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N. M. Elemam, M. Hachim, S. Hannawi, A. A. Maghazachi
Published: 19 May 2021
 by  BMJ

Abstract: Background: Rheumatoid arthritis (RA) is the most common inflammatory type of arthritis, with various immune players implicated in its pathogenesis. Natural killer (NK) cells are innate lymphocytes that showed controversial roles in RA, whether pathogenic or protective (Shegarfi, H. et al. 2012, Yap, H.-Y. et al. 2018). Previously, we were able to identify a gene signature in NK cells of RA patients that can aid in understanding the state of NK cells in RA disease and identify RA patients from healthy controls (Elemam, N.M. et al. 2019, Elemam, N.M. et al. 2020). Furthermore, this signature might facilitate the selection of biomarkers that can be used for early detection of RA and prediction of effectiveness of RA treatment. Objectives: In this study we aimed at exploring the effect of several RA therapeutic agents such as tocilizumab, rituximab and anti-TNFα (adalimumab, etanercept and golimumab) on the previously identified gene signature in NK cells of RA patients. Methods: Whole blood transcriptomic data from publicly available dataset (GSE93272) was used to predict the percentage of activated NK cells in the blood of RA patients using the software CIBERSORT. Then, a correlation analysis was done between the percentage of NK cells and number of days of receiving tocilizumab treatment. Whole blood samples were collected from the recruited 17 RA patients (satisfying the 2010 ACR/EULAR classification criteria for RA). NK cells were isolated using RosetteSep negative selection method and RNA was extracted and gene expression was assessed using qRT-PCR. RA patients taking tocilizumab, rituximab, or anti-TNFα (adalimumab, etanercept or golimumab but none of the patients received infliximab) were compared to those not receiving any biological DMARDs. Statistical analysis was done using Student’s t-test. Results: In silico analysis has shown that the percentage of activated NK cells is positively correlated with the number of days of tocilizumab therapy in RA patients, suggesting a direct enhancing effect of tocilizumab on NK cell activity. Then, it was crucial to investigate the effect of different biological DMARDs on NK gene expression in RA patients. All the investigated chemokines (CCL2, CXCL10, CXCL16, CXCR1, CXCR2, CXCR6 and CCR4) in the identified gene signature showed a significant change in RA patients receiving tocilizumab, rituximab, or anti-TNFα therapies. Furthermore, the other genes including RELA, ICAM, IL1RN, TLR3 and TLR10 were significantly changed in NK cells of RA patients receiving biological DMARDs in comparison to patients not receiving the treatments. However, some of the genes including CD56, BTK, IBTK, ITGB7, IL1B, PECAM-1, IL12RB2, IFNG and CKLF did not show a significant change upon receipt of biological DMARDs. Conclusion: In conclusion, NK cell activity and gene expression could be affected by the type of biological DMARDs received by RA patients. Therefore, this identified gene signature of NK cells could be used as a diagnostic tool to identify RA patients and a target for biological DMARDs in RA. References: [1]Elemam, N. M., M. Y. Hachim, S. Hannawi and A. A. Maghazachi (2019). “Natural Killer Cells Gene Expression Can Differentiate Rheumatoid Arthritis Patients from Healthy Controls [abstract].” ACR/ARP Annual Meeting, supplement of Arthritis & Rheumatology 71(suppl 10). [2]Elemam, N. M., M. Y. Hachim, S. Hannawi and A. A. Maghazachi (2020). “Differentially Expressed Genes of Natural Killer Cells Can Distinguish Rheumatoid Arthritis Patients from Healthy Controls.” Genes (Basel) 11(5). [3]Shegarfi, H., F. Naddafi and A. Mirshafiey (2012). “Natural killer cells and their role in rheumatoid arthritis: friend or foe?” TheScientificWorldJournal 2012: 491974-491974. [4]Yap, H.-Y., S. Z.-Y. Tee, M. M.-T. Wong, S.-K. Chow, S.-C. Peh and S.-Y. Teow (2018). “Pathogenic Role of Immune Cells in Rheumatoid Arthritis: Implications in Clinical Treatment and Biomarker Development.” Cells 7(10): 161. Figure 1. In silico analysis and correlation of NK cell activity with the number of days of Tocilizumab therapy in RA patients. Disclosure of Interests: None declared
Keywords: gene expression / RNA was extracted / treatment / Healthy Controls / Patients from Healthy / Elemam / DMARDs

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