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良好表征的模型系统来定义对自身抗原的耐受性与自身免疫性的过程。为此，我们开发了表达流感病毒血凝素（HA）作为标称自身抗原的转基因小鼠谱系，并分析了它们诱导CD 4 + T和B细胞对HA耐受的程度和基础。在最近的资助期内，我们发现表达由MHC II类启动子驱动的HA的小鼠（HACII小鼠）和共表达HA特异性CD 4 + T细胞受体的小鼠（TCRxHACII小鼠）自发地发展自身免疫，其中炎性关节炎是突出的疾病表现。我们发现关节炎的发展是由CD 4 + T细胞驱动的，并依赖于抗原呈递细胞（APC）合成新的自身HA分子。此外，关节炎的发病率可以通过改变CD 4 + T细胞对HA的反应性来调节，因为大多数TCR将HA识别为激动剂肽的小鼠（TS 1xHACII小鼠）发生关节炎，而表达对HA具有约100倍低反应性的TCR的小鼠（TS 1（SW）xHACII小鼠）发生关节炎时的发病率显著较低。该提案将使用该模型系统来了解自身反应性CD 4 + T细胞与全身分布的APC合成的自身肽之间的相互作用如何导致自身免疫性关节炎的发展。在目的1中，我们将分析如何相互作用与APC合成其靶肽促进致关节炎的CD 4 + T细胞的发展，并检查关节炎是否与靶抗原表达升高和/或区域APC激活。我们还将研究淋巴细胞减少诱导的CD 4 + T细胞增殖是否有助于TCRxHACII小鼠的关节炎发展。在目标2中，我们将研究可能导致TCR xHACII小鼠疾病发生率和严重程度的因素。我们将确定CD 4 + 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复发率，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CD 4 + T细胞库的变化敏感。在目标3中，我们将确定关节炎的发展是否可以预测或促进在低发病率的设置。我们将研究CD 4 + 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遗传易感个体中关节炎的发病率。这些研究将为免疫谱系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性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，但这些疾病是如何发生的仍然知之甚少。该提案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。这些研究的目的是发展新的见解的自身免疫性疾病的过程，这将有助于诊断和治疗人类自身免疫性疾病，特别是类风湿性关节炎。

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.