Generation of IgG and IgE autoantibodies in an active mouse model of Bullous pemphigoid

在大疱性类天疱疮活跃小鼠模型中产生 IgG 和 IgE 自身抗体

• 批准号: 10283432
• 负责人: Kelly A.N. Messingham
• 金额: $ 7.73万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-14 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283432
• 关键词: Abbreviations; Address; Adhesions; Affect; Animal Disease Models; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; BP180 autoantigen; Basement membrane; Binding; Biopsy; Bulla; Bullous Pemphigoid; Cells; Collagen Type XVII; Cutaneous; Data; Deposition; Development; Disease; Disease Progression; Disease model; Dose; Elderly; Event; Formalin; Future; Generations; Goals; Health; Homologous Gene; Human; IgE; IgG autoantibodies; Immune; Immunization; Immunize; Immunoglobulin G; Immunologics; Immunosuppression; Inflammation; Injections; Intranasal Administration; Investigation; Knowledge; Lead; Lesion; Life; Mediating; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Nature; Onset of illness; Paraffin Embedding; Passive Transfer of Immunity; Pathogenesis; Pathogenicity; Patients; Play; Population; Prevention; Protein Isoforms; Proteins; Recombinants; Regimen; Research; Role; Route; SJL/J Mouse; Sampling; Secondary Immunization; Skin; Study models; Testing; Tissues; Translating; United States National Institutes of Health; cellular targeting; effective therapy; human disease; human model; human subject; immune activation; improved; improved outcome; in vivo; innovation; insight; mortality; mouse model; peripheral tolerance; response; skin disorder; standard care; targeted treatment; therapy outcome; tool

PROJECT SUMMARY There is a fundamental gap in our understanding of the pathogenic mechanisms of Bullous pemphigoid (BP), an autoimmune blistering disease. Thus, standard treatment consists of high dose immunosuppression, which is associated with significant morbidity and mortality in the elderly population typically affected by BP. Our long- term goal is to identify the cellular and molecular events that lead to the development and propagation of cutaneous autoimmunity so that better therapies can be developed. The objective of this proposal is to develop an active mouse model of BP that recapitulates human disease by eliciting both IgE and IgG autoantibodies BP. Although BP is one of a growing number of autoimmune diseases characterized by pathogenic IgE autoantibodies, and these IgE antibodies are critical for recapitulation of human disease in passive transfer models of disease, there is no active disease model that includes both an IgG and an IgE response to the BP autoantigen. Our hypothesis that the route of antigen exposure is critical for the development of an IgE autoantibody response. The rationale for the proposed research is generation of a robust active model of BP will address the shortcomings of current passive models and will facilitate studies of the basic mechanisms of BP and other instances of IgE-mediated autoimmunity. Guided by our preliminary data, this hypothesis will be tested by pursuing the following specific aim: To identify the immunization regimen that generates mBP180-specific IgE and IgG and cutaneous lesions consistent with BP. Mice will be immunized with the murine homolog of the BP autoantigen to determined how the route of antigen exposure influences the form and nature of the autoantibody response. At regular intervals, the extent of skin disease, the level of circulating antibodies, and the cutaneous immune cell populations will be assessed. These studies are relevant to the NIH’s mission aimed at enhancing health, lengthening life and reducing illness, and to that of the NIAID to better understand the immunologic basis of disease, including developing a greater understanding of fundamental immunologic principles underlying disease onset and progression and developing improved animal models of disease. This approach is innovative because there are currently no established mouse models of human autoimmune diseases that feature IgE. The proposed studies are significant because they will advance and expand our understanding of the basic mechanisms of cutaneous autoimmunity and will lay the groundwork for future studies aimed at identifying the cellular and molecular mechanisms of disease that can be targeted therapeutically.

项目概要 我们对大疱性类天疱疮 (BP) 的致病机制的理解存在根本性差距。 自身免疫性水疱病。因此，标准治疗包括高剂量免疫抑制，即 与通常受血压影响的老年人群的显着发病率和死亡率相关。我们的长期 术语目标是识别导致发育和繁殖的细胞和分子事件 皮肤自身免疫，以便开发更好的治疗方法。该提案的目标是开发 一种活跃的 BP 小鼠模型，通过引发 IgE 和 IgG 自身抗体 BP 来重现人类疾病。 尽管 BP 是越来越多以致病性 IgE 为特征的自身免疫性疾病之一 自身抗体，这些 IgE 抗体对于被动转移中重现人类疾病至关重要 疾病模型中，没有同时包含对 BP 的 IgG 和 IgE 反应的活动性疾病模型 自身抗原。我们的假设是抗原暴露途径对于 IgE 的发育至关重要 自身抗体反应。拟议研究的基本原理是生成一个稳健的 BP 主动模型 解决当前被动模型的缺点，将有助于BP基本机制的研究 以及 IgE 介导的自身免疫的其他实例。根据我们的初步数据，该假设将得到检验 通过追求以下具体目标： 确定产生 mBP180 特异性 IgE 的免疫方案 且IgG和皮肤病变与BP一致。将用 BP 的鼠同系物对小鼠进行免疫 自身抗原以确定抗原暴露途径如何影响自身抗体的形式和性质 回复。定期检查皮肤病的程度、循环抗体的水平以及皮肤的情况。 将评估免疫细胞群。这些研究与 NIH 旨在加强 健康、延长寿命和减少疾病，以及 NIAID 更好地了解免疫学基础 疾病，包括加深对基本免疫学原理的理解 疾病的发生和进展以及开发改进的疾病动物模型。这个方法很有创新性 因为目前还没有建立以 IgE 为特征的人类自身免疫性疾病小鼠模型。这 拟议的研究意义重大，因为它们将增进和扩大我们对基本知识的理解 皮肤自身免疫机制，并将为未来的研究奠定基础，旨在确定 可作为治疗目标的疾病的细胞和分子机制。