Longitudinal study of chemokine receptor expression on peripheral lymphocytes in multiple sclerosis: CXCR3 upregulation is associated with relapse

Abstract

The interaction between chemokines and their recepto rs leads to selective recruitment of cells to foci of inflammation. C ross-sectional studies have reported significantly different expression of chemokine recepto rs C XC R3, C C R5 and C C R2 on peripheral blood lymphocytes in multiple sclerosis (MS) compared with controls. C ells expressing these receptors are likely to play a pathogenic role as suggested by studies of experimental autoimmune encephalo myelitis. A lso, immunogenetic studies of nonfunctional C C R5 recepto rs in MS patients, due to 32d deletion, demonstrated a delay in time to next relapse. The aims of this study were to detect any changes in the serial expression of chemokine recepto rs C C R2, C C R3, C C R5 and C XCR3 on peripheral blood C D4 lymphocytes from patients with MS and to correlate the changes with relapses. Upregulation of C XCR3 expression on peripheral blood C D4 lymphocytes was associated with all relapses and C C R5 expression was significantly affected with all relapses. C linical recovery, with or without intravenous methylprednisolone treatment, coincided with the return of C XC R3 towards baseline in all but one case. Fluctuation in the expression of C XC R3 and C C R5 was also significantly greater in clinically stable patients with MS compared with controls, which may be due to subclinical disease activity. These findings provide further support for the view that C XC R3 and C C R5 antagonists could have a therapeutic value in MS.

Keywords

chemokine receptors CCR5 CXCR3 longitudinal multiple sclerosis

Get full access to this article

View all access options for this article.

References

Lucchinetti C , Bruck W , Parisi J , Scheithauer B et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination . Ann Neurol 2000; 47: 707-717 .

Baggiolini M. Chemokines and leukocyte traffic . Nature 1998; 392: 565-568 .

Campbell JJ , Hedrick J , Zlotnik A , Siani MA et al. Chemokines and the arrest of lymphocytes rolling under flow conditions . Science 1998; 279: 381-384 .

Zlotnik A , Yoshie O. Chemokines: a new classification system and their role in immunity . Immunity 2000; 12: 121-127 .

McManus C , Berman JW , Brett FM , Staunton H et al. MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study . J Neuroimmunol 1998; 86: 20-29 .

Mahad DJ , Howell SJ , Woodroofe MN. Expression of chemokines in the CSF and correlation with clinical disease activity in patients with multiple sclerosis . J Neurol Neurosurg Psychiatry 2002; 72: 498-502 .

Van der Voorn P , Tekstra J , Beelen RH , Tensen CP , De Groot CJ. Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions . Am J Pathol 1999; 154: 45-51 .

Sørensen TL , Tani M , Jensen J , Pierce V et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients . J Clin Invest 1999; 103: 807-815 .

Balashov KE , Rottman JB , Weiner HL , Hancock WW. CCR5(-) and CXCR3(-) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions . Proc Natl Acad Sci USA 1999; 96: 6873-6878 .

10.

Simpson JE , Newcombe J , Cuzner ML , Woodroofe MN. Expression of the interferon-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions . Neuropathol Appl Neurobiol 2000; 26: 133-142 .

11.

Simpson J , Rezaie P , Newcombe J , Cuzner ML et al. Expression of the beta-chemokine receptors CCR2, CCR3 and CCR5 in multiple sclerosis central nervous system tissue . J Neuroimmunol 2000; 108: 192-200 .

12.

Goldberg SH , van der Meer P , Hesselgesser J , Jaffer S et al. CXCR3 expression in human central nervous system diseases . Neuropathol Appl Neurobiol 2001; 27: 127-138 .

13.

Ransohoff RM. Mechanisms of inflammation in MS tissue: adhesion molecules and chemokines . J Neuroimmunol 1999; 98: 57-68 .

14.

Miyagishi R , Kikuchi S , Fukazawa T , Tashiro K. Macrophage inflammatory protein-1 alpha in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological diseases . J Neurol Sci 1995; 129: 223-227 .

15.

Franciotta D , Martino G , Zardini E , Furlan R et al. Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies . J Neuroimmunol 2001; 115: 192-198 .

16.

Misu T , Onodera H , Fujihara K , Matsushima K et al. Chemokine receptor expression on T cells in blood and cerebrospinal fluid at relapse and remission of multiple sclerosis: imbalance of Th1/Th2-associated chemokine signalling . J Neuroimmunol 2001; 114: 207-212 .

17.

