存活素；一种新的治疗靶点，与从强直性脊柱炎患者中获得的自身反应性 T 淋巴细胞的存活相关。
Survivin; a novel therapeutic target that correlates with survival of autoreactive T lymphocytes obtained from patients with ankylosing spondylitis.
机构信息
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
出版信息
Gene. 2022 Nov 30;844:146829. doi: 10.1016/j.gene.2022.146829. Epub 2022 Aug 19.
Ankylosing spondylitis (AS) is progressive immune-mediated arthritis. Persistent autoreactivity of T cells with an up-regulated Survivin expression is strongly implicated in AS immunopathogenesis. Besides, Survivin can inhibit proapoptotic caspase 9 activations. Moreover, microRNAs are small non-coding RNAs that are dysregulated in various diseases, in which their altered expression could modulate Survivin expression. The primary goal of this study was to assess the role of Survivin and its-targeting microRNAs in the immunopathogenesis of AS disease. For this aim, peripheral blood mononuclear cells (PBMCs) were isolated from 15 patients with AS and healthy matched controls using Ficoll-Hypaque. T cells were obtained using the magnetic-activated cell sorting (MACS) method. After that, the expression levels of Survivin, Caspase 9, and specific miRNAs were determined using qT-qPCR. Also, the expression of Survivin and Caspase 9 at protein levels was determined by western blotting. Then, the isolated T cells were co-cultured with interleukin (IL)-2 and muromonab-CD3 (OKT-3) for active-induced cell death (AICD) induction, Survivin siRNA for inhibition of Survivin expression, and their combination to assess the implication of Survivin expression in autoreactive T lymphocytes' resistance to apoptosis by determining the rate of apoptosis by Flowcytometry assay. The results showed that Survivin was up-regulated while Caspase 9 was downregulated in patients with AS. It was also revealed that microRNAs that directly or indirectly target the Survivin mRNA were dysregulated in patients with AS. It was also revealed that T cells obtained from AS patients were more resistant to apoptosis induction than those obtained from healthy people. In summary, the results obtained from this study showed that dysregulation of Survivin and Survivin-targeting miRNAs in T lymphocytes obtained from AS patients contribute to their resistance to apoptosis, suggesting the future development of targeted therapies for AS.
强直性脊柱炎（AS）是一种进行性免疫介导的关节炎。T 细胞持续的自身反应性，伴有 Survivin 表达上调，强烈提示 AS 的免疫发病机制。此外，Survivin 可以抑制促凋亡 caspase9 的激活。此外，microRNAs 是一类小的非编码 RNA，在各种疾病中失调，其表达的改变可以调节 Survivin 的表达。本研究的主要目的是评估 Survivin 及其靶向 microRNAs 在 AS 疾病免疫发病机制中的作用。为此，使用 Ficoll-Hypaque 从 15 名 AS 患者和健康匹配对照者的外周血单核细胞（PBMCs）中分离 PBMCs，使用磁性激活细胞分选（MACS）方法获得 T 细胞。之后，使用 qT-qPCR 测定 Survivin、Caspase 9 和特定 microRNAs 的表达水平，使用 Western blot 测定 Survivin 和 Caspase 9 的蛋白表达水平。然后，将分离的 T 细胞与白细胞介素（IL）-2 和 muromonab-CD3（OKT-3）共培养，用于主动诱导细胞死亡（AICD）诱导、Survivin siRNA 抑制 Survivin 表达及其组合，通过流式细胞术测定凋亡率来评估 Survivin 表达对自身反应性 T 淋巴细胞抗凋亡的影响。结果显示，AS 患者的 Survivin 上调，Caspase 9 下调。还发现 AS 患者的 Survivin mRNA 直接或间接靶向的 microRNAs 失调。还发现，与健康人相比，AS 患者获得的 T 细胞对凋亡诱导的抵抗性更强。总之，本研究结果表明，AS 患者 T 淋巴细胞中 Survivin 和 Survivin 靶向 microRNAs 的失调导致其抗凋亡，提示针对 AS 的靶向治疗的未来发展。
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