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

项目总结 对于大疱性类天疱疮(BP)的发病机制，我们的认识存在着根本的差距。 自身免疫性水泡病。因此，标准治疗包括大剂量免疫抑制，这是 在通常受BP影响的老年人口中与显著的发病率和死亡率有关。我们的长- 术语目标是确定导致发展和传播的细胞和分子事件 皮肤自身免疫，以便开发更好的治疗方法。这项提议的目标是发展 一种活性的BP小鼠模型，通过诱导IgE和Ig G自身抗体BP来概括人类疾病。 尽管BP是以致病IgE为特征的越来越多的自身免疫性疾病之一 自身抗体和这些IgE抗体对于被动转移中人类疾病的重现至关重要 疾病模型，没有同时包括对BP的免疫球蛋白和免疫球蛋白E反应的活动疾病模型 自身抗原。我们的假设是，抗原暴露的途径对IgE的发展至关重要 自身抗体反应。拟议研究的基本原理是生成一个健壮的BP Will主动模型 解决了当前被动模型的不足，将有助于BP基本机理的研究 以及其他由IgE介导的自身免疫的例子。在我们初步数据的指导下，这一假设将得到检验 通过追求以下具体目标：确定产生mBP180特异性IgE的免疫方案 免疫球蛋白和皮肤病变与BP一致。小鼠将用BP的小鼠同源物免疫 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 回应。定期检测皮肤病的程度、循环抗体水平和皮肤 将对免疫细胞群进行评估。这些研究与美国国立卫生研究院旨在加强 健康、延寿、减病，更好地了解NIAID的免疫学基础 包括更好地了解疾病的基本免疫学原理 疾病的发生和发展，以及发展改进的疾病动物模型。这种方法是创新的。 因为目前还没有建立起以IgE为特征的人类自身免疫性疾病的小鼠模型。这个 拟议的研究具有重要意义，因为它们将促进和扩大我们对基本 皮肤自身免疫的机制，并将为未来的研究奠定基础，旨在确定 可作为治疗靶点的疾病的细胞和分子机制。

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.