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Journal of Clinical Immunology

, Volume 33, Issue 1, pp 151–161 | Cite as

Levels of Circulating Th17 Cells and Regulatory T Cells in Ankylosing Spondylitis Patients with an Inadequate Response to Anti−TNF-α Therapy

  • Li Xueyi
  • Chen Lina
  • Wu Zhenbiao
  • Han Qing
  • Li Qiang
  • Ping ZhuEmail author
Original Research

Abstract

Purpose

To investigate the effects of TNF-α blockage on levels of circulating Th17, Treg and their related cytokines in ankylosing spondylitis (AS) patients with different response to anti-TNF-α therapy.

Methods

The frequencies of circulating Th17 and Treg and serum levels of related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 222 AS patients both before (baseline) and 6 months after anti-TNF-α therapy. Therapeutic response was defined according to ASAS (Assessment in Spondyloarthritis International Society) response criteria.

Results

Significantly higher baseline circulating Th17 and serum TNF-α, IL-6, IL-17, IL-23 were observed in active AS patients than in healthy controls. After anti-TNF-α therapy, 168 patients (75.7 %) were responders and 54 (24.3 %) were non-responders. Frequencies of Th17 significantly decreased in responders, but significantly increased in non-responders. Treg increased significantly in responders but decreased significantly in non-responders. Levels of TNF-α, IL-6, IL-17, and IL-23 were significantly decreased in responders. In contrast, IL-17 and IL-23 significantly increased in non-responders. TGF-β were significantly increased only in responders, whereas no significant changes were seen in IL-10 in either responders or non-responders. Spearman correlation analysis showed that frequencies of Th17 and levels of TNF-α, IL-6, IL-17, and IL-23 were positively correlated with BASDAI score. They were also positively correlated with BASFI score except for IL-6. Treg were found to be negatively correlated with BASDAI score.

Conclusions

The beneficial effect of anti-TNF-α therapy in AS might not only neutralize the effects of TNF-α but also down-regulate Th17 and Th17-related cytokines accompanied by up-regulating the Treg/TGF-β axis in responders.

Keywords

Anti-TNF-α ankylosing spondylitis Th17 regulatory T cell IL-17 

Notes

Disclosure statement

Li Xueyi, Chen Lina and Wu Zhenbiao contributed equally to this work. Funding: This work was supported by grants from the Key Program of the National Natural Science Foundation of China (No. 81030058) and the National Basic Research Program (No. 2009CB521705). Ethics approval: The approval was granted from the Ethics Committee of the Fourth Military Medical University (No. 20080814–2). All patients and controls gave their informed consent to participate in the study.

