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

项目摘要 我们对大疱性类天疱疮（BP）的致病机制的理解存在根本性的差距， 自身免疫性水疱病因此，标准治疗包括高剂量免疫抑制， 与通常受BP影响的老年人群的显著发病率和死亡率相关。我们长久以来- 术语目标是识别导致发展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。本提案的目的是发展 BP的活跃小鼠模型，其通过引发IgE和IgG自身抗体BP来重现人类疾病。 虽然BP是越来越多的以致病性IgE为特征的自身免疫性疾病之一， 自身抗体，这些IgE抗体是关键的重演人类疾病的被动转移 在疾病模型中，没有包括对BP的IgG和IgE应答的活动性疾病模型 自身抗原我们假设抗原暴露途径对IgE的发展至关重要， 自身抗体反应提出的研究的基本原理是产生一个强大的主动模型的BP将 解决了目前被动模型的缺点，并将促进对BP基本机制的研究 和其他IgE介导的自身免疫的情况。在我们初步数据的指导下， 通过追求以下具体目标：鉴定产生mBP 180特异性IgE的免疫方案 IgG和皮肤损伤与BP一致。小鼠将用BP的鼠同源物免疫 确定抗原暴露途径如何影响自身抗体的形式和性质 反应定期检测皮肤病的程度、循环抗体的水平和皮肤免疫功能。 将评估免疫细胞群体。这些研究与NIH的使命有关， 健康，延长寿命和减少疾病，以及NIAID的免疫学基础，以更好地了解 包括更好地了解疾病的基本免疫学原理， 疾病发作和进展以及开发改进的疾病动物模型。这种做法是创新的 因为目前还没有建立以IgE为特征的人类自身免疫性疾病的小鼠模型。的 拟议的研究是重要的，因为它们将促进和扩大我们对基本的 皮肤自身免疫的机制，并将奠定基础，为今后的研究，旨在确定 细胞和分子机制的疾病，可以有针对性的治疗。

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.