Innate Immune Activation in Autoimmune Myopathy

项目总结/摘要 特发性炎性肌病（IIM）代表一组全身性自身免疫性疾病，其中 肌肉和肌外器官是免疫介导破坏的目标。我们先前已经 建立了组氨酰-tRNA合成酶（HRS）诱导的肌炎模型，涉及MyD 88依赖性 Toll样受体2和4（TLR 2、TLR 4）为特征的先天免疫信号传导途径。鉴于突出的 在我们的HRS诱导的肌炎模型中，这些TLR的作用，我们假设， 下游转录调节因子NF-κB最终也负责各种炎症级联反应 作为非免疫途径，促进该系统中的肌肉功能障碍-有效地将HRS诱导的 肌炎/IIM伴其他疾病（包括肌营养不良以及败血症和创伤/缺血） 诱导的肌病），其中NF-κB失调导致肌肉炎症，肌肉变性， 和受损的再生潜能通过一系列的体外培养系统和体内免疫 策略涉及敲除小鼠缺乏MyD 88依赖性信号通路的关键组成部分，我们 将系统地研究HRS诱导的TLR信号传导和NF-κB活化对T细胞迁移的影响， T细胞活化和肌肉无力。而具体目标1将重点关注HRS诱导的T细胞变化， 功能和TLR介导的血管内皮活化（导致靶细胞的淋巴细胞浸润） 具体目标2将定义肌肉中HRS诱导的NF-κB活化的直接和间接途径 通过体外成肌细胞刺激试验以及其他免疫研究， 肌肉炎症、NF-κB活化与肌肉在体/离体参数之间的相关性 弱点补充体内评估工具，包括MRI和使用NF-κ B-荧光素酶转基因 小鼠将进一步确定HRS介导的NF-κB活化和肌肉功能障碍之间的关系， 为特异性目的3中比较NF-κB抑制的实验试验提供基础。总的来说， 这些研究将阐明先天性免疫对IIM发病机制的贡献，补充更多 抗原特异性、适应性免疫识别和鉴定治疗靶点的传统范例 可能与一系列人类炎症性肌肉疾病有关。

PROJECT SUMMARY/ABSTRACT The idiopathic inflammatory myopathies (IIMs) represent a group of systemic autoimmune disorders in which muscle and extra-muscular organs are targeted for immune-mediated destruction. We have previously established a model of histidyl-tRNA synthetase (HRS)-induced myositis that involves MyD88-dependent innate immune signaling pathways featuring Toll-like receptors 2 and 4 (TLR2, TLR4). Given the prominent role of these TLRs in our model of HRS-induced myositis, we hypothesize that heightened activation of the downstream transcription regulator NF-κB is ultimately responsible for various inflammatory cascades as well as non-immune pathways promoting muscle dysfunction in this system—effectively linking HRS-induced myositis/IIM with other disorders (including muscular dystrophy as well as sepsis- and trauma/ischemia- induced myopathies) in which NF-κB dysregulation contributes to muscle inflammation, muscle degeneration, and impaired regenerative potential. Through a series of in vitro culture systems and in vivo immunization strategies involving knockout mice lacking critical components of MyD88-dependent signaling pathways, we will systematically examine the impact of HRS-induced TLR signaling and NF-κB activation on T cell migration, T cell activation, and muscle weakness. While Specific Aim 1 will focus on HRS-induced changes in T cell function and TLR-mediated activation of vascular endothelium (leading to lymphocytic infiltration of target organs), Specific Aim 2 will define direct and indirect pathways of HRS-induced NF-κB activation in muscle tissue through in vitro myoblast stimulation assays as well as additional immunization studies focusing on correlations between muscle inflammation, NF-κB activation, and in vivo/ex vivo parameters of muscle weakness. Complementary in vivo assessment tools including MRI and the use of NF-κB-luciferase transgenic mice will further define the relationship between HRS-mediated NF-κB activation and muscle dysfunction, providing the foundation for experimental trials of comparative NF-κB inhibition in Specific Aim 3. Collectively, these studies will elucidate the contribution of innate immunity to the pathogenesis of IIM, supplementing more traditional paradigms of antigen-specific, adaptive immune recognition and identifying therapeutic targets that are potentially relevant to a range of human inflammatory muscle diseases.