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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 2/2006

Open Access 01-04-2006 | Research article

Expression of the inflammatory chemokines CCL5, CCL3 and CXCL10 in juvenile idiopathic arthritis, and demonstration of CCL5 production by an atypical subset of CD8+ T cells

Authors: Daniel S Pharoah, Hemlata Varsani, Richard W Tatham, Katy R Newton, Wilco de Jager, Berent J Prakken, Nigel Klein, Lucy R Wedderburn

Published in: Arthritis Research & Therapy | Issue 2/2006

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Abstract

This study focuses upon three chemokines, namely CCL5, CXCL10 and CCL3, which are potential novel therapeutic targets in arthritis. The aim of the study was to analyse the expression and production of these three chemokines within the joints of children with juvenile idiopathic arthritis (JIA) of the oligoarticular and polyarticular subtypes. All three of these chemokines are highly expressed at the level of mRNA, with the most significant increase in mRNA levels being demonstrated for CCL5 when compared with matched peripheral blood samples and controls. We show that high levels of all three chemokines are present in synovial fluid of children with JIA. We investigate the major source of CCL5 from inflammatory synovial cells, which we show to be CD8+ T cells. This CD8+ synovial T cell population has an unexpected phenotype that has not been described previously, being CCR7- yet predominantly CD28+ and CD45RA-. These cells contain high levels of stored intracellular CCL5, and rapid release of CCL5 takes place on T cell stimulation, without requiring new protein synthesis. In addition, we demonstrate that CCL5 is present in synovial biopsies from these patients, in particular on the endothelium of small and medium sized vessels. We believe this to be the first in depth analysis of these mediators of inflammation in JIA.
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Literature
1.
Bywaters EG: Pathologic aspects of juvenile chronic polyarthritis. Arthritis Rheum. 1977, 20: 271-276.PubMed
2.
Wynne-Roberts CR, Anderson CH, Turano AM, Baron M: Light- and electron-microscopic findings of juvenile rheumatoid arthritis synovium: comparison with normal juvenile synovium. Semin Arthritis Rheum. 1978, 7: 287-302. 10.1016/0049-0172(78)90027-6.CrossRefPubMed
3.
Wedderburn LR, Maini MK, Patel A, Beverley PCL, Woo P: Molecular fingerprinting reveals non-overlapping T cell oligoclonality between an inflamed site and peripheral blood. Int Immunol. 1999, 11: 535-543. 10.1093/intimm/11.4.535.CrossRefPubMed
4.
Butcher EC, Scollay RG, Weissman IL: Organ specificity of lymphocyte migration: mediation by highly selective lymphocyte interaction with organ-specific determinants on high endothelial venules. Eur J Immunol. 1980, 10: 556-561.CrossRefPubMed
5.
Jalkanen S, Reichert RA, Gallatin WM, Bargatze RF, Weissman IL, Butcher EC: Homing receptors and the control of lymphocyte migration. Immunol Rev. 1986, 91: 39-60. 10.1111/j.1600-065X.1986.tb01483.x.CrossRefPubMed
6.
7.
Moser B, Loetscher P: Lymphocyte traffic control by chemokines. Nat Immunol. 2001, 2: 123-128. 10.1038/84219.CrossRefPubMed
8.
Zlotnik A, Yoshie O: Chemokines: a new classification system and their role in immunity. Immunity. 2000, 12: 121-127. 10.1016/S1074-7613(00)80165-X.CrossRefPubMed
9.
Qin S, Rottman J, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR: The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 1998, 101: 746-754.PubMedCentralCrossRefPubMed
