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Elevated Th22 Cells Correlated with Th17 Cells in Patients with Rheumatoid Arthritis

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Abstract

Background

T-helper (Th) 22 and Th17 cells are implicated in the pathogenesis of autoimmune diseases. The roles of Th22 cells in the pathophysiology of rheumatoid arthritis (RA) remain unsettled.

Materials and Methods

CD4+IFNγ−IL17−IL-22+ T cells (Th22 cells), CD4+IFNγ−IL-22−IL17+ T cells (pure Th17 cells), CD4+IL17+ T cells (Th17 cells), and CD4+IFNγ+ T cells (Th1 cells) in RA, osteoarthritis patients, and healthy controls were examined by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay.

Results

Th22 cells, pure Th17 cells, Th17 cells, and interleukin-22 were significantly elevated in RA patients compared with osteoarthritis and healthy controls, but there were no significant differences regarding Th1 cells and interleukin-17. Th22 cells showed a positive correlation with interleukin-22 as well as pure Th17 cells or Th17 cells in RA patients. Additionally, the percentages of Th22 cells, pure Th17 cells as well as Th17 cells correlated positively with both C-reactive protein levels and 28-joints disease activity score.

Conclusion

Together, our results indicated a possible role of Th22 pure Th17 cells and Th17 cells in RA, and blockade of the interleukin-22 may be a reasonable therapeutic strategy for RA.

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Abbreviations

RA:

Rheumatoid arthritis

OA:

Osteoarthritis

CRP:

C-reactive protein

DAS28:

28-joints disease activity score

PB:

Peripheral blood

SF:

Synovial fluid

SLE:

Systemic lupus erythematosus

SS:

Systemic sclerosis

IBD:

Inflammatory bowel disease

PDGF:

Platelet-derived growth factor

CCR:

Chemokine receptor

ERK1/2:

Extracellular regulated kinase1/2

MAPK:

Mitogen-activated protein kinases

References

  1. Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996;85:307–10.

    Article  PubMed  CAS  Google Scholar 

  2. Dolhain RJ, van der Heiden AN, ter Haar NT, Breedveld FC, Miltenburg AM. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum. 1996;39:1961–9.

    Article  PubMed  CAS  Google Scholar 

  3. Berner B, Akca D, Jung T, Muller GA, Reuss-Borst MA. Analysis of Th1 and Th2 cytokines expressing CD4+ and CD8+ T cells in rheumatoid arthritis by flow cytometry. J Rheumatol. 2000;27:1128–35.

    PubMed  CAS  Google Scholar 

  4. Kawashima M, Miossec P. mRNA quantification of T-bet, GATA-3, IFN-gamma, and IL-4 shows a defective Th1 immune response in the peripheral blood from rheumatoid arthritis patients: link with disease activity. J Clin Immunol. 2005;25:209–14.

    Article  PubMed  CAS  Google Scholar 

  5. Shen H, Goodall JC, Hill Gaston JS. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 2009;60:1647–56.

    Article  PubMed  CAS  Google Scholar 

  6. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–40.

    Article  PubMed  CAS  Google Scholar 

  7. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006;24:677–88.

    Article  PubMed  CAS  Google Scholar 

  8. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-β induces development of the TH17 lineage. Nature. 2006;441:231–4.

    Article  PubMed  CAS  Google Scholar 

  9. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, 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;6:1123–32.

    Article  PubMed  CAS  Google Scholar 

  10. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.

    Article  PubMed  CAS  Google Scholar 

  11. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of TH17 cells. Nature. 2008;453:1051–7.

    Article  PubMed  CAS  Google Scholar 

  12. Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. New Engl J Med. 2009;361:888–98.

    Article  PubMed  CAS  Google Scholar 

  13. Shahrara S, Huang Q, Mandelin AM, Pope RM. TH-17 cells in rheumatoid arthritis. Arthritis Res Ther. 2008;10:R93.

    Article  PubMed  Google Scholar 

  14. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009;10:857–63.

    Article  PubMed  CAS  Google Scholar 

  15. Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009;119:3573–85.

    PubMed  CAS  Google Scholar 

  16. Trifari S, Kaplan C, Tran E, Crellin N, Spits H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol. 2009;10:864–71.

    Article  PubMed  CAS  Google Scholar 

  17. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol. 2010;130:1373–83.

    Article  PubMed  CAS  Google Scholar 

  18. Dumoutier L, Louahed J, Renauld JC. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol. 2000;164:1814–9.

    PubMed  CAS  Google Scholar 

  19. Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chem. 2000;275:31335–9.

    Article  PubMed  CAS  Google Scholar 

  20. Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, et al. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J Biol Chem. 2001;276:2725–32.