References

  1. 1.
    Baek HJ, Shin KC, et al. Clinical features of adult-onset ankylosing spondylitis in Korean patients: patients with peripheral joint disease (PJD) have less severe spinal disease course than those without PJD. Rheumatology (Oxford). 2004;43(12):1526–31.CrossRefGoogle Scholar
  2. 2.
    Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369(9570):1379–90.PubMedCrossRefGoogle Scholar
  3. 3.
    Szalay B, Mészáros G, Cseh Á, Ács L, Deák M, Kovács L, Vásárhelyi B, Balog A. Adaptive immunity in ankylosing spondylitis: phenotype and functional alterations of T-cells before and during infliximab therapy. Clin Dev Immunol. 2012;2012:808724. Epub 2011 Sep 28.Google Scholar
  4. 4.
    Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39(11):1329–37.PubMedCrossRefGoogle Scholar
  5. 5.
    Rueda B, Orozco G, Raya E, Fernandez-Sueiro JL, Mulero J, Blanco FJ, et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann Rheum Dis. 2008;67(10):1451–4.PubMedCrossRefGoogle Scholar
  6. 6.
    Karaderi T, Harvey D, Farrar C, Appleton LH, Stone MA, Sturrock RD, et al. Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case–control study and meta-analysis of published series. Rheumatology (Oxford). 2009;48(4):386–9.CrossRefGoogle Scholar
  7. 7.
    Rahman P, Inman RD, Gladman DD, Reeve JP, Peddle L, Maksymowych WP. Association of interleukin-23 receptor variants with ankylosing spondylitis. Arthritis Rheum. 2008;58(4):1020–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Shen H, Goodall JC, Hill Gaston JS. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 2009;60(6):1647–56.PubMedCrossRefGoogle Scholar
  9. 9.
    Jandus C, Bioley G, Rivals JP, Dudler J, Speiser D, Romero P. Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum. 2008;58(8):2307–17.PubMedCrossRefGoogle Scholar
  10. 10.
    Bettelli E, Carrier Y, Gao W, Korn T, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Wu Y, Ren M, Yang R, et al. Reduced immunomodulation potential of bone marrow-derived mesenchymal stem cells induced CCR4 + CCR6 + Th/Treg cell subset imbalance in ankylosing spondylitis. Arthritis Res Ther. 2011;13(1): article R29.Google Scholar
  12. 12.
    Bettelli E, Oukka M, Kuchroo VK. Th-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8(4):345–50.PubMedCrossRefGoogle Scholar
  13. 13.
    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(3):515–9.PubMedGoogle Scholar
  14. 14.
    Van Bezooijen RL, Van Der Wee-Pals L, Papapoulos SE, Lowik CW. Interleukin 17 synergies with tumor necrosis factor alpha to induce cartilage destruction in vitro. Ann Rheum Dis. 2002;61(10):870–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol. 2006;18(6):670–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Cooper AM, Khader SA. IL-12p40: an inherently agonistic cytokine. Trends Immunol. 2007;28(1):33–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Taylan A, Sari I, Kozaci DL, et al. Evaluation of the T helper 17 axis in ankylosing spondylitis. Rheumatol Int. 2011 Jul 16. [Epub ahead of print].Google Scholar
  18. 18.
    Iwamoto S, Iwai S, Tsujiyama K, Kurahashi C, Takeshita K, Naoe M, Masunaga A, Ogawa Y, Oguchi K, Miyazaki A. TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evolving Th1 and Th17 responses. J Immunol. 2007;179(3):1449–57.PubMedGoogle Scholar
  19. 19.
    Ma HL, Napierata L, Stedman N, Benoit S, Collins M, Nickerson-Nutter C, Young DA. Tumor necrosis factor α blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells. Arthritis Rheum. 2010;62(2):430–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO. Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J Exp Med. 2008;205(11):2491–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Carmona L, Gomez-Reino JJ. Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Arthritis Res Ther. 2006;8:R72.PubMedCrossRefGoogle Scholar
  22. 22.
    McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, Hill RA, Jones A, Mujica Mota R, Walley T. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation. Health Technol Assess. 2007;11(28):1–158.Google Scholar
  23. 23.
    Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, Chen F, Magliocco M, Krueger JG. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol. 2005;175(4):2721–9.PubMedGoogle Scholar
  24. 24.
    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(4):596–605.PubMedCrossRefGoogle Scholar
  25. 25.
    Yue C, You X, Zhao L, Wang H, Tang F, Zhang F, Zhang X, He W. The effects of adalimumab and methotrexate treatment on peripheral Th17 cells and IL-17/IL-6 secretion in the rheumatoid arthritis patients. Rheumatol Int. 2009;30(12):1553–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Zochling J, van der Heijde D, Dougados M, et al. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis. 2006;65(4):423–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the bath ankylosing spondylitis disease activity index. J Rheumatol. 1994;21(12):2286–91.PubMedGoogle Scholar
  29. 29.
    Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the bath ankylosing spondylitis functional index. J Rheumatol. 1994;21(12):2281–5.PubMedGoogle Scholar
  30. 30.
    Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A. Ankylosing spondylitis: an overview. Ann Rheum Dis. 2002;61(3):iii8–18.PubMedGoogle Scholar
