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自身免疫性疾病的原因，超过 2300 万美国人患有这种疾病。自从 Frank Macfarlane Burnet 爵士在 20 世纪 50 年代末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负责 T 细胞耐受的基因，特别是外周 T 细胞耐受的分子机制仍然是一个免疫学之谜。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的激活，以促进抑制自身反应性T细胞激活的基因（称为无能基因）的表达。然而，尚待确定其他因素来充分解释 T 细胞耐受性的分子难题。我们推测，除了上调抑制基因外，无能信号传导还可能下调 T 细胞的某些激活剂（正调节因子），以诱导和维持外周耐受。通过比较无反应性 T 细胞与幼稚和活化 T 细胞的基因表达谱，我们证明滑膜蛋白表达下调会导致 T 细胞耐受。然后我们生成了 T 细胞特异性滑膜素基因敲除小鼠。利用这种独特的小鼠模型，我们证明了Synoviolin基因的遗传删除可促进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侵害，这意味着Synoviolin是自身免疫性疾病的潜在治疗靶点。目前的研究旨在阐明 Synoviolin 在 T 细胞耐受和激活中的分子机制。我们还将使用遗传和药理学方法来评估滑膜素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.