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）：Pemphigus是一组潜在的致命起泡疾病，其特征是针对Desmoglein（DSG）细胞粘附蛋白的自身抗体。当前的疗法需要普遍的免疫抑制，这会冒着致命感染和继发性癌症的风险。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，其长期目标是设计有理的，有针对性的疗法。我们已经开创了Pemphigus中抗体克隆技术的使用，以识别引起疾病的患者自身抗体的可变和恒定区域的特征。我们已经确定了一种可变区域基因使用模式用于致病性自身抗体，即使在不同的患者中也可以共享。在定义了足以使皮肤起泡的抗DSG变量区域的子集之后，我们现在是独特的，可以解决抗体常数区域（FC）在Pemphigus发病机理中的作用。我们假设IgG4，IgA和IgE是Pemphigus中关键的致病同种型，这是疾病的完整临床和组织学谱。抗DSG IgG1在缓解患者及其健康亲戚中发现，而患有活性疾病的患者表现出IgG4自身抗体。在Iga pemphigus中，嗜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，抗DSG IgE可能会通过类比引起嗜酸性粒细胞的pemphigus。由于慢性抗原刺激促进了从IgG1转换为IgG4，IgA和IgE的类别的类别，因此这些同种型可以用作区分疾病特异性抗体和其他IgG亚类的临床标志物，这些抗体对于提供免疫力免受感染的免疫力更为重要。在AIM 1中，我们将克隆IgG1和IgG4抗DSG单克隆抗体（MAB）从Pemphigus患者进行，以确定在IgG1，IgG4中是否发现致病性抗体或两种同型。如果在IgG1和IgG4中都发现，我们将确定抗DSG IgG4是由类别从IgG1切换而引起的还是由单独的B细胞群体转换而引起的，从而深入了解Pemphigus中IgG4类切换的机制。在AIMS 2和3中，我们将分别来自具有嗜中性粒细胞和嗜酸性粒细胞形式的Pemphigus的患者的抗DSG IgA和IgE mAb。我们将评估抗DSG IgA和IgE是否在人性化的相关FC受体的小鼠中再现炎症性泡沫疾病，并通过用FC效应器功能的抑制剂治疗小鼠来证明泡沫和/或炎症的FC依赖性。通过系统地表征Pemphigus mAb同种型的可变和恒定区域的致病性，我们可以定义哪些结构特征引起疾病。这些研究将创建一个合理的框架，以预测不同形式的Pemphigus对治疗的反应，描述用于评估FC介导的疾病的新型小鼠模型，并可以鉴定出新型的治疗策略，例如同型特异性靶向。由于类似的同种型谱发生在Pemphigoid，表皮分解Bullosa Accuisita和其他慢性自身免疫性条件中，我们的研究可能与广泛的自身抗体介导的疾病具有治疗性相关。 公共卫生相关性：我们建议将抗体克隆技术用作一种新型方法，以识别患者自身抗体中引起Pemphigus的特征，这是一种潜在的致命自身免疫性泡沫性皮肤病。我们假设IgG4，IgA和IgE是Pemphigus中关键的致病性抗体同种型，因此可以用作将特异性抗体与其他IgG亚类区分开的临床标志物，这些抗体对于提供免疫感染的其他IgG亚类很重要。我们的研究将创建一个合理的框架，以预测不同形式的Pemphigus对治疗的反应，描述用于评估疾病的新型小鼠模型，并可能提出新颖且可能更安全的治疗策略，例如同性型特定于靶向。