Abstract
In order to elucidate the differences between systemic and central nervous system (CNS) immunity that are relevant to exacerbations of multiple sclerosis (MS), paired peripheral blood and cerebrospinal fluid (CSF) samples obtained from 36 non–treated patients with relapsing–remitting MS (RRMS) were simultaneously examined using flow cytometry to determine the percentages of functional lymphocyte subsets, as well as enzyme–linked immunosorbent assays for measuring soluble immune mediators.Active RRMS patients (n = 27) were characterized by an increase in CD4+CXCR3+ Th1 cells in blood as compared with inactive patients (n = 9), and this parameter was inversely correlated with plasma levels of IL–10 and IL– 12p70. In contrast, an increase in the percentage of CD4+CD25+ cells and a decrease in the percentage of CD8+CD11ahigh cells were features of CSF samples from those with active RRMS. Further, CSF CD4+CD25+ cells had a close association with leukocyte counts as well as albumin and CXCL10 levels in the CSF, and, thus, could be useful as a measure for inflammatory reactions in the CNS. On the other hand, CD8+CD11ahigh cells may function as immunoregulatory cells, as their percentage in the CSF showed a positive correlation with CSF levels of the anti–inflammatory cytokine IL–4. These findings suggest that MS relapses occur in a combination with altered cell–mediated immunity that differs between the peripheral blood and CSF compartments, while measurement of lymphocyte subsets may be helpful for monitoring disease status.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Calder V, Owen S, Watson C, Feldmann M, Davison A (1989) MS: a localized immune disease of the central nervous system. Immunol Today 10:99–103
Calopa M, Bas J, Mestre M, Arbizu T, Peres J, Buendia E (1995) T cell subsets in multiple sclerosis: a serial study. Acta Neurol Scand 92:361–368
Crucian B, Dunne P, Friedman H, Ragsdale R, Pross S, Widen R (1995) Alterations in levels of CD28–/CD8+ suppressor cell precursor and CD45RO+/CD4+ memory T lymphocytes in the peripheral blood of multiple sclerosis patients. Clin Diag Lab Immunol 2:249–252
Danilov AI, Andersson M, Bavand N, Wiklund NP, Olsson T, Brundin L (2003) Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis. J Neuroimmunol 136:112–118
Eikelenboom MJ, Killestein J, Izeboud T, Kalkers NF, van Lier RAW, Barkhof F, Uitdehaag BMJ, Polman CH (2002) Chemokine receptor expression on T cells is related to new lesion development in multiple sclerosis. J Neuroimmunol 133:225–232
Eoli M, Ferrarini M, Dufour A, Heltaj S, Bevilacqua L, Comi G, Cosi V, Filippini G, Martinelli V, Milanese C, La Mantia L, Salmaggi A (1993) Presence of T-cell subset abnormalities in newly diagnosed cases of multiple sclerosis and relationship with short-term clinical activity. J Neurol 240:79–82
Fassbender K, Ragoschke A, Rossol S, Schwartz A, Mielke O, Pauling A, Hennerici M (1998) Increased release of interleukin-12p40 in MS. Association with intracerebral inflammation. Neurology 51:753–758
Franciotta D, Martino G, Zardini E, Furlan R, Bergamaschi R, Andreoni L, Cosi V (2001) 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 115:192–198
Hafler DA, Weiner HL (1989) MS: a CNS and systemic autoimmune disease. Immunol Today 10:104–107
Hemler ME, Brenner MB, McLean JM, Strominger JL (1984) Antigenic stimulation regulates the level of expression of interleukin 2 receptor on human T cells. Proc Natl Acad Sci USA 81:2172–2175
Illés Z, Kondo T, Yokoyama K, Ohashi T, Tabira T, Yamamura T (1999) Identification of autoimmune T cells among in vivo expanded CD25+ T cells in multiple sclerosis. J Immunol 162:1811–1817
Karp CL (1999) Interleukin-12: amiss in MS. Ann Neurol 45:689–692
Khoury SJ, Guttmann CRG, Orav EJ, Kikinis R, Jolesz FA, Weiner HL (2000) Changes in activated T cells in the blood correlate with disease activity in multiple sclerosis. Arch Neurol 57:1183–1189
Kieseier BC, Seifert T, Giovannoni G, Hartung H-P (1999) Matrix metalloproteinases in inflammatory demyelination. Targets for treatment. Neurology 53:20–25
Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, Butcher EC (2001) Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest 108:1331–1339
Kivisäkk P, Trebst C, Liu Z, Tucky BH, Sørensen TL, Rudick RA, Mack M, Ransohoff RM (2002) T-cells in the cerebrospinal fluid express a similar repertoire of inflammatory chemokine receptors in the absence or presence of CNS inflammation: implications for CNS trafficking. Clin Exp Immunol 129:510–518
Leppert D, Ford J, Stabler G, Grygar C, Lienert C, Huber S, Miller KM, Hauser SL, Kappos L (1998) Matrix metalloproteinase- 9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 121:2327–2334
Mahad DJ, Howell SJL, Woodroofe MN (2002) Expression of chemokines in the CSF and correlation with clinical disease activity in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 72:498–502
Matsui M, Araya S, Wang H-Y, Onai N, Matsushima K, Saida T (2003) Circulating lymphocyte subsets linked to intracellular cytokine profiles in normal humans. Clin Exp Immunol 134:225–231
McDonald WI, Compston A, Edan G, Goodkin D, Hartung H-S, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127
Misu T, Onodera H, Fujihara K, Matsushima K, Yoshie O, Okita N, Takase S, Itoyama Y (2001) Chemokine receptor expression on T cells in blood and cerebrospinal fluid at relapse and remission of multiple sclerosis: imbalance of Th1/Th2-associated chemokine signaling. J Neuroimmunol 114:207–212
Morimoto C, Rudd CE, Letvin NL, Schlossman SF (1987) A novel epitope of the LFA-1 antigen which can distinguish killer effector and suppressor cells in human CD8 cells. Nature 330:479–482
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N EngL J Med 343:938–952
Olsson T (1995) Critical influences of the cytokine orchestration on the outcome of myelin antigen-specific T-cell autoimmunity in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol Rev 144:245–268
Porrini AM, Gambi D, Malatesta G (1992) Memory and naive CD4+ lymphocytes in multiple sclerosis. J Neurol 239:437–440
Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic selftolerance. Cell 101:455–458
Salonen R, Ilonen J, Jägerroos H, Syrjälä H, Nurmi T, Reunanen M (1989) Lymphocyte subsets in the cerebrospinal fluid in active multiple sclerosis. Ann Neurol 25:500–502
Sørensen PS (1999) Biological markers in body fluids for activity and progression in multiple sclerosis. Mult Scler 5:287–290
Sørensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JL, Ransohoff RM (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 103:807–815
Sørensen TL, Sellebjerg F, Jensen CV, Strieter RM, Ransohoff RM (2001) Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis. Eur J Neurol 8:665–672
Tourtellotte WW, Staugaitis SM, Walsh MJ, Shapshak P, Baumhefner RW, Potvin AR, Syndulko K (1985) The basis of intra-blood-brain-barrier IgG synthesis. Ann Neurol 17:21–27
Trebst C, Ransohoff RM (2001) Investigating chemokines and chemokine receptors in patients with multiple sclerosis. Opportunities and challenges. Ann Neurol 58:1975–1980
van Boxel-Dezaire AHH, Hoff SCJ, van Oosten BW, Verweij CL, Dräger AM, Adèr HJ, van Houwelingen JC, Barkhof F, Polman CH, Nagelkerken L (1999) Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis. Arch Neurol 45:695–703
Wang H-Y, Matsui M, Araya S-i, Onai N, Matsushima K, Saida T (2002) Chemokine receptors associated with immunity within and outside the central nervous system in early relapsingremitting multiple sclerosis. J Neuroimmunol 133:184–192
Wang H-Y, Matsui M, Saida T (2002) Immunological disturbances in the central nervous system linked to MRI findings in multiple sclerosis. J Neuroimmunol 125:149–154
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Matsui, M., Araya, S., Wang, H. et al. Differences in systemic and central nervous system cellular immunity relevant to relapsing–remitting multiple sclerosis. J Neurol 252, 908–915 (2005). https://doi.org/10.1007/s00415-005-0778-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-005-0778-z