Molecular regulation of TLR2-mediated autoimmune inflammation

总结 自身免疫性疾病中CD4+ T细胞活化和功能的调控机制仍不充分 尽管自身反应性CD4+ T细胞是启动和发展几乎所有免疫缺陷的核心， 所有自身免疫性疾病。多发性硬化症（MS）是中枢神经系统（CNS）的脱髓鞘疾病， 这是一个典型的例子，说明无法控制自身反应性CD4+ T细胞如何导致破坏性炎症， 组织损伤致脑性CD4+辅助性T（Th）细胞，特别是Th17和Th1细胞，通过以下方式促进CNS炎症： 在MS和鼠MS模型中，实验性自身免疫性脑脊髓炎（EAE）对自身抗原应答。 我们的开创性工作已经确定了一种在驱动致脑炎性疾病致病性中起关键作用的先天性样受体， 体内Th17细胞。从那时起，我们进一步确定了与此相关的关键转录和表观遗传机制。 这表明，先天性信号转导驱动签名编程事件，使Th17细胞更 自身免疫性炎症的病原体。我们在此提出的初步工作表明，激活这种 途径放大了Th17相关基因座的基因促进染色质修饰，可能导致Th17相关基因的获得增加。 促炎转录因子以及新的染色质调节因子的结合。这个染色质 调节因子最近由我们的实验室表征，我们证明了它在介导Th17细胞中的重要性， 依赖性自身免疫性炎症最后，我们的数据表明，内源性配体是这一过程的有效放大器。 途径以及Th17细胞中的致脑炎性。总之，这些新的结果表明， 可以通过靶向该途径的下游效应以抑制Th17细胞来治疗疾病。因此 这些研究的目的是描述导致我们所具有的增加的炎症潜能的机制。 在Th17细胞中牢固地建立。将进行转录、表观遗传和功能分析， 我们的初步工作确定的新的调节因子的贡献。因此，我们的项目设计 通过两个相互关联的具体目标来检验我们的中心假设。

SUMMARY The mechanisms governing CD4+ T cell activation and function in autoimmune disease remain insufficiently understood even though autoreactive CD4+ T cells are central orchestrators for the initiation and progression of virtually all autoimmune diseases. Multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), is a well characterized example of how the failure to control autoreactive CD4+ T cells can lead to devastating inflammation and tissue damage. Encephalitogenic CD4+ T helper (Th) cells, especially Th17 and Th1 cells, promote CNS inflammation by responding to self-antigens both in MS and the murine MS model, experimental autoimmune encephalomyelitis (EAE). Our seminal work has identified an innate-like receptor with critical roles in driving the pathogenicity of encephalitogenic Th17 cells in vivo. Since, we have further identified key transcriptional and epigenetic mechanisms associated with this pathway, indicating that innate-like signaling drives signature programming events that render Th17 cells altogether more pathogenic for autoimmune inflammation. Our preliminary work presented herein demonstrates that activation of this pathway amplifies gene-promoting chromatin modifications at Th17-related loci, likely resulting in increased access for pro-inflammatory transcription factors as well as the binding of a novel chromatin regulatory factor. This chromatin regulator was recently characterized by our laboratory and we demonstrate its essentiality in mediating Th17 cell- dependent autoimmune inflammation. Finally, our data demonstrates that endogenous ligands are potent amplifiers of this pathway as well as encephalitogenicity in Th17 cells. Taken together, these novel results suggest that autoimmune disorders may be treated through targeting the downstream effects of this pathway to inhibit Th17 cells. Therefore, the goal of these studies is to characterize the mechanisms responsible for the increased inflammatory potential that we have firmly established in these Th17 cells. Transcriptional, epigenetic, and functional analyses will be performed to tease out the contributions of the novel regulatory factors identified by our preliminary work. Consequently, our project is designed to test our central hypothesis through two interlinked specific aims.