Abstract：
BACKGROUND: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4+ T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4+ T cells will yield new insights into its pathogenesis.
METHODS: Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14+ monocytes.
RESULTS: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA.
CONCLUSIONS: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis.
METHODS: Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14+ monocytes.
RESULTS: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA.
CONCLUSIONS: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis.
摘要：
背景：巨细胞动脉炎（GCA）是一种免疫介导的大血管血管炎，病因复杂。尽管致病机制仍然知之甚少，已经证明了CD4+T细胞的核心作用。在这种情况下，了解GCACD4+T细胞的转录组失调将对其发病机制产生新的见解。
方法：对70例具有不同疾病活动性和治疗状态的GCA患者（治疗前活跃患者和有或没有糖皮质激素治疗的缓解患者）的CD4+T细胞进行转录组分析，和28个健康对照。该研究还评估了DNA甲基化对基因表达改变的潜在影响，并评估了CD14+单核细胞的串扰。
结果：这项研究发现了大量可能导致GCA中CD4+T细胞致病性的基因和途径。具体来说,来自活动性疾病的GCA患者的CD4+T细胞表现出参与多种免疫相关过程的基因表达水平的改变，包括各种白细胞介素（IL）信号通路。值得注意的是,IL-2，调节性T细胞稳态的决定性白细胞介素，是最重要的。此外,受损的凋亡途径在GCA发育中显得至关重要。我们的发现还表明，组蛋白相关的表观遗传途径可能与促进GCA活跃患者的炎症表型有关。最后,我们的研究观察到信令通信改变，比如锯齿形缺口信号，CD4+T细胞和单核细胞之间可能与GCA致病相关。
结论：我们的研究表明新的细胞因子和通路的参与以及单核细胞-T细胞串扰的破坏驱动GCA发病机制的发生。
方法：对70例具有不同疾病活动性和治疗状态的GCA患者（治疗前活跃患者和有或没有糖皮质激素治疗的缓解患者）的CD4+T细胞进行转录组分析，和28个健康对照。该研究还评估了DNA甲基化对基因表达改变的潜在影响，并评估了CD14+单核细胞的串扰。
结果：这项研究发现了大量可能导致GCA中CD4+T细胞致病性的基因和途径。具体来说,来自活动性疾病的GCA患者的CD4+T细胞表现出参与多种免疫相关过程的基因表达水平的改变，包括各种白细胞介素（IL）信号通路。值得注意的是,IL-2，调节性T细胞稳态的决定性白细胞介素，是最重要的。此外,受损的凋亡途径在GCA发育中显得至关重要。我们的发现还表明，组蛋白相关的表观遗传途径可能与促进GCA活跃患者的炎症表型有关。最后,我们的研究观察到信令通信改变，比如锯齿形缺口信号，CD4+T细胞和单核细胞之间可能与GCA致病相关。
结论：我们的研究表明新的细胞因子和通路的参与以及单核细胞-T细胞串扰的破坏驱动GCA发病机制的发生。