10.
Sallusto F, Kremmer E, Palermo B, Hoy A, Ponath P, Qin S, Forster R, Lipp M, Lanzavecchia A: Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur J Immunol. 1999, 29: 2037-2045. 10.1002/(SICI)1521-4141(199906)29:06<2037::AID-IMMU2037>3.3.CO;2-M.CrossRefPubMed
11.
Bonecchi R, Bianchi G, Bordignon PP, D'Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F: Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th-2s. J Exp Med. 1998, 187: 129-134. 10.1084/jem.187.1.129.PubMedCentralCrossRefPubMed
12.
Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999, 401: 708-712. 10.1038/44385.CrossRefPubMed
13.
Wong M, Fish EN: RANTES and MIP-1alpha activate stats in T cells. J Biol Chem. 1998, 273: 309-314. 10.1074/jbc.273.1.309.CrossRefPubMed
14.
Bacon KB, Premack BA, Gardner P, Schall TJ: Activation of dual T cell signaling pathways by the chemokine RANTES. Science. 1995, 269: 1727-1730.CrossRefPubMed
15.
Appay V, Dunbar PR, Cerundolo V, McMichael A, Czaplewski L, Rowland-Jones S: RANTES activates antigen-specific cytotoxic T lymphocytes in a mitogen-like manner through cell surface aggregation. Int Immunol. 2000, 12: 1173-1182. 10.1093/intimm/12.8.1173.CrossRefPubMed
16.
Fischer FR, Luo Y, Luo M, Santambrogio L, Dorf ME: RANTES-induced chemokine cascade in dendritic cells. J Immunol. 2001, 167: 1637-1643.CrossRefPubMed
17.
Molon B, Gri G, Bettella M, Gomez-Mouton C, Lanzavecchia A, Martinez AC, Manes S, Viola A: T cell costimulation by chemokine receptors. Nat Immunol. 2005, 6: 465-471. 10.1038/ni1191.CrossRefPubMed
18.
Wedderburn LR, Robinson N, Patel A, Varsani H, Woo P: Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis. Arthritis Rheum. 2000, 43: 765-774. 10.1002/1529-0131(200004)43:4<765::AID-ANR7>3.0.CO;2-B.CrossRefPubMed
19.
Gattorno M, Prigione I, Morandi F, Gregorio A, Chiesa S, Ferlito F, Favre A, Uccelli A, Gambini C, Martini A: Phenotypic and functional characterisation of CCR7+ and CCR7- CD4+ memory T cells homing to the joints in juvenile idiopathic arthritis. Arthritis Res Ther. 2005, 7: R256-267. 10.1186/ar1485.PubMedCentralCrossRefPubMed
20.
Tak PP, Taylor PC, Breedveld FC, Smeets TJ, Daha MR, Kluin PM, Meinders AE, Maini RN: Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1077-1081.CrossRefPubMed
21.
Taylor PC, Peters AM, Paleolog E, Chapman PT, Elliott MJ, McCloskey R, Feldmann M, Maini RN: Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum. 2000, 43: 38-47. 10.1002/1529-0131(200001)43:1<38::AID-ANR6>3.0.CO;2-L.CrossRefPubMed
22.
Bingham S, Veale D, Fearon U, Isaacs JD, Morgan G, Emery P, McGonagle D, Reece R, Clague R, Snowden JA: High-dose cyclophosphamide with stem cell rescue for severe rheumatoid arthritis: short-term efficacy correlates with reduction of macroscopic and histologic synovitis. Arthritis Rheum. 2002, 46: 837-839. 10.1002/art.10093.CrossRefPubMed
23.
Aeberli D, Seitz M, Juni P, Villiger PM: Increase of peripheral CXCR3 positive T lymphocytes upon treatment of RA patients with TNF-alpha inhibitors. Rheumatology (Oxford). 2005, 44: 172-175. 10.1093/rheumatology/keh437.CrossRef
24.
Haringman JJ, Kraan MC, Smeets TJ, Zwinderman KH, Tak PP: Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis. 2003, 62: 715-721. 10.1136/ard.62.8.715.PubMedCentralCrossRefPubMed
25.
Szekanecz Z, Koch AE: Therapeutic inhibition of leukocyte recruitment in inflammatory diseases. Curr Opin Pharmacol. 2004, 4: 423-428. 10.1016/j.coph.2004.03.013.CrossRefPubMed
26.
27.
Barnes DA, Tse J, Kaufhold M, Hesselgesser J, Strieter R, Horuk R, Perez HD: Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest. 1998, 101: 2910-2919.PubMedCentralCrossRefPubMed
