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mRNA Quantification of T-bet, GATA-3, IFN-γ, and IL-4 Shows a Defective Th1 Immune Response in the Peripheral Blood from Rheumatoid Arthritis Patients: Link with Disease Activity

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Abstract

A T helper (Th)1 cytokine profile is predominant in the inflamed synovium of rheumatoid arthritis (RA). Since the situation in the blood is more controversial, we studied the Th1/Th2 balance in the peripheral blood of RA patients using mRNA markers. Total RNA was isolated directly from whole blood from 20 RA patients and 14 healthy controls. T-bet and GATA-3 transcription factors associated with Th1 and Th2 responses respectively, and IFNγ and IL-4 mRNA levels were measured by real-time PCR. In RA but not in control samples, T-bet mRNA levels correlated positively with IFNγ mRNA levels, and negatively with CRP levels. Accordingly, RA patients were divided into two groups according to CRP levels. In comparison to RA patients with a low CRP (CRP < 40 mg/l), patients with a high CRP (CRP≥40 mg/l) had lower IFNγ/β-actin, T-bet/β-actin mRNA levels and T-bet/GATA-3 expression ratios. In conclusion, RA blood cells showed a decreased Th1 situation as indicated by low IFNγ and T-bet mRNA expression. This pattern was found only in patients with the most active disease.

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References

  1. Janossy G, Panayi G, Duke O, Bofill M, Poulter LW, Goldstein G: Rheumatoid arthritis: A disease of T-lymphocyte/macrophage immunoregulation. Lancet 2:839–842, 1981

    CAS  PubMed  Google Scholar 

  2. Qu Z, Garcia CH, O’Rourke LM, Planck SR, Kohli M, Rosenbaum JT: Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia. Results of proliferating cell nuclear antigen/cyclin, c-myc, and nucleolar organiser region staining. Arthritis Rheum 37:212–220, 1994

    CAS  PubMed  Google Scholar 

  3. Firestein GS, Zvaifler NJ: How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 33:768–773 1990

    CAS  PubMed  Google Scholar 

  4. Panayi GS, Lanchbury JS, Kingsley GH: The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum 35:729–735, 1992

    CAS  PubMed  Google Scholar 

  5. Miossec P, van den Berg W: Th1/Th2 cytokine balance in arthritis. Arthritis Rheum 40:2105–2115, 1997,

    CAS  PubMed  Google Scholar 

  6. Miltenburg AM, van Laar JM, de Kuiper R, Daha MR, Breedveld FC: T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. Scand J Immunol 35:603–610, 1992

    CAS  PubMed  Google Scholar 

  7. Quayle AJ, Chomarat P, Miossec P, Kjeldsen-Kragh J, Forre O, Natvig JB: Rheumatoid inflammatory T-cell clones express mostly Th1 but also Th2 and mixed (Th0-like) cytokine patterns. Scand J Immunol 38:75–82, 1993

    CAS  PubMed  Google Scholar 

  8. Simon AK, Seipelt E, Sieper J: Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci USA 91:8562–8566, 1994

    CAS  PubMed  Google Scholar 

  9. Schulze-Koops H, Lipsky PE, Kavanaugh AF, Davis LS: Elevated Th1- or Th0-like cytokine mRNA in peripheral circulation of patients with rheumatoid arthritis. Modulation by treatment with anti- ICAM-1 correlates with clinical benefit. J Immunol 155:5029–5037, 1995

    CAS  PubMed  Google Scholar 

  10. Mangge H, Felsner P, Herrmann J, el-Shabrawi Y, Liebmann P, Schauenstein K: Early rheumatoid arthritis is associated with diminished numbers of th1 cells in stimulated peripheral blood. Immunobiology 200:290–294, 1999

    CAS  PubMed  Google Scholar 

  11. van Roon JA, Verhoef CM, van Roy JL, Gmelig-Meyling FH, Huber-Bruning O, Lafeber FP, Bijlsma JW: Decrease in peripheral type 1 over type 2 T cell cytokine production in patients with rheumatoid arthritis correlates with an increase in severity of disease. Ann Rheum Dis 56:656–660, 1997

    CAS  PubMed  Google Scholar 

  12. Haddad A, Bienvenu J, Miossec P: Increased production of a Th2 cytokine profile by activated whole blood cells from rheumatoid arthritis patients. J Clin Immunol 18:399–403, 1998

