Receptor Diversity in Recognition of Influenza HA

描述（由申请人提供）：该项目的长期目标是使用一个特征良好的模型系统来定义控制对自身抗原的耐受性和自身免疫的过程。为此，我们开发了表达流感病毒血凝素（HA）作为名义自身抗原的转基因小鼠谱系，并分析了它们诱导CD4+ T细胞和B细胞对HA耐受的程度和基础。在最近的资助期内，我们发现由MHC II类启动子驱动表达HA的小鼠（HACII小鼠）和共同表达HA特异性CD4+ T细胞受体的小鼠（TCRxHACII小鼠）自发产生自身免疫，炎症性关节炎是主要的疾病表现。我们发现关节炎的发展是由CD4+ T细胞驱动的，并依赖于抗原呈递细胞（APCs）合成新自我HA分子。此外，关节炎的外显率可以通过改变CD4+ T细胞对HA的反应性来调节，因为大多数TCR识别HA为激动剂肽的小鼠（TS1xHACII小鼠）发展为关节炎，而表达TCR的小鼠（TS1(SW)xHACII小鼠）的HA反应性低约100倍，而关节炎的外显率则低得多。本研究将利用该模型系统来了解自身反应性CD4+ T细胞与全身分布的apc合成的自肽之间的相互作用如何导致自身免疫性关节炎的发展。在Aim 1中，我们将分析与APC合成其靶肽的相互作用如何促进关节炎性CD4+ T细胞的发育，并检查关节炎是否与靶抗原表达升高和/或区域APC激活有关。我们还将研究淋巴细胞减少诱导的CD4+ T细胞增殖是否有助于TCRxHACII小鼠关节炎的发展。在Aim 2中，我们将研究影响TCRxHACII小鼠疾病外显率和严重程度的因素。我们将确定CD4+ T细胞频率和/或B细胞功能如何影响关节炎的严重程度和外显率，并检查细胞因子阻断调节关节炎严重程度的能力是否对自身反应性CD4+ T细胞库的变化敏感。在Aim 3中，我们将确定在低外显率环境下是否可以预测或促进关节炎的发展。我们将研究CD4+ T细胞库或血清细胞因子组成的差异是否可以前瞻性地识别将发展为关节炎的个体，并分析感染如何增加关节炎在遗传易感个体中的外显率。这些研究将为免疫库形成和耐受机制提供基本见解，将对自身免疫过程具有普遍适用性，并将使用与人类类风湿关节炎的诊断和治疗直接相关的实验模型。自身免疫性疾病是免疫系统攻击人体自身细胞和组织的结果，但这些疾病是如何产生的仍然知之甚少。该建议使用转基因小鼠来分析可能导致自身免疫性关节炎发展的机制和细胞过程。这些研究旨在发展自身免疫性疾病过程的新见解，这将促进人类自身免疫性疾病，特别是类风湿性关节炎的诊断和治疗。

DESCRIPTION (provided by applicant): This project's long-term goal is to use a well-characterized model system to define processes governing tolerance versus autoimmunity to self-antigens. To this end, we have developed lineages of transgenic mice expressing the influenza virus hemagglutinin (HA) as a nominal self-antigen, and have been analyzing the extent and basis by which they induce CD4+ T and B cell tolerance to the HA. In the most recent funding period, we showed that mice expressing HA driven by a MHC Class II promoter (HACII mice) and co- expressing HA-specific CD4+ T cell receptors (TCRxHACII mice) spontaneously develop autoimmunity, with inflammatory arthritis as the prominent disease manifestation. We showed that arthritis development is driven by CD4+ T cells and depends on the synthesis of the neo-self HA molecule by antigen presenting cells (APCs). Moreover, the penetrance of arthritis could be modulated by varying the reactivity of CD4+ T cells for the HA, since the majority of mice in which the TCR recognizes HA as an agonist peptide (TS1xHACII mice) developed arthritis, whereas mice expressing a TCR with ~100-fold lower reactivity for the HA (TS1(SW)xHACII mice) developed arthritis with substantially lower penetrance. This proposal will use this model system to understand how interactions between autoreactive CD4+ T cells and a self-peptide synthesized by systemically distributed APCs can lead to the development of autoimmune arthritis. In Aim 1 we will analyze how reciprocal interactions with APCs synthesizing their target peptide promote arthritogenic CD4+ T cell development, and examine whether arthritis is associated with elevated target antigen expression and/or regional APC activation. We will also examine whether lymphopenia-induced CD4+ T cell proliferation contributes to arthritis development in TCRxHACII mice. In Aim 2 we will examine factors that can contribute to disease penetrance and severity in TCRxHACII mice. We will determine how CD4+ T cell frequency and/or B cell function can shape the severity and penetrance of arthritis, and examine whether the ability of cytokine blockade to modulate arthritis severity is sensitive to variations in the autoreactive CD4+ T cell repertoire. In Aim 3 we will determine whether arthritis development can be predicted or promoted in a low penetrance setting. We will examine whether differences in the CD4+ T cell repertoire or serum cytokine composition can prospectively identify individuals that will develop arthritis, and analyze how infections might increase the penetrance of arthritis among genetically susceptible individuals. These studies will provide fundamental insights into the mechanisms of immune repertoire formation and tolerance, will have general applicability to the processes of autoimmunity, and will use experimental models with direct relevance to the diagnosis and treatment of human rheumatoid arthritis. PUBLIC HEALTH RELEVANCE Statement Autoimmune diseases are a result of the immune system attacking the body's own cells and tissues, but how these diseases arise remains poorly understood. This proposal uses genetically-modified mice to analyze mechanisms and cellular processes than can lead to the development of autoimmune arthritis. These studies aim to develop novel insights into the autoimmune disease process that will facilitate the diagnosis and treatment of human autoimmune diseases, particularly rheumatoid arthritis.