The roles of Synoviolin in immune tolerance and autoimmunity

描述（由申请人提供）：T细胞耐受性受损是所有类型的自身免疫性疾病的原因，超过2300万美国人患有这种疾病。自20世纪50年代末Frank Macfarlane伯内特爵士首次描述免疫耐受并获得1960年诺贝尔生理学或医学奖以来，人们付出了巨大的努力来鉴定与T细胞耐受有关的基因，特别是外周T细胞耐受的分子机制仍然是免疫学上的一个谜。目前的教条是，自身反应性T细胞上的TCR在没有CD28共刺激的情况下识别自身抗原后，介导NFAT的活化以促进抑制自身反应性T细胞活化的基因（称为无反应性基因）的表达。然而，其他因素尚未确定，以充分解释T细胞耐受性的分子难题。我们推测，除了上调抑制性基因外，无反应性信号可能下调T细胞的某些激活因子（正调节因子）以诱导和维持外周耐受。通过比较无反应性T细胞与na？我们证明，下调滑膜蛋白表达导致T细胞耐受。然后，我们产生了T细胞特异性Synoviolin敲除小鼠。使用这种独特的小鼠模型，我们证明了Synoviolin基因的遗传缺失促进T细胞耐受诱导，抑制T细胞活化并保护小鼠免受自身免疫性疾病的影响，这意味着Synoviolin作为自身免疫性疾病的潜在治疗靶点。本研究旨在阐明滑膜素在T细胞免疫耐受和活化中的分子机制。我们还将使用遗传学和药理学方法来评估Synoviolin抑制在小鼠自身免疫治疗中的功效。

DESCRIPTION (provided by applicant): Impaired T cell tolerance is the cause of all types of autoimmune diseases, which suffers more than 23 million Americans. Since Sir Frank Macfarlane Burnet first described immune tolerance in late 1950s and received the 1960 Nobel Prize in Physiology or Medicine, tremendous efforts have identified genes that are responsible for T cell tolerance, the molecular mechanisms in particularly underlying the peripheral T cell tolerance remain an immunological mystery. The current dogma is that TCRs on self-reactive T cells, upon recognition of self-antigens without CD28 co-stimulation, mediate the activation of NFAT to promote the expression of genes that suppress the activation of self-reactive T cells (known as anergic genes). However, additional factors yet to be identified to fully explain the molecular puzzles of T cell tolerance. We speculate that, in addition to upregulating the suppressive genes, anergic signaling may down-regulate certain activators (positive regulators) of T cells to induce and maintain the peripheral tolerance. By comparing the gene expression profiles of anergic T cells with na?ve and activated T cells, we demonstrated that downregulation of Synoviolin expression leads to T cell tolerance. We then generated T cell-specific Synoviolin knockout mice. Using this unique mouse model, we demonstrated that genetic deletion of Synoviolin gene promotes T cell tolerance induction, inhibits T cell activation and protects mice from autoimmune disease, implying Synoviolin as a potential therapeutic target for autoimmune diseases. The current study is to illuminate the molecular mechanisms of Synoviolin in T cell tolerance and activation. We will also use both the genetic and pharmacological approaches to evaluate the efficacy of Synoviolin suppression in autoimmune treatment in mice.