Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Front Immunol. 2021 Dec 23;12:791099. doi: 10.3389/fimmu.2021.791099. eCollection 2021.
The aim of this study was to quantitatively assess distinct immune cell subsets comprising inflammatory infiltrate in temporal artery biopsies (TABs) from patients with giant cell arteritis (GCA), and to link the obtained histopathological data with expression profiles of immune-related microRNAs (miRNAs).
The study included 68 formalin-fixed, paraffin-embedded TABs from treatment-naïve patients, including 30 histologically positive GCA and 16 negative GCA TABs, and 22 control non-GCA TABs. Quantitative assessment of histological parameters was performed using histopathological and immunohistochemical techniques. miRNA expression analysis was performed by quantitative real-time PCR.
Intense transmural mononuclear inflammatory infiltrates in TAB-positive GCA arteries were predominantly composed of CD3, CD4 and CD8 T lymphocytes, and CD68 macrophages, accompanied by a strong nuclear overexpression of the nuclear factor of activated T cells, cytoplasmic 1 (NFATC) in the lymphocyte infiltrate fraction. Furthermore, TAB-positive GCA arteries were characterized by significant overexpression of nine pro-inflammatory miRNAs (miR-132-3p/-142-3p/-142-5p/-155-5p/-210-3p/-212-3p/-326/-342-5p/-511-5p) and a significant under-expression of six regulatory immune-related miRNAs (miR-30a-5p/-30b-5p/-30c-5p/-30d-5p/-30e-5p/-124-3p), whose expression levels significantly associated with most evaluated histopathological parameters. Notably, we revealed miR-132-3p/-142-3p/-142-5p/-155-5p/-212-3p/-511-5p as major promoters of arterial inflammation and miR-30a-5p/-30c-5p/-30d-5p as putative regulators of NFATC signaling in TAB-positive GCA arteries.
Overall, we demonstrated that an altered arterial tissue-specific pro-inflammatory miRNA signature favors enhanced T cell-driven inflammation and macrophage activity in TAB-positive GCA arteries. Moreover, dysregulation of several immune-related miRNAs seems to contribute crucially to GCA pathogenesis, through impairing their regulatory activity towards T cell-mediated immune responses driven by the calcineurin (CaN)/NFAT signaling pathway, indicating their therapeutic, diagnostic and prognostic potential.
本研究旨在定量评估巨细胞动脉炎（GCA）患者颞动脉活检（TAB）中炎症浸润的不同免疫细胞亚群，并将获得的组织病理学数据与免疫相关 microRNA（miRNA）的表达谱相关联。
该研究纳入了 68 例未经治疗的患者的福尔马林固定、石蜡包埋的 TAB，包括 30 例组织学阳性的 GCA 和 16 例组织学阴性的 GCA TAB，以及 22 例非 GCA TAB 对照。使用组织病理学和免疫组织化学技术对组织学参数进行定量评估。通过实时定量 PCR 进行 miRNA 表达分析。
TAB 阳性 GCA 动脉中的强烈壁内单核炎症浸润主要由 CD3、CD4 和 CD8 T 淋巴细胞以及 CD68 巨噬细胞组成，伴有淋巴细胞浸润部分核因子活化 T 细胞细胞质 1（NFATC）的强烈核过表达。此外，TAB 阳性 GCA 动脉的特征是前炎症 miRNA（miR-132-3p/-142-3p/-142-5p/-155-5p/-210-3p/-212-3p/-326/-342-5p/-511-5p）的显著过度表达和六个调节性免疫相关 miRNA（miR-30a-5p/-30b-5p/-30c-5p/-30d-5p/-30e-5p/-124-3p）的显著低表达，其表达水平与大多数评估的组织病理学参数显著相关。值得注意的是，我们发现 miR-132-3p/-142-3p/-142-5p/-155-5p/-212-3p/-511-5p 作为动脉炎症的主要促进因子，miR-30a-5p/-30c-5p/-30d-5p 作为 TAB 阳性 GCA 动脉中 NFATC 信号的潜在调节因子。
总体而言，我们表明，改变的动脉组织特异性前炎症 miRNA 特征有利于增强 TAB 阳性 GCA 动脉中的 T 细胞驱动的炎症和巨噬细胞活性。此外，几种免疫相关 miRNA 的失调似乎通过损害其对钙调神经磷酸酶（CaN）/NFAT 信号通路驱动的 T 细胞介导免疫反应的调节活性，对 GCA 发病机制有重要贡献，表明它们具有治疗、诊断和预后潜力。
