Comparison of SKG and ZAP-70 YYAA mutant mice in the development of arthritis

描述（由申请人提供）：已知免疫细胞中失调的信号转导与各种自身免疫性和炎性疾病的发展相关。风湿性关节炎（RA）是一种自身免疫性疾病，其特征在于关节的持续炎症，其导致慢性组织破坏。许多动物模型和RA患者的研究表明，CD 4 + T细胞在RA的发生发展中起着重要作用。然而，人们对T细胞受体（TCR）信号传导中的遗传性和获得性缺陷如何转化为不同的结果（如自身免疫）以及哪些因素影响致病性自身反应性T细胞的激活和扩增知之甚少。这个建议的主要目的是阐明RA发病机制中胸腺自身耐受和滑膜细胞因子环境的作用。在这个提议中，我将专注于两种小鼠变体，SKG小鼠和YYAA小鼠，由于ZAP-70（一种对TCR信号传导至关重要的酪氨酸激酶）突变，每种小鼠都有TCR信号传导的部分缺陷。SKG小鼠和YYAA小鼠表现出几个相似之处，如受损的T细胞发育，改变的TCR信号传导，以及有缺陷的阳性和阴性选择。尽管有相似之处，SKG小鼠最近显示出与人类RA相似的自发性关节炎，而在YYAA小鼠中未发现严重的关节炎。为了理解SKG小鼠和YYAA小鼠之间差异的机制，我提出了两个具体的目标。首先，我将通过将YYAA小鼠与SKG小鼠或ZAP-70缺失小鼠杂交来确定胸腺阈值的分级变化对自身免疫性疾病发展的影响。其次，我将确定如何稳态增殖和细胞因子的产生，从自身反应性T细胞有助于RA的发展，通过比较细胞因子的两种小鼠和检查的增殖指数和促生存蛋白的表达水平的记忆CD 4 + T细胞从两种小鼠。这些研究将有助于了解TCR信号传导的定量差异如何导致RA的发展，并可能提供与T细胞自身免疫相关的机制的见解，这些机制可能导致新的治疗方法。 公共卫生相关性：类风湿关节炎的主要特征是自身免疫、慢性炎症和关节破坏。我们对自身免疫阈值的研究可能会提高我们对T细胞耐受性如何被破坏的理解。此外，研究细胞因子如何在分级调控网络中组织，应该有助于确定促进从自身免疫到慢性炎症进展的重要检查点。

DESCRIPTION (provided by applicant): Dysregulated signal transduction in immune cells is known to be associated with the development of various autoimmune and inflammatory diseases. Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by persistent inflammation of the joints, which results in chronic tissue destruction. Many studies from animal models and RA patients have revealed an important role for CD4+ T cells in the development of RA. However, little is known about how inherited and acquired defects in T cell receptor (TCR) signaling translate into different outcomes such as autoimmunity, and which factors affect the activation and expansion of pathogenic self-reactive T cells. The broad objective of this proposal is to elucidate the roles of self-tolerance in the thymus and cytokine milieu in the synovium in the pathogenesis of RA. In this proposal, I will focus on two mouse variants, the SKG mice and YYAA mice, each with partial defects in TCR signaling due to mutation in ZAP-70, a tyrosine kinase crucial to TCR signaling. SKG mice and YYAA mice exhibit several similarities such as impaired T cell development, altered TCR signaling, and defective positive and negative selection. Despite the similarities, SKG mice have recently shown to develop spontaneous arthritis similar to human RA whereas severe arthritis was not found in the YYAA mice. To understand the mechanisms underlying the difference between SKG mice and YYAA mice, I proposed two specific aims. First, I will determine the impact of a graded change in thymic threshold on the development of autoimmune disease by crossing YYAA mice with SKG mice or with ZAP-70 null mice. Second, I will determine how homeostatic proliferation and cytokine production from autoreactive T cells contribute to the development of RA by comparing the cytokine profile of both mice and examining the proliferation index and the expression levels of pro-survival proteins in memory CD4+ T cells from both mice. These studies will help to understand how quantitative differences in TCR signaling will lead to the development of RA and may provide insights into mechanisms relevant to T cell autoimmunity that could lead to novel therapeutics. PUBLIC HEALTH RELEVANCE: The key features of RA are autoimmunity, chronic inflammation and joint destruction. Our studies of autoimmunity threshold might improve our understanding of how T cell tolerance is breached. In addition, studying how cytokines are organized within a hierarchical regulatory network should help identify important checkpoints that facilitate the progression from autoimmunity to chronic inflammation.