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

描述(申请人提供)：免疫细胞信号转导失调与各种自身免疫性和炎症性疾病的发生有关。类风湿关节炎(RA)是一种自身免疫性疾病，其特征是关节持续发炎，导致慢性组织破坏。许多动物模型和RA患者的研究表明，CD4+T细胞在RA的发生发展中起着重要作用。然而，关于T细胞受体(TCR)信号的遗传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的自身反应性T细胞的激活和扩张，目前还知之甚少。本研究的主要目的是阐明胸腺自身耐受和滑膜细胞因子环境在类风湿关节炎发病机制中的作用。在这项提案中，我将重点介绍两种小鼠变体，SKG小鼠和YYAA小鼠，每一种小鼠都由于ZAP-70突变而导致TCR信号的部分缺陷，ZAP-70是一种对TCR信号至关重要的酪氨酸激酶。SKG小鼠和YYAA小鼠表现出一些相似之处，如T细胞发育受损，TCR信号改变，以及正负选择缺陷。尽管有相似之处，但SKG小鼠最近表现出与人类RA相似的自发性关节炎，而YYAA小鼠中没有发现严重关节炎。为了了解SKG小鼠和YYAA小鼠之间差异的机制，我提出了两个特定的目标。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，我将通过比较两只小鼠的细胞因子谱并检测两只小鼠记忆中CD4+T细胞的增殖指数和促生存蛋白的表达水平，来确定自体反应性T细胞的动态平衡增殖和细胞因子产生如何促进类风湿关节炎的发展。这些研究将有助于理解TCR信号的数量差异如何导致RA的发展，并可能为T细胞自身免疫的相关机制提供见解，从而可能导致新的治疗方法。 与公共卫生相关：RA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细胞耐受性如何被打破的理解。此外，研究细胞因子在分级调控网络中是如何组织的，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.