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CC BY 4.0 · Journal of Child Science 2019; 09(01): e75-e83
DOI: 10.1055/s-0039-1693158
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Investigating the Balance between Th17/Treg Cells in Rheumatoid Arthritis and its Association with Disease Activity

Hanan Aly Taha
1   Department of Internal Medicine, Faculty of Medicine, Beni Suef University, Beni Suef, Egypt
,
Walaa G. Hozayen
2   Department of Biotechnology and Life Sciences, Faculty of Postgraduate Studies for Advanced Sciences, Beni Suef University, Beni Suef, Egypt
,
Ahmed Mohamed Okasha
3   Department of Biochemistry, Faculty of Medicine, Minia University, Minia, Egypt
,
Amr E. Ahmed
2   Department of Biotechnology and Life Sciences, Faculty of Postgraduate Studies for Advanced Sciences, Beni Suef University, Beni Suef, Egypt
,
Manar Ali A. Shata
2   Department of Biotechnology and Life Sciences, Faculty of Postgraduate Studies for Advanced Sciences, Beni Suef University, Beni Suef, Egypt
,
Emad A. Abdel-Naem
4   Department of Clinical Pathology, Faculty of Medicine, Minia University, Minia, Egypt
,
Sheren Esam Maher
5   Department of Pediatrics, Faculty of Medicine, Minia University, Minia, Egypt
› Author Affiliations Funding None.
Further Information

Publication History

11 February 2019

27 May 2019

Publication Date:
17 July 2019 (online)

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Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by articular inflammation and joint destruction. The mechanism of RA pathogenesis is not fully understood, but humoral and cellular immunity are known to be involved. CD4+ T lymphocytes and cytokines released by these cells are suggested to initiate inflammation in RA. This study aimed to assess T helper 17 (Th17)/regulatory T (Treg) cell ratio and its correlation with disease activity in adult and juvenile RA. This study included 80 patients, with RA, including 40 adults (mean age: 36.4 ± 11.1 years and 40 juveniles mean age: 12.7 ± 2.2 years), and 80 healthy controls. For all patients and control subjects, patient and disease characteristics; laboratory tests for complete blood count, erythrocyte sedimentation rate, C-reactive protein (CRP), rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP), anti-nuclear antibodies (ANA), and flow cytometry to determine the numbers of Th17 and Treg cells. There was a statistically significant increase in the Th17/Treg ratio in patients with active disease compared with those with inactive disease for both adult and juvenile RA compared with controls. However, a similar significant difference was not observed between those with inactive adult and juvenile RA and controls. There were significant positive correlations between the Th17/Treg ratio and disease activity score 28 (DAS28), CRP, anti-CCP, and ANA in active adult and juvenile RA. The Th17/Treg ratio was increased in active form of adult and juvenile RA compared with inactive RA and control, indicating the Th17/Treg ratio as a potentially useful marker of disease activity.

Keywords

Th17 cell - regulatory T cell - rheumatoid arthritis - disease activity

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.


 