Sørensen TL , Sellebjerg F. Distinct chemokine receptor and cytokine expression profile in secondary progressive MS . Neurology 2001; 57: 1371-1376 .

18.

Trebst C , Sørensen TL , Kivisakk P , Cathcart MK et al. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis . Am J Pathol 2001; 159: 1701-1710 .

19.

Sørensen TL , Sellebjerg F , Jensen CV , Strieter RM , Ransohoff RM. Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis . Eur J Neurol 2001; 8: 665-672 .

20.

Bennetts BH , Teutsch SM , Buhler MM , Heard RN , Stewart GJ. The CCR5 deletion mutation fails to protect against multiple sclerosis . Hum Immunol 1997; 58: 52-59 .

21.

Barcellos LF , Schito AM , Rimmler JB , Vittinghoff E et al. CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Multiple Sclerosis Genetics Group . Immunogenetics 2000; 51: 281-288 .

22.

Sellebjerg F , Madsen HO , Jensen CV , Jensen J , Garred P. CCR5 delta32, matrix metalloproteinase-9 and disease activity in multiple sclerosis . J Neuroimmunol 2000; 102: 98-106 .

23.

Sørensen TL , Sellebjerg F. Selective suppression of chemokine receptor CXCR3 expression by interferon-beta1a in multiple sclerosis . Mult Scler 2002; 8: 104-107 .

24.

Bonecchi R , Bianchi G , Bordignon PP , D’Ambrosio D et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s . J Exp Med 1998; 187: 129-134 .

25.

Poser CM , Paty DW , Scheinberg L , McDonald WI et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol 1983; 13: 227-231 .

26.

Schumacher GA. Critique of experimental trials of therapy in multiple sclerosis . Neurology 1974; 24: 1010-1014 .

27.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS) . Neurology 1983; 33: 1444-1452 .

28.

Kieseier BC , Tani M , Mahad D , Oka N et al. Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10 . Brain 2002; 125: 823-834 .

29.

Confalonieri P , Bernasconi P , Megna P , Galbiati S et al. Increased expression of beta-chemokinesin muscle of patients with inflammatory myopathies . J Neuropathol Exp Neurol 2000; 59: 164-169 .

30.

Verma MJ , Lloyd A , Rager H , Strieter R et al. Chemokines in acute anterior uveitis . Curr Eye Res 1997; 16: 1202-1208 .

31.

Miller RJ , Meucci O. AIDS and the brain: is there a chemokine connection ? Trends Neurosci 1999; 22: 471-479 .

32.

Lahrtz F , Piali L , Spanaus KS , Seebach J , Fontana A. Chemokines and chemotaxis of leukocytes in infectious meningitis . J Neuroimmunol 1998; 85: 33-43 .

33.

Calabresi PA , Martin R , Jacobson S. Chemokines in chronic progressive neurological diseases: HTLV-1 associated myelopathy and multiple sclerosis . J Neurovirol 1999; 5: 102-108 .

34.

Rempel SA , Dudas S , Ge S , Gutierrez JA. identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma . Clin Cancer Res 2000; 6: 102-111 .

35.

Simpson JE , Newcombe J , Cuzner ML , Woodroofe MN. Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions . J Neuroimmunol 1998; 84: 238-249 .

36.

Kim CH , Rott L , Kunkel EJ , Genovese MC et al. Rules of chemokine receptor association with T cell polarization in vivo . J Clin Invest 2001; 108: 1331-1339 .

37.

Qin S , Rottman JB , Myers P , Kassam N et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions . J Clin Invest 1998; 101: 746-754 .

38.

Thorpe JW , Kidd D , Moseley IF , Kenndall BE et al. Serial gadolinium-enhanced MRI of the brain and spinal cord in early relapsing -remitting multiple sclerosis . Neurology 1996; 46: 373-378 .

39.

Loetscher M , Loetscher P , Brass N , Meese E , Moser B. Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization . Eur J Immunol 1998; 28: 3696-3705 .

40.

Liu MT , Keirstead HS , Lane TE. Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis . J Immunol 2001; 167: 4091-4097 .

41.

Boskovich SA , Lowder CY , Meisler DM , Gutman FA. Systemic diseases associated with intermediate uveitis . Cleve Clin J Med 1993; 60: 460-465 .

42.

Kojima K , Berger T , Lassmann H , Hinze-Selch D et al. Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100 beta molecule, a calcium binding protein of astroglia . J Exp Med 1994; 180: 817-829 .

43.

Loetscher M , Gerber B , Loetscher P , Jones SA et al. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes . J Exp Med 1996; 184: 963-969 .