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。类风湿性关节炎（RA）是一种自身免疫性疾病，其特征是关节持续炎症，导致慢性组织破坏。许多来自动物模型和RA患者的研究揭示了CD4+ T细胞在RA发生发展中的重要作用。然而，对于T细胞受体（TCR）信号传导中的遗传和获得性缺陷如何转化为自身免疫等不同结果，以及哪些因素影响致病性自反应性T细胞的激活和扩增，人们知之甚少。该建议的主要目的是阐明胸腺的自我耐受和滑膜中的细胞因子环境在RA发病机制中的作用。在本提案中，我将重点研究两种小鼠变异，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）的突变，它们在TCR信号传导中都存在部分缺陷。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，阳性和阴性选择缺陷。尽管有相似之处，SKG小鼠最近显示出与人类类风湿性关节炎相似的自发性关节炎，而YYAA小鼠没有发现严重的关节炎。为了理解SKG小鼠和YYAA小鼠之间差异的潜在机制，我提出了两个具体目标。首先，我将通过YYAA小鼠与SKG小鼠或与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，我将通过比较两种小鼠的细胞因子谱，并检查两种小鼠的记忆性CD4+ T细胞的增殖指数和促生存蛋白的表达水平，确定自身反应性T细胞的稳态增殖和细胞因子的产生如何促进RA的发展。这些研究将有助于了解TCR信号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，从而可能导致新的治疗方法。

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.