  • References

  • 1 Nepom GT. Major histocompatibility complex-directed susceptibility to rheumatoid arthritis. Adv Immunol 1998; 68: 315-332
    PubMedGoogle Scholar
  • 2 Wagner UG, Kurtin PJ, Wahner A. , et al. The role of CD8+ CD40L+ T cells in the formation of germinal centers in rheumatoid synovitis. J Immunol 1998; 161 (11) 6390-6397
    PubMedGoogle Scholar
  • 3 Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383 (6603): 787-793
    CrossrefPubMedGoogle Scholar
  • 4 Nakayamada S, Takahashi H, Kanno Y, O'Shea JJ. Helper T cell diversity and plasticity. Curr Opin Immunol 2012; 24 (03) 297-302
    CrossrefPubMedGoogle Scholar
  • 5 Boniface K, Blom B, Liu YJ, de Waal Malefyt R. From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited. Immunol Rev 2008; 226: 132-146
    CrossrefPubMedGoogle Scholar
  • 6 Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007; 8 (04) 345-350
    CrossrefPubMedGoogle Scholar
  • 7 Agarwal S, Misra R, Aggarwal A. Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J Rheumatol 2008; 35 (03) 515-519
    PubMedGoogle Scholar
  • 8 Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 2003; 171 (11) 6173-6177
    CrossrefPubMedGoogle Scholar
  • 9 Boissier MC, Assier E, Falgarone G, Bessis N. Shifting the imbalance from Th1/Th2 to Th17/treg: the changing rheumatoid arthritis paradigm. Joint Bone Spine 2008; 75 (04) 373-375
    CrossrefPubMedGoogle Scholar
  • 10 Eisenstein EM, Williams CB. The T(reg)/Th17 cell balance: a new paradigm for autoimmunity. Pediatr Res 2009; 65 (5 Pt 2): 26R-31R
    CrossrefPubMedGoogle Scholar
  • 11 Wang W, Shao S, Jiao Z, Guo M, Xu H, Wang S. The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis. Rheumatol Int 2012; 32 (04) 887-893
    CrossrefPubMedGoogle Scholar
  • 12 Ichikawa T, Kageyama Y, Kobayashi H, Kato N, Tsujimura K, Koide Y. Etanercept treatment reduces the serum levels of interleukin-15 and interferon-gamma inducible protein-10 in patients with rheumatoid arthritis. Rheumatol Int 2010; 30 (06) 725-730
    CrossrefPubMedGoogle Scholar
  • 13 Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis 2006; 65 (07) 845-851
    PubMedGoogle Scholar
  • 14 Castro C, Gourley M. Diagnostic testing and interpretation of tests for autoimmunity. J Allergy Clin Immunol 2010; 125 (02) (Suppl. 02) S238-S247
    CrossrefPubMedGoogle Scholar
  • 15 Carvalho AM, Cristal JR, Muniz AC. , et al. Interleukin 10-dominant immune response and increased risk of cutaneous leishmaniasis after natural exposure to lutzomyia intermedia sand flies. J Infect Dis 2015; 212 (01) 157-165
    CrossrefPubMedGoogle Scholar
  • 16 Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007; 37 (01) 129-138
    CrossrefPubMedGoogle Scholar
  • 17 Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136 (07) 2348-2357
    PubMedGoogle Scholar
  • 18 Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989; 7: 145-173
    CrossrefPubMedGoogle Scholar
  • 19 Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996; 17 (03) 138-146
    CrossrefPubMedGoogle Scholar
  • 20 D'Elios M, Del Prete G. Th1/Th2 balance in human disease. Transplant Proc 1998; 30 (05) 2373-2377
    CrossrefPubMedGoogle Scholar
  • 21 Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet 2009; 373 (9664): 659-672
    CrossrefPubMedGoogle Scholar
  • 22 McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7 (06) 429-442
    CrossrefPubMedGoogle Scholar
  • 23 Zhang L, Li JM, Liu XG. , et al. Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. J Clin Immunol 2011; 31 (04) 606-614
    CrossrefPubMedGoogle Scholar
  • 24 Yuan X, Malek TR. Cellular and molecular determinants for the development of natural and induced regulatory T cells. Hum Immunol 2012; 73 (08) 773-782
    CrossrefPubMedGoogle Scholar
  • 25 Chen DY, Chen YM, Chen HH, Hsieh CW, Lin CC, Lan JL. Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy. Arthritis Res Ther 2011; 13 (04) R126
