Immune Regulation by Gadd45b and Gadd45g

描述（由申请人提供）：我们的长期目标是了解控制自身免疫性疾病的分子机制。我们目前关注的是一个名为Gadd45（生长抑制和DNA损伤诱导）的基因家族，它由三个成员组成，Gadd45a， Gadd45b和Gadd45g。Gadd45a被证明参与调节T细胞的稳态，已知缺乏Gadd45a会导致狼疮。另外两个家族成员Gadd45b和Gadd45g在自身免疫性疾病中的作用尚不清楚。在Th1细胞中，Gadd45b和Gadd45g可被TCP信号或IL-12和IL-18诱导，而Gadd45a不受其影响。我们发现缺乏Gadd45b和Gadd45g会导致抗单核增生李斯特菌的Th1细胞数量急剧减少。预期Th1细胞数量较少，我们惊讶地发现Gadd45b缺失导致实验性变应性脑脊髓炎（EAE）加重，临床症状更严重，病程延长，炎症中枢神经系统中自身反应性Th1细胞增加。Gadd45b缺失也会导致老年小鼠脾脏增大。与Gadd45b单缺失相比，Gadd45b/Gadd45g双缺失进一步加重了这种表型，导致老年小鼠的脾脏大大增大。脾脏肿大是由于活化型CD4+ T细胞和B细胞的积累所致。我们的数据表明，Gadd45b和Gadd45g在调节活化的CD4+ T细胞中发挥协同作用。此外，我们发现Gadd45b和Gadd45g抑制增殖，并且是活化CD4+ T细胞凋亡所必需的。在本提案中，我们正在验证Gadd45蛋白家族成员Gadd45b和Gadd45g是自身免疫的重要负调节因子的假设。具体来说，我们计划：1。为Gadd45b和Gadd45g协同调节自身免疫性疾病提供了明确证据，2。2 .确定Gadd45b和Gadd45g是否对EAE中T细胞增殖和凋亡的控制起关键作用；研究Gadd45b和Gadd45g调控Th1细胞增殖和凋亡的分子机制。Gadd45家族分子对外周效应CD4+ T细胞增殖和凋亡的调控为自身免疫提供了新的调控机制。相关性：这项研究将导致针对这些分子治疗或预防自身免疫性疾病的新策略的发展。本研究还将揭示自身免疫性疾病的新疾病标志物。

DESCRIPTION (provided by applicant): Our long term objective is to understand the molecular mechanisms that control autoimmune diseases. Our immediate focus is on a gene family called Gadd45 (growth-arrest and DNA damage-inducible) which consists of three members,Gadd45a, Gadd45b, and Gadd45g. Gadd45a was shown to be involved in regulating homeostasis of T cells and lack of Gadd45a was known to cause lupus. The role of the other two family members, Gadd45b and Gadd45g, in autoimmune diseases is not clear. In Th1 cells, Gadd45b and Gadd45g, but not Gadd45a, are induced by TCP signaling or IL-12 and IL-18. We have found that the lack of Gadd45b and Gadd45g results in a drastically reduced number of Th1 cells against Listeria monocytogenes. Expecting low numbers of Th1 cells, we were surprised to see that Gadd45b deletion resulted in exacerbated experimental allergic encephalomyelitis (EAE) with more severe clinical signs, a prolonged disease course and increased autoreactive Th1 cells in the inflamed CNS. Gadd45b deletion also resulted in enlarged spleens in older mice. Gadd45b/Gadd45g double-deficiency further aggravated this phenotype and resulted in greatly enlarged spleens in older mice compared to Gadd45b single deletion. The enlargement of spleens was due to the accumulation of CD4+ T cells with an activated phenotype and B cells. Our data suggest that Gadd45b and Gadd45g play a synergistic role in regulating activated CD4+ T cells. In addition, we found that Gadd45b and Gadd45g inhibited proliferation and were required for apoptosis of activated CD4+ T cells. In this proposal we are testing the hypothesis that Gadd45 protein family members Gadd45b and Gadd45g are important negative regulators of autoimmunity. Specifically we plan to: 1. provide definitive proof that Gadd45b and Gadd45g coordinately regulate autoimmune diseases, 2. determine if Gadd45b and Gadd45g are critical for the control of T cell proliferation and apoptosis in EAE, and 3. study molecular mechanisms that regulate the proliferation and apoptosis of Th1 cells by Gadd45b and Gadd45g. Regulation of proliferation and apoptosis in peripheral effector CD4+ T cells by Gadd45 family of molecules provides a new regulatory mechanism for autoimmunity. Relevance: This study will lead to the development of novel strategies targeting these molecules to treat or prevent autoimmune diseases. This study will also reveal new disease markers for autoimmune diseases.