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Survivin; a novel therapeutic target that correlates with survival of autoreactive T lymphocytes obtained from patients with ankylosing spondylitis

2022; Elsevier BV; Volume: 844; Linguagem: Inglês

10.1016/j.gene.2022.146829

1879-0038

Navid Shomali, Behzad Baradaran, Amin Daei Sorkhabi, Aila Sarkesh, Mohammad Saeed Kahrizi, Foad Tosan, Ata Mahmoodpoor, Amirhossein Mardi, Hamed Mohammadi, Ali Hassanzadeh, Hossein Saeedi, Mehrzad Hajialilo, Maryam Hemmatzadeh, Faroogh Marofi, Siamak Sandoghchian Shotorbani,

Inflammasome and immune disorders

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.