    Article  CAS  PubMed  Google Scholar 

  13. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM: Tuberculosis associated with infliximab, a tumor necrosis factor alpha- neutralising agent. N Engl J Med 345:1098–1104, 2001

    CAS  PubMed  Google Scholar 

  14. Carmona L, Hernandez-Garcia C, Vadillo C, Pato E, Balsa A, Gonzalez-Alvaro I, Belmonte MA, Tena X, Sanmarti R: Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 30:1436–1439, 2003

    PubMed  Google Scholar 

  15. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH: A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669, 2000

    Article  CAS  PubMed  Google Scholar 

  16. Zheng W, Flavell RA: The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587–596, 1997

    Article  CAS  PubMed  Google Scholar 

  17. Merika M, Orkin SH: DNA-binding specificity of gata family transcription factors. Mol Cell Biol 13:3999–4010, 1993

    CAS  PubMed  Google Scholar 

  18. Rainen L, Oelmueller U, Jurgensen S, Wyrich R, Ballas C, Schram J, Herdman C, Bankaitis-Davis D, Nicholls N, Trollinger D, Tryon V: Stabilisation of mRNA expression in whole blood samples. Clin Chem 48:1883–1890, 2002

    CAS  PubMed  Google Scholar 

  19. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al.: The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324, 1988

    CAS  PubMed  Google Scholar 

  20. Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R, Giese T, Engelmann H, Endres S, Krieg AM, Hartmann G: Toll-like receptor expression reveals cpg DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of il-12. Eur J Immunol 31:3026–3037, 2001

    Article  CAS  PubMed  Google Scholar 

  21. Johnson K, Choi Y, DeGroot E, Samuels I, Creasey A, Aarden L: Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol 160:5130–5135, 1998

    CAS  PubMed  Google Scholar 

  22. Esnault S, Malter JS: Primary peripheral blood eosinophils rapidly degrade transfected granulocyte-macrophage colony-stimulating factor mRNA. J Immunol 163:5228–5234, 1999

    CAS  PubMed  Google Scholar 

  23. Hartel C, Bein G, Muller-Steinhardt M, Kluter H: Ex vivo induction of cytokine mRNA expression in human blood samples. J Immunol Methods 249:63–71, 2001

    Article  CAS  PubMed  Google Scholar 

  24. Lighvani AA, Frucht DM, Jankovic D, Yamane H, Aliberti J, Hissong BD, Nguyen BV, Gadina M, Sher A, Paul WE, O’Shea JJ: T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci USA 98:15137–15142, 2001

    Article  CAS  PubMed  Google Scholar 

  25. Leiden JM: Transcriptional regulation of T cell receptor genes. Annu Rev Immunol 11:539–570, 1993

    Article  CAS  PubMed  Google Scholar 

  26. Kawashima M, Miossec P: Decreased response to IL-12 and IL-18 of peripheral blood cells in rheumatoid arthritis. Arthritis Res Ther 6:R39–R45, 2004

    Article  CAS  PubMed  Google Scholar 

  27. Kawashima M, Miossec P: Effect of treatment of rheumatoid arthritis with infliximab on IFNγ, IL-4, T-bet, and GATA-3 expression: Link with improvement of systemic inflammation and disease activity. Ann Rheum Dis, 64:415–418, 2005

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology and Rheumatology and INSERM U-403, Hospital Edouard Herriot, Lyon, France

    Masanori Kawashima & Pierre Miossec

  2. Clinical Immunology Unit, Department of Immunology and Rheumatology, Hospital Edouard Herriot, 69437, Lyon Cedex 03, France

    Pierre Miossec

Authors
  1. Masanori Kawashima
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  2. Pierre Miossec
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Corresponding author

Correspondence to Pierre Miossec.

Additional information

RA, rheumatoid arthritis; Th, T helper; IFN, interferon; CRP, C-reactive protein; IL, interleukin.

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Kawashima, M., Miossec, P. mRNA Quantification of T-bet, GATA-3, IFN-γ, and IL-4 Shows a Defective Th1 Immune Response in the Peripheral Blood from Rheumatoid Arthritis Patients: Link with Disease Activity. J Clin Immunol 25, 209–214 (2005). https://doi.org/10.1007/s10875-005-4092-4

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  • DOI: https://doi.org/10.1007/s10875-005-4092-4

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