28.
Xie JH, Nomura N, Lu M, Chen SL, Koch GE, Weng Y, Rosa R, Di Salvo J, Mudgett J, Peterson LB, et al: Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation. J Leukoc Biol. 2003, 73: 771-780. 10.1189/jlb.1102573.CrossRefPubMed
29.
Shahrara S, Proudfoot AE, Woods JM, Ruth JH, Amin MA, Park CC, Haas CS, Pope RM, Haines GK, Zha YY, et al: Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum. 2005, 52: 1907-1919. 10.1002/art.21033.PubMedCentralCrossRefPubMed
30.
Plater-Zyberk C, Hoogewerf AJ, Proudfoot AE, Power CA, Wells TN: Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett. 1997, 57: 117-120. 10.1016/S0165-2478(97)00075-8.CrossRefPubMed
31.
Quinones MP, Estrada CA, Kalkonde Y, Ahuja SK, Kuziel WA, Mack M, Ahuja SS: The complex role of the chemokine receptor CCR2 in collagen-induced arthritis: implications for therapeutic targeting of CCR2 in rheumatoid arthritis. J Mol Med. 2005, 83: 672-81. 10.1007/s00109-005-0637-5.CrossRefPubMed
32.
Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, Maldonado-Cocco J, Orozco-Alcala J, Prieur AM, et al: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004, 31: 390-392.PubMed
33.
Kameyoshi Y, Dorschner A, Mallet AI, Christophers E, Schroder JM: Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. J Exp Med. 1992, 176: 587-592. 10.1084/jem.176.2.587.CrossRefPubMed
34.
de Jager W, Wedderburn LR, Rijkers G, Kuis W, Prakken B: Simultaneous detection of 30 soluble mediators in plasma and synovial fluid of patients with JIA. Clin Exp Rheum. 2004, 22: 538-
35.
de Jager W, Prakken B, Bijlsma JW, Kuis W, Rijkers G: Improved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibdoies. J Immunol Methods. 2005, 300: 124-135. 10.1016/j.jim.2005.03.009.CrossRefPubMed
36.
Catalfamo M, Karpova T, McNally J, Costes SV, Lockett SJ, Bos E, Peters PJ, Henkart PA: Human CD8+ T cells store RANTES in a unique secretory compartment and release it rapidly after TcR stimulation. Immunity. 2004, 20: 219-230. 10.1016/S1074-7613(04)00027-5.CrossRefPubMed
37.
Wagner L, Yang OO, Garcia-Zepeda EA, Ge Y, Kalams SA, Walker BD, Pasternack MS, Luster AD: Beta-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature. 1998, 391: 908-911. 10.1038/35750.CrossRefPubMed
38.
Fukada K, Sobao Y, Tomiyama H, Oka S, Takiguchi M: Functional expression of the chemokine receptor CCR5 on virus epitope-specific memory and effector CD8+ T cells. J Immunol. 2002, 168: 2225-2232.CrossRefPubMed
39.
Swanson BJ, Murakami M, Mitchell TC, Kappler J, Marrack P: RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process. Immunity. 2002, 17: 605-615. 10.1016/S1074-7613(02)00456-9.CrossRefPubMed
40.
Walzer T, Marcais A, Saltel F, Bella C, Jurdic P, Marvel J: Cutting edge: immediate RANTES secretion by resting memory CD8 T cells following antigenic stimulation. J Immunol. 2003, 170: 1615-1619.CrossRefPubMed
41.
Black AP, Bhayani H, Ryder CA, Gardner-Medwin JM, Southwood TR: T-cell activation without proliferation in juvenile idiopathic arthritis. Arthritis Res. 2002, 4: 177-183. 10.1186/ar403.PubMedCentralCrossRefPubMed
42.
Pilling D, Akbar AN, Bacon PA, Salmon M: CD4+ CD45RA+ T cells from adults respond to recall antigens after CD28 ligation. Int Immunol. 1996, 8: 1737-1742.CrossRefPubMed
43.
Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein M, Rvan Lier RA: Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med. 1997, 186: 1407-1418. 10.1084/jem.186.9.1407.PubMedCentralCrossRefPubMed
44.
