的关键致病同种型，解释了疾病的全部临床和组织学谱。在缓解期患者及其健康亲属中发现抗Dsg IgG 1，而活动性疾病患者则表现出IgG 4自身抗体。在伊加天疱疮中，嗜酸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，并且抗Dsg IgE可通过类推引起嗜酸性粒细胞形式的天疱疮。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，所以这些同种型可以用作临床标记物，以区分疾病特异性抗体与对于提供抗感染免疫力更重要的其他IgG亚类。在目的1中，我们将从天疱疮患者中克隆IgG 1和IgG 4抗Dsg单克隆抗体（mAb），以确定是否在IgG 1、IgG 4或两种同种型中发现致病性抗体。如果在IgG 1和IgG 4中均发现，我们将确定抗Dsg IgG 4是由IgG 1的类别转换引起的还是由单独的B细胞群引起的，从而深入了解天疱疮中IgG 4类别转换的机制。在目的2和3中，我们将分别从嗜酸性和嗜酸性形式的天疱疮患者克隆抗Dsg伊加和IgE mAb。我们将评估抗Dsg伊加和IgE是否在针对相关Fc受体人源化的小鼠中再现炎性起泡疾病，并通过用Fc效应子功能抑制剂治疗小鼠来证明起泡和/或炎症的Fc依赖性。通过系统地表征天疱疮mAb同种型的可变区和恒定区的致病性，我们可以确定哪些结构特征引起疾病。这些研究将为预测不同形式天疱疮对治疗的反应建立一个合理的框架，描述用于评估Fc介导疾病的新型小鼠模型，并可能确定新的治疗策略，如同种型特异性靶向。由于类天疱疮、获得性大疱性表皮病和其他慢性自身免疫性疾病中存在相似的同种型特征，因此我们的研究可能对广泛的自身抗体介导的疾病具有治疗相关性。 公共卫生相关性：我们建议使用抗体克隆技术作为一种新的方法，以确定患者自身抗体内的功能，导致天疱疮，一个潜在的致命的自身免疫性起泡皮肤疾病。我们假设IgG 4、伊加和IgE是天疱疮中的关键致病性抗体同种型，因此可以作为临床标记物，以区分疾病特异性抗体与其他IgG亚类，这些亚类对提供免疫力非常重要。我们的研究将建立一个合理的框架来预测不同形式的天疱疮对治疗的反应，描述新的小鼠模型来评估疾病，并可能提出新的和潜在的更安全的治疗策略，如同种型特异性靶向。