Skip to main content

Advertisement

Log in

Decreased CD200R expression on monocyte-derived macrophages correlates with Th17/Treg imbalance and disease activity in rheumatoid arthritis patients

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objectives

CD200 is expressed on various cell types, including T cells, while the CD200 receptor (CD200R) is expressed on myeloid cells such as monocytes-derived macrophages (MDMs). The CD200–CD200R interaction has been shown to play an important role in the prevention of autoimmune disease. Thus, we hypothesized that CD200/CD200R1 is involved in the pathogenesis of rheumatoid arthritis (RA).

Methods

In total, 35 RA patients and 17 healthy controls (HCs) were enrolled in this study. CD200/CD200R1 expression and Th17/Treg were examined by flow cytometry. Serum levels of interleukin (IL)-2, interferon-γ (IFN-γ), IL-4 and IL-10 were detected by ELISA. Disease activity was evaluated according to the C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR) and 28-joint disease activity score (DAS28) scores.

Results

Compared with HCs, RA patients exhibited a significantly decreased level of CD200R1 on MDMs. CD200R1 expression correlated negatively with DAS28, ESR, and CRP levels. This abnormal expression was associated with Th17/Treg imbalance in the active RA patients. However, expression of CD200R1 was not correlated with Th1 (IL-2, IFN-γ) or Th2 (IL-4, IL-10) cytokine responses.

Conclusion

In this study, we demonstrate a significant correlation between CD200R1+ cells and disease severity in RA patients, thus indicating the relevance of the CD200/CD200R1 signaling pathway's potential involvement in the pathogenesis of RA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–61.

    Article  CAS  PubMed  Google Scholar 

  2. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440.

    Article  CAS  PubMed  Google Scholar 

  3. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–19.

    Article  CAS  PubMed  Google Scholar 

  4. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.

    Article  CAS  PubMed  Google Scholar 

  5. Yudoh K, Matsuno H, Nakazawa F, Yonezawa T, Kimura T. Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis. Arthr Rheum. 2000;43:617–27.

    Article  CAS  Google Scholar 

  6. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol. 2005;6:331–7.

    Article  CAS  PubMed  Google Scholar 

  7. Pernis AB. Th17 cells in rheumatoid arthritis and systemic lupus erythematosus. J Intern Med. 2009;265:644–52.

    Article  CAS  PubMed  Google Scholar 

  8. Boissier MC, Assier E, Falgarone G, Bessis N. Shifting the imbalance from Th1/Th2 to Th17/Treg: the changing rheumatoid arthritis. Joint Bone Spine. 2008;75:373–5.

    Article  CAS  PubMed  Google Scholar 

  9. Wright GJ, Jones M, Puklavec MJ, Brown MH, Barclay AN. The unusual distribution of the neuronal/lymphoid cell-surface CD200 (OX2) glycoprotein is conserved in humans. Immunology. 2001;102:173–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wright GJ, Cherwinski H, Foster-Cuevas M, Brooke G, Puklavec MJ, Bigler M, et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J Immunol. 2003;171:3034–46.

    Article  CAS  PubMed  Google Scholar 

  11. Gorczynski RM, Chen Z, Kal Y, Lee L, Wong S, Marsden PA. CD200 is a ligand for all members of the CD200R family of immunoregulatory molecules. J Immunol. 2004;172:7744–9.

    Article  CAS  PubMed  Google Scholar 

  12. Gorczynski RM. Transplant tolerance modifying antibody to CD200 receptor, but not CD200, alters cytokine production profile from stimulated macrophages. Eur J Immunol. 2001;31:2331–7.

    Article  CAS  PubMed  Google Scholar 

  13. Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290:1768–71.

    Article  CAS  PubMed  Google Scholar 

  14. Broderick C, Hoek RM, Forrester JV, Liversidge J, Sedgwick JD, Dick AD. Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis. Am J Pathol. 2002;161:1669–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gorczynsi RM, Chen Z, Yu K, Hu J. CD200 immunoadhesin suppresses collagen-induced arthritis in mice. Clin Immunol. 2001;101:328–34.

    Article  Google Scholar 

  16. Koning N, Bö L, Hoek RM, Huitinga I. Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions. Ann Neurol. 2007;62:504–14.

    Article  CAS  PubMed  Google Scholar 

  17. Garza LA, Yang CC, Zhao T, Blatt HB, Lee M, He H, et al. Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells. J Clin Invest. 2011;121:613–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Coles SJ, Hills RK, Wang EC, Burnett AK, Man S, Darley RL, et al. Increased CD200 expression in acute myeloid leukemia is linked with an increased frequency of FoxP3+ regulatory T cells. Leukemia. 2012;26:2146–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rygiel TP, Karnam G, Goverse G, van der Marel AP, Greuter MJ, van Schaarenburg RA. CD200–CD200R signaling suppresses antitumor responses independently of CD200 expression on the tumor. Oncogene. 2012;31:2979–88.

