Rheumatoid arthritis, Th1, Treg, CD4 CD39 cells, IL-6, IL-10, IL-4, IL-17, IL-21, TNF- and TGF-1


Rheumatoid arthritis (RA) is a systemic inflammatory disease. It is characterized by damage of cartilages and bones which results in destruction of joint function. Multi-organic disorders of lung, heart and kidney can be developed in time. Complex network of immune and stromal cells, cytokines and chemokines produced by these cells participate in onset of the disease, in the systemic active phase and during the transition to more localized inactive disease after the treatment. To evaluate the Th1, Th17, Tregs and CD4+CD39+ cells pattern and pro- and anti-inflammatory cytokines in peripheral blood of patients with RA, 47 RA patients and 20 healthy individuals were included in the study. RA patients were divided into active and inactive RA groups. Frequencies of circulating Th1, Th17, Tregs and CD4+CD39+ cells were analyzed by flow cytometry. Serum levels of cytokines: IL-6, IL-10, IL-4, IL-17, TNF-a and TGF-b1 were detected by ELISA. The results demonstrated an increase of Th1, Th17 cell frequencies in active RA patients, whereas Tregs remain unchanged in RA groups. CD39 marker expression shows significant decline in active RA patients in comparison with inactive RA group and controls. Concentrations of innate cytokines IL-6, TNF-a in the peripheral blood was significantly increased in active RA while according to IL-17/IL-21 serum concentration this group was divided into two subgroups. Anti-inflammatory cytokines TGF-b, IL-4 shows decrease in active RA group compared to healthy controls. Study demonstrated that development of RA is associated with changes of serum pro- and anti-inflammatory cytokines which influence balance of T helpers subsets and could provide therapeutic opportunities.


Download data is not yet available.


Nistala K, Wedderburn LR. Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis // Rheumatology, vol.48, pp.602–6, 2009.

Liu J, Hong X, Lin D, et al. Artesunate influences Th17/Treg lymphocyte balance by modulating Treg apoptosis and Th17 proliferation in a murine model of rheumatoid arthritis // J. Experimental and Therapeutic Medicine, vol.13, no.5, pp.2267-2273, 2017.

Gerli R, Bistoni O, Russano A, Fiorucci S, Borgato L, Cesarotti ME, Lunardi C. In vivo activated T cells in rheumatoid synovitis. Analysis of Th1- and Th2-type cytokine production at clonal level in different stages of disease // Clin Exp Immunol vol.29, pp.549-555, 2002.

Morita Y, Yamamura M, Nishida K, Harada S, Okamoto H, Inoue H, et al. Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis // Arthritis Rheum., vol.41 pp.306–14, 1998, doi: 10.1002/1529- 0131(199802)41:2<306:AID-ART15>3.0.CO;2-4.

Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, et al. A proinflammatory role for IL-18 in rheumatoid arthritis // J Clin Invest., Vol.104, pp.1393–401, 1999, doi: 10.1172/JCI7317.

Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes // J Exp Med., vol.187, pp.875–83, 1998.

DiFusco D., Izzo R., Figliuzzi M.M. Pallone F., Monteleone G. IL-21 as a therapeutic target in inflammatory disorders // Ex Opin. Ther. Targets, vol.18, pp.1329-1338, 2014.

Sato K., Suematsu A., Okamoto K., Yamaguchi A., Morishita Y., Kadono Y., Tanaka S., Kodama T., Akira S., Iwakura Y., et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction//J. Exp. Med., vol.203, pp.2673–2682, 2006, doi: 10.1084/jem.20061775.

Komatsu N., Okamoto K., Sawa S., Nakashima T., Oh-hora M., Kodama T., Tanaka S., Bluestone J.A., Takayanagi H. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis // Nat. Med., vol.20, pp.62–68, 2014, doi: 10.1038/nm.3432.