Wedderburn LR, Jeffery R, White H, Patel A, Varsani H, Linch D, Murray K, Woo P: Autologous stem cell transplantation for paediatric-onset polyarteritis nodosa: changes in autoimmune phenotype in the context of reduced diversity of the T- and B-cell repertoires, and evidence for reversion from the CD45RO(+) to RA(+) phenotype. Rheumatology (Oxford). 2001, 40: 1299-1307. 10.1093/rheumatology/40.11.1299.CrossRef
45.
Hidaka T, Suzuki K, Kawakami M, Okada M, Kataharada K, Shinohara T, Takamizawa-Matsumoto M, Ohsuzu F: Dynamic changes in cytokine levels in serum and synovial fluid following filtration leukocytapheresis therapy in patients with rheumatoid arthritis. J Clin Apheresis. 2001, 16: 74-81. 10.1002/jca.1016.CrossRefPubMed
46.
Patel DD, Zachariah JP, Whichard LP: CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol. 2001, 98: 39-45. 10.1006/clim.2000.4957.CrossRefPubMed
47.
Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, et al: Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature. 2001, 410: 106-111. 10.1038/35065118.CrossRefPubMed
48.
Varsani H, Patel A, van Kooyk Y, Woo P, Wedderburn LR: Synovial dendritic cells in juvenile idiopathic arthritis (JIA) express receptor activator of NF-kappaB (RANK). Rheumatology (Oxford). 2003, 42: 583-590.
49.
Patel DD, Koopmann W, Imai T, Whichard LP, Yoshie O, Krangel MS: Chemokines have diverse abilities to form solid phase gradients. Clin Immunol. 2001, 99: 43-52. 10.1006/clim.2000.4997.CrossRefPubMed
50.
Devergne O, Marfaing-Koka A, Schall TJ, Leger-Ravet MB, Sadick M, Peuchmaur M, Crevon MC, Kim KJ, Schall TT, Kim T, et al: Production of the RANTES chemokine in delayed-type hypersensitivity reactions: involvement of macrophages and endothelial cells. J Exp Med. 1994, 179: 1689-1694. 10.1084/jem.179.5.1689.CrossRefPubMed
51.
Patterson AM, Siddall H, Chamberlain G, Gardner L, Middleton J: Expression of the duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium. J Pathol. 2002, 197: 108-116. 10.1002/path.1100.CrossRefPubMed
52.
Volin MV, Shah MR, Tokuhira M, Haines GK, Woods JM, Koch AE: RANTES expression and contribution to monocyte chemotaxis in arthritis. Clin Immunol Immunopathol. 1998, 89: 44-53. 10.1006/clin.1998.4590.CrossRefPubMed
53.
Haringman JJ, Smeets TJ, Reinders-Blankert P, Tak PP: Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of rheumatoid arthritis, osteoarthritis and reactive arthritis patients. Ann Rheum Dis. 2006, 65: 294-300. 10.1136/ard.2005.037176.PubMedCentralCrossRefPubMed
54.
Bonecchi R, Locati M, Galliera E, Vulcano M, Sironi M, Fra AM, Gobbi M, Vecchi A, Sozzani S, Haribabu B, et al: Differential recognition and scavenging of native and truncated macrophage-derived chemokine (macrophage-derived chemokine/CC chemokine ligand 22) by the D6 decoy receptor. J Immunol. 2004, 172: 4972-4976.CrossRefPubMed
55.
Jamieson T, Cook DN, Nibbs RJ, Rot A, Nixon C, McLean P, Alcami A, Lira SA, Wiekowski M, Graham GJ: The chemokine receptor D6 limits the inflammatory response in vivo. Nat Immunol. 2005, 6: 403-411. 10.1038/ni1182.CrossRefPubMed
Metadata
Title
Expression of the inflammatory chemokines CCL5, CCL3 and CXCL10 in juvenile idiopathic arthritis, and demonstration of CCL5 production by an atypical subset of CD8+ T cells
Authors
Daniel S Pharoah
Hemlata Varsani
Richard W Tatham
Katy R Newton
Wilco de Jager
Berent J Prakken
Nigel Klein
Lucy R Wedderburn
Publication date
01-04-2006
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 2/2006
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar1913

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