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.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10875-011-9540-8/MediaObjects/10875_2011_9540_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10875-011-9540-8/MediaObjects/10875_2011_9540_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10875-011-9540-8/MediaObjects/10875_2011_9540_Fig3_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10875-011-9540-8/MediaObjects/10875_2011_9540_Fig4_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10875-011-9540-8/MediaObjects/10875_2011_9540_Fig5_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10875-011-9540-8/MediaObjects/10875_2011_9540_Fig6_HTML.gif)
Similar content being viewed by others
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
Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996;85:307–10.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of TH17 cells. Nature. 2008;453:1051–7.
Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. New Engl J Med. 2009;361:888–98.
Shahrara S, Huang Q, Mandelin AM, Pope RM. TH-17 cells in rheumatoid arthritis. Arthritis Res Ther. 2008;10:R93.
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.
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.
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.
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.
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.
**e 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.
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.
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.
Nickoloff BJ. Cracking the cytokine code in psoriasis. Nat Med. 2007;13:242–4.
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.
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.
Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–61.
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.
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.
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.
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.
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.
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.
Bettelli E, Oukka M, Kuchroo VK. Th-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–50.
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.
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.
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.
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.
Andoh A, Zhang Z, Inatomi O, Fu**o 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.
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.
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.
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.
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.
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.
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.
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
Corresponding author
Additional information
Lei Zhang, Jian-min Li, and **n-guang Liu contributed equally to this study.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Supplementary Table 1
Frequencies of T-helper cells and the related ratio in RA, OA patients, and healthy controls (DOC 30 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-011-9540-8