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  21. Hepburn AL, Mason JC, Davies KA. Expression of Fcgamma and complement receptors on peripheral blood monocytes in systemic lupus erythematosus and rheumatoid arthritis. Rheumatology (Oxford). 2004;43:547–54.

    Article  CAS  Google Scholar 

  22. Baran J, Kowalczyk D, Ozóg M, Zembala M. Three-color flow cytometery detection of intracellular cytokine in peripheral blood mononuclear cells: comparative analysis of phorbol myristate acetate-ionomycin and phytohemagglutinin stimulation. Clin Diagn Lab Immunol. 2001;8:303–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jenmalm MC, Cherwinski H, Bowman EP, Phillips JH, Sedgwick JD. Regulation of myeloid cell function through the CD200 receptor. J Immunol. 2006;176:191–9.

    Article  CAS  PubMed  Google Scholar 

  24. Mihrshahi R, Barclay AN, Brown MH. Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. J Immunol. 2009;183:4879–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brentano F, Kyburz D, Schorr O, Gay R, Gay S. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol. 2005;233:90–6.

    Article  CAS  PubMed  Google Scholar 

  26. Snelgrove RJ, Goulding J, Didierlaurent AM, Lyonga D, Vekaria S, Edwards L, et al. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat Immunol. 2008;9:1074–83.

    Article  CAS  PubMed  Google Scholar 

  27. Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol. 2003;171:6173–7.

    Article  CAS  PubMed  Google Scholar 

  28. Lubberts E, van den Bersselaar L, Oppers-Walgreen B, Schwazenberger P, Coenen-de Roo CJ, Kolls JK. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NK-κB ligand/osteoprotegerin balance. J Immunol. 2003;170:2655–62.

    Article  CAS  PubMed  Google Scholar 

  29. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8:639–46.

    Article  CAS  PubMed  Google Scholar 

  30. Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthr Rheum. 1988;31:784–8.

    Article  CAS  Google Scholar 

  31. Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med. 2013;19:322–8.

    Article  CAS  PubMed  Google Scholar 

  32. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M. Reciprocal developmental pathways for the generation of path ogenic effector Th17 and regulatory T cells. Nature. 2006;441:235–8.

    Article  CAS  PubMed  Google Scholar 

  33. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nature Immunol. 2010;11:7–13.

    Article  CAS  Google Scholar 

  34. Evans HG, Gullick NJ, Kelly S, Pitzalis C, Lord GM, Kirkham BW, et al. In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses. Proc Natl Acad Sci USA. 2009;106:6232–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jiao Z, Hua S, Wang W, Wang H, Gao J, Wang X. Increased circulating myeloid-derived suppressor cells correlated negatively with Th17 cells in patients with rheumatoid arthritis. Scand J Rheumatol. 2013;42:85–90.

    Article  CAS  PubMed  Google Scholar 

  36. Pallasch CP, Ulbrich S, Brinker R, Hallek M, Uger RA, Wendtner CM. Disruption of T cell suppression in chronic lymphocytic leukemia by CD200 blockade. Leuk Res. 2009;33:460–4.

    Article  CAS  PubMed  Google Scholar 

  37. Gorczynsi RM, Lee L, Boudakov I. Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation. 2005;79:1180–3.

    Article  Google Scholar 

  38. Simelyte E, Alzabin S, Boudakov I, Williams R. CD200R1 regulates the severity of arthritis but has minimal impact on the adaptive immune response. Clin Exp Immunol. 2010;162:163–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Scientific Research Foundation of Zhejiang Provincial Education Department (Y201121334) (Y201226006), Medical Science and Technology Project of Zhejiang Province (2012KYB088), and Science and Technology Project of Zhejiang Province Department of Science and Technology (2012F82G2010026) (2013C33G2010397).

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bing Hao.

Additional information

Responsible Editor: Liwu Li.

S. Gao and B. Hao contributed equally to this work and should be considered co-first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gao, S., Hao, B., Yang, X.F. et al. Decreased CD200R expression on monocyte-derived macrophages correlates with Th17/Treg imbalance and disease activity in rheumatoid arthritis patients. Inflamm. Res. 63, 441–450 (2014). https://doi.org/10.1007/s00011-014-0716-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-014-0716-6

Keywords

Navigation