Molecular regulation of TLR2-mediated autoimmune inflammation

摘要 自身免疫性疾病中调节CD4+T细胞活化和功能的机制仍不充分 即使自身反应性的CD4+T细胞是虚拟的启动和进展的中央协调者 所有的自身免疫性疾病。多发性硬化症(MS)是一种中枢神经系统(CNS)脱髓鞘疾病，是一种 未能控制自身反应性CD4+T细胞如何导致破坏性炎症和 组织损伤。脑源性CD4+T辅助细胞，特别是Th17和Th1细胞，通过以下途径促进中枢神经系统炎症 实验性自身免疫性脑脊髓炎(EAE)对多发性硬化和小鼠多发性硬化模型中的自身抗原均有反应。 我们的开创性工作已经确定了一种先天的类似受体，它在驱动脑源性疾病的致病性方面起着关键作用。 Th17细胞在体内。此后，我们进一步确定了与此相关的关键转录和表观遗传机制 途径，表明先天类似的信号驱动签名编程事件，使Th17细胞总体上更多地 自身免疫性炎症的致病因素。我们在这里介绍的初步工作表明，激活这一功能 通路放大了Th17相关基因座上的基因促进染色质修饰，可能导致更多的人获得 促炎转录因子以及一种新的染色质调节因子的结合。这个染色质 我们的实验室最近确定了调节子的特征，我们证明了它在调节Th17细胞- 依赖性自身免疫性炎症。最后，我们的数据表明，内源性配体是这方面的有效放大因子。 在Th17细胞中的致脑作用和途径。综上所述，这些新的结果表明，自身免疫 可以通过靶向这一途径的下游效应来抑制Th17细胞来治疗疾病。因此， 这些研究的目的是描述导致我们的炎症潜在性增加的机制 在这些Th17细胞中站稳脚跟。将进行转录、表观遗传学和功能分析，以梳理出 通过我们的初步工作确定的新的调节因子的贡献。因此，我们的项目被设计成 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.