The Role of TNFSF14 (LIGHT) In Preventing Severe Colitis

LIGHT是肿瘤坏死因子超家族的一员，它涉及两个受体，淋巴毒素B受体（LTBR）和疱疹病毒进入介质（HVEM）。转基因小鼠T细胞过度表达LIGHT导致结肠炎。然而，我们已经做出了令人惊讶的观察，在免疫缺陷的Rag-/-小鼠中缺乏LIGHT表达导致T细胞转移模型中结肠炎增加。本应用中的实验旨在了解LIGHT表达在预防严重结肠炎中的惊人抗炎作用。我们的初步数据表明，LIGHT通过与LTBR结合在先天免疫系统中起作用。根据我们的数据和已发表的文献，我们提出巨噬细胞表达的LIGHT作用于这些细胞表达的LTBR，促进其凋亡，从而限制炎症。我们将使用免疫学和遗传学方法的结合来验证我们的假设，并了解除T淋巴细胞外的细胞表达LIGHT在预防严重结肠炎中的意外作用。在目的1中，我们将描述Rag-/-受体缺乏LIGHT小鼠严重结肠炎的免疫发病机制。我们还将分析仅涉及先天免疫细胞的结肠炎模型中LIGHT表达减少的影响，我们将确定LIGHT缺乏是否会影响某些细胞类型的凋亡，这是LIGHT:LTBR相互作用的已知结果。在目的2中，我们将证实（或驳斥）表明严重结肠炎的预防依赖于LTBR表达的初步数据。在目标3中，我们将确定是否需要可溶性光，因为它是在豆豆蛋白a诱导的肝损伤。aim 4的实验将确定必须表达LIGHT及其受体才能预防严重疾病的关键细胞类型。最后，Aim 5的实验将把小鼠模型的发现与患者的研究联系起来。我们将研究影响IBD患者结肠炎发病机制的TNFSF14 （LIGHT）基因多态性，以确定这些多态性是否与LIGHT表达水平或LIGHT结合其受体的能力有关。因此，本项目的实验应该会对缺乏LIGHT表达的严重结肠炎的机制有很大的了解。

LIGHT is a member of the tumor necrosis factor super family that engages two receptors, the lymphotoxin B receptor (LTBR) and the herpes virus entry mediator (HVEM). Over expression of LIGHT by transgenic mouse T cells causes colitis. We have made the surprising observation, however, that the absence of LIGHT expression in immune deficient Rag-/- mice leads to increased colitis in the T cell transfer model. The experiments in this application are designed to understand the surprising anti-inflammatory role of LIGHT expression in preventing severe colitis. Our preliminary data indicate that LIGHT acts in the innate Immune system by binding to the LTBR. Based on our data and published literature, we propose that LIGHT expression by macrophages acts on the LTBR also expressed by these cells to promote their apoptosis, thereby limiting inflammation. We will use a combination of Immunologic and genetic methods to test our hypothesis and to understand the unexpected role of LIGHT expression by cells other than T lymphocytes in the prevention of severe colitis. In aim 1, we will characterize the immunopathogenesis of the severe colitis in Rag-/- recipient mice deficient for LIGHT. We also will analyze the effects of reduced LIGHT expression in models of colitis that involve only innate immune cells, and we will determine if the absence of LIGHT affects apoptosis of some cell type, a known outcome of the LIGHT:LTBR Interaction. In aim 2 we will confirm (or refute) the preliminary data indicating that prevention of severe colitis is dependent upon LTBR expression. In aim 3 we will determine if soluble LIGHT Is required, as It Is In concanavalin A-induced liver damage. Experiments in aim 4 will determine the critical cell types that must express LIGHT and its receptor in order to prevent severe disease. Finally, experiments in Aim 5 will bridge the findings from mouse models to the study of patients. We will investigate TNFSF14 (LIGHT) gene polymorphisms that affect colitis pathogenesis In IBD patients, to determine if these are related either to LIGHT expression levels or to the ability of LIGHT to bind its receptors. Therefore, the experiments in this project should lead to great Insights into the mechanism underlying severe colitis in the absence of LIGHT expression.