  31. 31.
    Dougados M, Baeten D. Spondyloarthritis. Lancet. 2011;377(9783):2127–37.PubMedCrossRefGoogle Scholar
  32. 32.
    Shahrara S, Huang Q, Mandelin 2nd AM, Pope RM. TH-17 cells in rheumatoid arthritis. Arthritis Res Ther. 2008;10(4):R93.PubMedCrossRefGoogle Scholar
  33. 33.
    Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007;9(6):461–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Maloy KJ. The Interleukin-23/Interleukin-17 axis in intestinal inflammation. J Intern Med. 2008;263(6):584–90.PubMedCrossRefGoogle Scholar
  35. 35.
    Wendling D, Cedoz JP, Racadot E, Dumoulin G. Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis. Joint Bone Spine. 2007;74(3):304–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Wang X, Lin Z, Wei Q, Jiang Y, Gu J. Expression of IL-23 and IL-17 and effect of IL-23 on IL-17 production in ankylosing spondylitis. Rheumatol Int. 2009;29(11):1343–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Melis L, Vandooren B, Kruithof E, Jacques P, De Vos M, Mielants H, et al. Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis. Ann Rheum Dis. 2010;69(3):618–23.PubMedCrossRefGoogle Scholar
  38. 38.
    Nomura T, Abe Y, Kamada H, Shibata H, Kayamuro H, Inoue M, Kawara T, Arita S, Furuya T, Yamashita T, Nagano K, Yoshikawa T, Yoshioka Y, Mukai Y, Nakagawa S, Taniai M, Ohta T, Serada S, Naka T, Tsunoda S, Tsutsumi Y. Therapeutic effect of PEGylated TNFR 1-selective antagonistic mutant TNF in experimental autoimmune encephalomyelitis mice. J Control Release. 2011;149(1):8–14.PubMedCrossRefGoogle Scholar
  39. 39.
    Raza K, Falciani F, Curnow SJ, Ross EJ, Lee CY, Akbar AN, Lord JM, Gordon C, Buckley CD, Salmon M. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cells and stromal cell origin. Arthritis Res Ther. 2005;7(4):R784–95.PubMedCrossRefGoogle Scholar
  40. 40.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203(12):2673–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, Mineau F, Pelletier JP. IL-17 stimulates the production of proinflammatory cytokines, IL-1β and TNF-α, by human macrophages. J Immunol. 1998;160(7):3513–21.PubMedGoogle Scholar
  42. 42.
    Katz Y, Nadiv O, Beer Y. Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins1, 6, and 8 in skin and synovial fibroblasts: a possible role as a “fine-tuning cytokine” in inflammation processes. Arthritis Rheum. 2001;44(9):2176–84.PubMedCrossRefGoogle Scholar
  43. 43.
    Langrish CL, Chen Y, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–40.PubMedCrossRefGoogle Scholar
  44. 44.
    Harrington LE, Hatton RD, et al. Interleukin 17-producing CD4 effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8(9):967–74.PubMedCrossRefGoogle Scholar
  46. 46.
    Romagnani S. Human Th17 cells. Arthritis Res Ther. 2008;10(2):206.PubMedCrossRefGoogle Scholar
  47. 47.
    Chen Z, Tato CM, Muul L, Laurence A, ÓShea JJ. Distinct regulation of interleukn-17 in human T helper lymphocytes. Arthritis Rheum. 2007;56(9):2936–46.PubMedCrossRefGoogle Scholar
  48. 48.
    Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):224–79.CrossRefGoogle Scholar
  49. 49.
    Eissner G, Kolch W, Scheurich P. Ligands working as receptors: reverse signaling by members of the TNF superfamily enhances the plasticity of the immune system. Cytokine Growth Factor Rev. 2004;15(5):353–66.PubMedCrossRefGoogle Scholar
  50. 50.
    Mitoma H, Horiuchi T, Hatta N, Tsukamoto H, Harashima S, Kikuchi Y, et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology. 2005;128(2):376–92.PubMedCrossRefGoogle Scholar
  51. 51.
    Lundy SK, Sarkar S, Tesmer LA, Fox DA, Lundy SK, Sarkar S, Tesmer LA, Fox DA. Cells of the synovium in rheumatoid arthritis. T lymphocytes. Arthritis Res Ther. 2007;9(1):202–12.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang J, Wang X, Fahmi H, Wojcik S, Fikes J, Yu Y, Wu J, Luo H. Role of TL1A in the pathogenesis of rheumatoid arthritis. J Immunol. 2009;183(8):5350–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Goldberg M, Nadiv O, Luknar-Gabor N, Agar G, Beer Y, Katz Y. Synergism between tumor necrosis factor alpha and interleukin-17 to induce IL-23 p19 expression in fibroblast-like synoviocytes. Mol Immunol. 2009;46(8–9):1854–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Ogawa K, Matsumoto T, Esaki M, Torisu T, Iida M. Profiles of circulating cytokines in patients with Crohn’s disease under maintenance therapy with infliximab. J Crohns Colitis. 2012;6(5):529–35.PubMedCrossRefGoogle Scholar
  55. 55.
    Charles P, Elliott MJ, Davis D, Potter A, Kalden JR, Antoni C, et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-α therapy in rheumatoid arthritis. J Immunol. 1999;163(3):1521–8.PubMedGoogle Scholar
  56. 56.
    Ehrenstein MR, Evans JG, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004;200(3):277–85.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Li Xueyi
    • 1
  • Chen Lina
    • 1
  • Wu Zhenbiao
    • 1
  • Han Qing
    • 1
  • Li Qiang
    • 1
  • Ping Zhu
    • 1
    Email author
  1. 1.Department of Clinical Immunology, State Key Discipline of Cell Biology, First Affiliated HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China

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