    Article  PubMed  CAS  Google Scholar 

  21. Cheng F, Guo Z, Xu H, Yan D, Li Q. Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis. 2009;68:604–6.

    Article  PubMed  CAS  Google Scholar 

  22. Nickoloff BJ. Cracking the cytokine code in psoriasis. Nat Med. 2007;13:242–4.

    Article  PubMed  CAS  Google Scholar 

  23. Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006;290:G827–38.

    Article  PubMed  CAS  Google Scholar 

  24. Lo YH, Torii K, Saito C, Furuhashi T, Maeda A, Morita A. Serum IL-22 correlates with psoriatic severity and serum IL-6 correlates with susceptibility to phototherapy. J Dermatol Sci. 2010;58:225–7.

    Article  PubMed  CAS  Google Scholar 

  25. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–61.

    Article  PubMed  CAS  Google Scholar 

  26. Raza K, Falciani F, Curnow SJ, Ross EJ, Lee CY, Akbar AN, et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther. 2005;7(4):R784–95.

    Article  PubMed  CAS  Google Scholar 

  27. Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, et al. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol. 2000;164(5):2832–8.

    PubMed  CAS  Google Scholar 

  28. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.

    Article  PubMed  CAS  Google Scholar 

  29. Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:44–8.

    Article  PubMed  CAS  Google Scholar 

  30. Flytlie HA, Hvid M, Lindgreen E, Kofod-Olsen E, Petersen EL, Jørgensen A, et al. Expression of MDC/CCL22 and its receptor CCR4 in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Cytokine. 2010;49:24–9.

    Article  PubMed  Google Scholar 

  31. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204:2803–12.

    Article  PubMed  CAS  Google Scholar 

  32. Bettelli E, Oukka M, Kuchroo VK. Th-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–50.

    Article  PubMed  CAS  Google Scholar 

  33. Zheng Y, Danilenko D, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445:648–51.

    Article  PubMed  CAS  Google Scholar 

  34. Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008;9:650–7.

    Article  PubMed  CAS  Google Scholar 

  35. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol. 2009;10:864–71.

    Article  PubMed  CAS  Google Scholar 

  36. Wolk K, Witte E, Wallace E, Docke WD, Kunz S, Asadullah K, et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol. 2006;36:1309–23.

    Article  PubMed  CAS  Google Scholar 

  37. Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005;129:969–84.

    Article  PubMed  CAS  Google Scholar 

  38. Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura K, Ueki K, et al. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 2005;52:1037–46.

    Article  PubMed  CAS  Google Scholar 

  39. Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line: pathways that are shared with and distinct from IL-10. J Biol Chem. 2002;277:33676–82.

    Article  PubMed  CAS  Google Scholar 

  40. Gitter BD, Labus JM, Lees SL, Scheetz ME. Characteristics of human synovial fibroblast activation by IL-1 beta and TNF alpha. Immunology. 1989;66:196–200.

    PubMed  CAS  Google Scholar 

  41. Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 2010;62(10):2876–85.

    Article  PubMed  CAS  Google Scholar 

  42. Niu X, He D, Zhang X, Yue T, Li N, Zhang JZ, et al. IL-21 regulates Th17 cells in rheumatoid arthritis. Hum Immunol. 2010;71(4):334–41.

    Article  PubMed  CAS  Google Scholar 

  43. Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 2010;62:2876–85.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was partially supported by research funding from the National Natural Science Foundation (30600680, 81070407, and 30973018), the Shandong Technological Development Project (2005BS03022, Q2008C07, and BS2009SW014), and the SRF for ROCS, SEM, GIIFSDU (yzc10147), and IIFSDU (2009TS063, 2009TS071).

Disclosures

The authors have no financial conflict of interest.

Author information

Authors and Affiliations

  1. Department of Orthopedics, Qilu Hospital, Shandong University, Jinan, 250012, China

    Lei Zhang, Jian-min Li & Yong-gang Li

  2. Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, China

    Xin-guang Liu, Dao-xin Ma, Yu Hu & Shuang Yu

  3. Department of Rheumatology, Provincial Hospital affiliated to Shandong University, Jinan, 250021, China

    Nai-wen Hu

  4. Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, 250012, China

    Wei Li & Guang-hui Wang

  5. Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, 250012, China

    Xun Qu, Mei-xiang Yang & A-lei Feng

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  1. Lei Zhang
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  2. Jian-min Li
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Corresponding author

Correspondence to Dao-xin Ma.

Additional information

Lei Zhang, Jian-min Li, and Xin-guang Liu contributed equally to this study.

Electronic Supplementary Material

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Supplementary Table 1

Frequencies of T-helper cells and the related ratio in RA, OA patients, and healthy controls (DOC 30 kb)

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Zhang, L., Li, Jm., Liu, Xg. et al. Elevated Th22 Cells Correlated with Th17 Cells in Patients with Rheumatoid Arthritis. J Clin Immunol 31, 606–614 (2011). https://doi.org/10.1007/s10875-011-9540-8

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  • DOI: https://doi.org/10.1007/s10875-011-9540-8

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