    CrossrefPubMedGoogle Scholar
  • 26 Byng-Maddick R, Ehrenstein MR. The impact of biological therapy on regulatory T cells in rheumatoid arthritis. Rheumatology (Oxford) 2015; 54 (05) 768-775
    CrossrefPubMedGoogle Scholar
  • 27 Chen J, Li J, Gao H. , et al. Comprehensive evaluation of different T-helper cell subsets differentiation and function in rheumatoid arthritis. J Biomed Biotechnol 2012; 2012: 535361
    PubMedGoogle Scholar
  • 28 Niu Q, Cai B, Huang ZC, Shi YY, Wang LL. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int 2012; 32 (09) 2731-2736
    CrossrefPubMedGoogle Scholar
  • 29 Mijnheer G, Prakken BJ, van Wijk F. The effect of autoimmune arthritis treatment strategies on regulatory T-cell dynamics. Curr Opin Rheumatol 2013; 25 (02) 260-267
    CrossrefPubMedGoogle Scholar
  • 30 Lina C, Conghua W, Nan L, Ping Z. Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis. J Clin Immunol 2011; 31 (04) 596-605
    CrossrefPubMedGoogle Scholar
  • 31 Jiao Z, Wang W, Jia R. , et al. Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis. Scand J Rheumatol 2007; 36 (06) 428-433
    CrossrefPubMedGoogle Scholar
  • 32 Möttönen M, Heikkinen J, Mustonen L, Isomäki P, Luukkainen R, Lassila O. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 2005; 140 (02) 360-367
    CrossrefPubMedGoogle Scholar
  • 33 van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS. CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum 2004; 50 (09) 2775-2785
    CrossrefPubMedGoogle Scholar
  • 34 Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014; 13 (06) 668-677
    CrossrefPubMedGoogle Scholar
  • 35 Duarte J, Agua-Doce A, Oliveira VG, Fonseca JE, Graca L. Modulation of IL-17 and Foxp3 expression in the prevention of autoimmune arthritis in mice. PLoS One 2010; 5 (05) e10558
    CrossrefPubMedGoogle Scholar
  • 36 Niu X, He D, Zhang X. , et al. IL-21 regulates Th17 cells in rheumatoid arthritis. Hum Immunol 2010; 71 (04) 334-341
    CrossrefPubMedGoogle Scholar
  • 37 Fujimoto M, Serada S, Mihara M. , et al. Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum 2008; 58 (12) 3710-3719
    CrossrefPubMedGoogle Scholar
  • 38 Samson M, Audia S, Janikashvili N. , et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum 2012; 64 (08) 2499-2503
    CrossrefPubMedGoogle Scholar
  • 39 McGovern JL, Nguyen DX, Notley CA, Mauri C, Isenberg DA, Ehrenstein MR. Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti-tumor necrosis factor antibody therapy. Arthritis Rheum 2012; 64 (10) 3129-3138
    CrossrefPubMedGoogle Scholar
  • 40 Nie H, Zheng Y, Li R. , et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med 2013; 19 (03) 322-328
    CrossrefPubMedGoogle Scholar
  • 41 Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmström V. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther 2004; 6 (04) R335-R346
    CrossrefPubMedGoogle Scholar
  • 42 Kawashiri S-Y, Kawakami A, Okada A. , et al. CD4+CD25(high)CD127(low/-) Treg cell frequency from peripheral blood correlates with disease activity in patients with rheumatoid arthritis. J Rheumatol 2011; 38 (12) 2517-2521
    PubMedGoogle Scholar
  • 43 Han GM, O'Neil-Andersen NJ, Zurier RB, Lawrence DA. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell Immunol 2008; 253 (1–2): 92-101
    CrossrefPubMedGoogle Scholar
  • 44 Turnier JL, Brunner HI. Tocilizumab for treating juvenile idiopathic arthritis. Expert Opin Biol Ther 2016; 16 (04) 559-566
    CrossrefPubMedGoogle Scholar
  • 45 Sieper J, Braun J, Kay J. , et al. Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis 2015; 74 (06) 1051-1057
    PubMedGoogle Scholar
  • 46 Wang C, Yosef N, Gaublomme J. , et al. CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity. Cell 2015; 163 (06) 1413-1427
    CrossrefPubMedGoogle Scholar