Skip to main content
Top
Published in: Inflammation Research 6/2014

01-06-2014 | Original Research Paper

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

Authors: Song Gao, Bing Hao, Xu Feng Yang, Wei Qian Chen

Published in: Inflammation Research | Issue 6/2014

Login to get access

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.
Literature
2.
go back to reference Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440.PubMedCrossRef Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440.PubMedCrossRef
3.
4.
5.
go back to reference 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.CrossRef 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.CrossRef
6.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
7.
go back to reference Pernis AB. Th17 cells in rheumatoid arthritis and systemic lupus erythematosus. J Intern Med. 2009;265:644–52.PubMedCrossRef Pernis AB. Th17 cells in rheumatoid arthritis and systemic lupus erythematosus. J Intern Med. 2009;265:644–52.PubMedCrossRef
8.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
9.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
10.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
11.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
12.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
13.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
14.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
15.
go back to reference Gorczynsi RM, Chen Z, Yu K, Hu J. CD200 immunoadhesin suppresses collagen-induced arthritis in mice. Clin Immunol. 2001;101:328–34.CrossRef Gorczynsi RM, Chen Z, Yu K, Hu J. CD200 immunoadhesin suppresses collagen-induced arthritis in mice. Clin Immunol. 2001;101:328–34.CrossRef
16.
go back to reference Koning N, Bö L, Hoek RM, Huitinga I. Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions. Ann Neurol. 2007;62:504–14.PubMedCrossRef Koning N, Bö L, Hoek RM, Huitinga I. Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions. Ann Neurol. 2007;62:504–14.PubMedCrossRef
17.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
18.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
19.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
20.
go back to reference 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. 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.
21.
go back to reference 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.CrossRef 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.CrossRef
22.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
23.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
24.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
25.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
26.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
27.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
28.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
29.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
30.
go back to reference 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.CrossRef 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.CrossRef
31.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
32.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
33.
go back to reference Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nature Immunol. 2010;11:7–13.CrossRef Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nature Immunol. 2010;11:7–13.CrossRef
34.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
35.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
36.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
37.
go back to reference Gorczynsi RM, Lee L, Boudakov I. Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation. 2005;79:1180–3.CrossRef Gorczynsi RM, Lee L, Boudakov I. Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation. 2005;79:1180–3.CrossRef
38.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
Metadata
Title
Decreased CD200R expression on monocyte-derived macrophages correlates with Th17/Treg imbalance and disease activity in rheumatoid arthritis patients
Authors
Song Gao
Bing Hao
Xu Feng Yang
Wei Qian Chen
Publication date
01-06-2014
Publisher
Springer Basel
Published in
Inflammation Research / Issue 6/2014
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-014-0716-6

Other articles of this Issue 6/2014

Inflammation Research 6/2014 Go to the issue