Yago T., Nanke Y., Ichikawa N., Kobashigawa T., Mogi M., Kamatani N., Kotake S. IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: A novel mechanism of osteoclastogenesis by IL-17 // J. Cell. Biochem., vol.108, pp.947–955, 2009, doi: 10.1002/jcb.22326.

Yao Z., Painter S.L., Fanslow W.C., Ulrich D., Macduff B.M., Spriggs M.K., Armitage R.J. Human IL-17: A novel cytokine derived from T cells // J. Immunol., vol.155, pp.5483–5486, 1995.

Jovanovic D.V., DiBattista J.A., Martel-Pelletier J., et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-1β and TNFα, by human macrophages // J. Immunol., vol.160, pp.3513–3521, 1998.

Palani Dinesh, Mahaboobkhan Rasool Multifaceted role of IL-21 in rheumatoid arthritis: Current understanding and future perspectives // J Cell Physiol., vol.233, pp.3918–3928, 2018.

Carbone, G., Wilson, A., Diehl, S. A., Bunn, J., Cooper, S. M., & Rincon, M. Interleukin-6 receptor blockade selectively reduces IL-21 production by CD4 T cells and IgG4 autoantibodies in rheumatoid arthritis // International Journal of Biological Sciences, vol.9, pp.279–288, 2013, https://

Piet Geusens The role of RANK ligand/osteoprotegerin in rheumatoid arthritis // Ther Adv Musculoskelet Dis., vol.4, no.4, pp.225-33, 2012, doi: 10.1177/1759720X12438080.

Mary-Clare Miller, Hugh B. Manning, Abhilash Jain, Linda Troeberg, Jayesh Dudhia, David Essex, Ann Sandison, Motoharu Seiki, Jagdeep Nanchahal, Hideaki Nagase, and Yoshifumi Itoh MT1-MMP is a crucial promotor of synovial invasion in human rheumatoid arthritis // Arthritis Rheum., Mar, vol.60, no.3, p.686, 2009, doi: 10.1002/art.24331.

Li Z, Li D, Tsun A, Li B. FOXP3+ regulatory T cells and their functional regulation // Cell Mol Immunol., vol.12, pp.558–565, 2015.

Nguyen D.X., Ehrenstein M.R. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis // J Exp Med., vol.213, pp.1241–1253, 2016.

Dao X. Nguyen, Alice Cotton, RN, Laura Attipoe, Coziana Ciurtin, Caroline J. Doré, and Michael R. Ehrenstein Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis // J Allergy Clin Immunol., Sep, vol.142, no.3, pp.978–980, 2018, doi: 10.1016/j.jaci.2018.04.026.

Kikuchi J., Hashizume M., Kaneko Y., Yoshimoto K., Nishina N. and Takeuchi Ts. Peripheral blood CD4+ CD25+ CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response // Arthritis Research & Therapy, vol.17, p.10, 2015, doi: 10.1186/s13075-015-0526-4.

Gupta V., Katyar Sh., Singh A., Misra R. and Amita Aggarwal A. CD39 positive regulatory T cell frequency as a biomarker of treatment response to methotrexate in rheumatoid arthritis // International Journal of Rheumatic Diseases, vol.21, pp.1548–1556, 2018.

Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression // J Exp Med., vol.204, pp.1257–1265, 2007.

Rissiek A, Baumann I, Cuapio A et al. The expression of CD39 on regulatory T cells is genetically driven and further upregulated at sites of inflammation // J Autoimmun., vol.58, pp.12–20, 2015.

Palmer TM, Trevethick MA Suppression of inflammatory and immune responses by the A(2A) adenosine receptor: an introduction // Br J Pharmacol vol.153 (Suppl. 1); S27–34, 2008.

Purvis HA, Anderson AE, Young DA, Isaacs JD, Hilkens CMU A negative feedback loop mediated by STAT3 limits human Th17 responses // J Immunol., vol.193, pp.1142–50, 2014.

