Characterization of IgA- and IgE- mediated pathogenicity using a humanized pemphigus mouse model

使用人源化天疱疮小鼠模型表征 IgA 和 IgE 介导的致病性

• 批准号: 221334494
• 负责人: Dr. Christoph Thomas Ellebrecht
• 金额: --
• 依托单位: Columbia University in the City of New York
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221334494?language=en
• 关键词: Characterization; IgA; IgE; mediated; pathogenicity

Pemphigus is a group of severe autoimmune blistering skin diseases characterized by antibodies to desmosomal proteins known as desmogleins (Dsg). Several clinical subtypes of pemphigus have been described, many of which are characterized not only by IgG binding to keratinocytes and blister formation but also by deposition of IgA or IgE and subsequent neutrophil and/or eosinophil infiltration. Although the role of the variable region of anti-Dsg antibodies has been characterized extensively, there are few data concerning different autoantibody isotypes in pemphigus and their influence on pathogenicity and response to therapy. Evaluation of IgA and IgE in the pathogenesis of pemphigus is highly desirable to reveal new therapeutic targets and more specific therapeutic approaches in IgA- /IgE- mediated skin diseases. We hypothesize that depending on the capability of the variable region of the autoantibodies to induce blisters (termed pathogenic), IgA/IgE can produce different clinical phenotypes of pemphigus and that these phenotypes can be specifically treated. Due to the innovative technique of phage display, we are able to produce full length monoclonal anti-Dsg-IgA and -IgE with pathogenic or nonpathogenic variable regions. We will assess our hypotheses 1) by producing monoclonal pathogenic and nonpathogenic IgA and IgE from pemphigus patients and 2) by characterizing their pathogenicity and effector function in a novel humanized mouse model with murine leukocytes expressing human Fcalpha/Fcepsilon receptors. Additionally, pathogenicity of IgA and IgE will be evaluated 3) by treatment with either dapsone or omalizumab to inhibit the Fc-mediated effector function of IgA or IgE, respectively. The knowledge that will be gained from the proposed studies is significant, since it enables a deeper understanding of the pathophysiology of pemphigus, rational treatment strategies, and a major advancement in technology for evaluating immunobullous diseases in general.

天疱疮是一组严重的自身免疫性水疱性皮肤病，其特征是对桥粒蛋白(DSG)产生抗体。天疱疮有几种临床亚型，其中许多亚型的特征不仅是与角质形成细胞结合的免疫球蛋白G和水泡形成，而且还表现为IgA或IgE沉积和随后的中性粒细胞和/或嗜酸性粒细胞浸润。尽管抗DSG抗体可变区的作用已被广泛描述，但关于天疱疮中不同自身抗体亚型及其对致病性和治疗反应的影响的数据很少。评价IgA和IgE在天疱疮发病机制中的作用，有助于揭示IgA/IgE介导的皮肤病新的治疗靶点和更特异的治疗途径。我们假设，根据自身抗体可变区诱导水泡(称为致病)的能力，IgA/IgE可以产生不同的天疱疮临床表型，并且这些表型可以被特异性地治疗。由于噬菌体展示技术的创新，我们能够生产出具有致病或非致病可变区的全长抗DSG-IgA和-IgE单抗。我们将评估我们的假说：1)通过生产天疱疮患者的单克隆性致病和非致病性IgA和IgE，以及2)在一个新的人源化小鼠模型中表征它们的致病性和效应功能，小鼠白细胞表达人Fcalpha/Fcepsilon受体。此外，免疫球蛋白A和免疫球蛋白E的致病性将通过分别用氨苯砜或奥马珠单抗抑制Fc介导的免疫球蛋白A或免疫球蛋白E的功能来评估。从拟议的研究中获得的知识将是重要的，因为它使人们能够更深入地了解天疱疮的病理生理学，合理的治疗策略，以及评估免疫性疾病的技术的重大进步。