Pandolfi JB, Ferraro AA, Sananez I et al. ATP-induced inflammation drives tissue-resident Th17 cells in metabolically unhealthy obesity // J Immunol., vol.196, pp.3287–96, 2016.

Chen Zh., Bozec A., Ramming A. and Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis //Nature Reviews Rheumatology, vol. 15, pp.9–17, 2019.

Shevach E.M., Tran D.Q., Davidson T.S., Andersson J. The critical contribution of TGF-beta to the induction of Foxp3 expression and regulatory T cell function // Eur. J. Immunol., vol.38, pp.915-917, 2008.

Peres R.S., Donate P.B., Talbot Jh., et al. TGF- signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis // Journal of Autoimmunity, pp.1-10, 2018.

Qu C.H., Hou Y., Bi Y.F., et al. Diagnostic values of serum IL-10 and IL-17 in rheumatoid arthritis and their correlation with serum 14-3-3η protein // European Review for Medical and Pharmacological Sciences, vol.23, pp.1899-1906, 2019.

IsomaÈ ki P., Punnonen J. Pro-and anti-inflammatory cytokines in rheumatoid arthritis // Annals of medicine, 29(6):499-507, 1997.

van Roon JA, Lafeber FP, Bijlsma J. Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis // Arthritis & Rheumatism, vol.44, no.1, pp.3-12, 2001.

Hui Shen, Liping Xia, and Jing Lu Interleukin-4 in rheumatoid arthritis patients with interstitial lung disease: a pilot study // Indian J Med Res., Dec, vol.138, no.6, pp.919–921, 2013.

Aletaha D, Neogi T, Silman AJ et al. Rheumatoid arthritis classification criteria: an American college of rheumatology/European league against rheumatism collaborative initiative // Ann Rheum Dis., vol.69, pp.1580–8, 2010.

Dulic S., Vásárhelyi Zs., Sava F., et al. T-Cell Subsets in Rheumatoid Arthritis Patients on Long-Term Anti-TNF or IL-6 Receptor Blocker // Therapy Mediators of Inflammation, Article ID 6894374, 19 pages, 2017.

Aravena O., Pescea B, Soto L. et al. Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-γ-producing NK cell and regulatory T cell subsets // Immunobiology, vol. 216, pp.1256–1263, 2011.

Huang Z., Yang B., Shi Y. et al. Anti-TNF-α therapy improves Treg and suppresses Teff in patients with rheumatoid arthritis // Cellular Immunology, vol. 279, no. 1, pp.25–29, 2012.

Iain B. McInnes I.B., Buckley Ch.D., John D., Isaacs J.D. Cytokines in rheumatoid arthritis — shaping the immunological landscape // Nature Reviews Rheumatology, Published online 2015, doi:10.1038/nrrheum.2015.171.

Hori S, Nomura T, Sakaguchi S Control of regulatory T cell development by the transcription factor Foxp3 // Science, vol.299, pp.1057–1061, 2003.

Borsellino G., Kleinewietfeld M., Di Mitri D., et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression // Blood, Aug, 15, vol.110, no.4, pp.1225-32, 2007, doi: 10.1182/blood-2006-12-064527.

Timperi E. and Barnaba V. CD39 Regulation and Functions in T Cells // Int. J. Mol. Sci., vol.22, p.8068, 2021,

Al-Saadany HM, Hussein MS, Gaber RA, Zaytoun HA Th-17 cells and serum IL-17 in rheumatoid arthritis patients: Correlation with disease activity and severity // The Egyptian Rheumatologist, vol.38, no.1, pp.1-7, 2016.

Ding L, Linsley P, Huang L, Germain R, Shevach E. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression // The Journal of Immunology, vol.151, no.3,pp.1224-34, 1993.

Lubberts E, Joosten L A B, Chabaud M. et al. IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion // J Clin Invest., vol.105, pp.1697–1710, 2000.




How to Cite





Most read articles by the same author(s)

Similar Articles

1 2 3 4 5 > >> 

You may also start an advanced similarity search for this article.