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Cerebrospinal Fluid IL-21 Levels in Neuromyelitis Optica and Multiple Sclerosis

  • Aimin Wu (a1), Xiaonan Zhong (a1), Honghao Wang (a1), Wen Xu (a1), Chen Cheng (a1), Yongqiang Dai (a1), Jian Bao (a1), Wei Qiu (a1), Zhengqi Lu (a1) and Xueqiang Hu (a1)...



Neuromyelitis optica (NMO) and multiple sclerosis (MS) are inflammatory demyelinating diseases of human central nervous system (CNS) with complex pathogenesis. IL-21/IL-21R regulates activation, proliferation and survival of both T cells and B cells, which are involved in the pathogenesis of NMO and MS. High levels of serum IL-21 were observed in NMO patients. However, concentration of cerebrospinal fluid (CSF) IL-21 in MS and NMO patients still remain unknown.


To detect the CSF concentration of IL-21 in NMO and MS patients and to evaluate its relationship with disease activity, particularly concerned about its impact on humoral immunity.


CSF IL-21 was detected by an enzyme-linked immunosorbent assay (ELISA) in NMO patients (n=21), MS patients (n=20) and controls (n=16).


CSF concentration of the IL-21 was noticeably elevated in NMO (p=0.012) and borderline significantly increased in MS (p=0.115). In addition, this occurrence was associated with humoral immune activity as shown by a correlation between IL-21 and complement in NMO cohort (p=0.023) and high IL-21 levels in autoantibody-positive subgroup (p=0.027).


The concentration of CSF IL-21 was noticeably elevated and might have a positive correlation with humoral immune activity in NMO.

RÉSUMÉ Contexte:

La neuromyélite optique (NMO) et la sclérose en plaques (SP) sont des maladies démyélinisantes inflammatoires du système nerveux central (SNC) humain dont la pathogenèse est complexe. IL-21/IL-21R régule l'activation, la prolifération et la survie des cellules T et des cellules B qui sont impliquées dans la pathogenèse de la NMO et de la SP. Des taux sériques élevés d'IL-21 ont été observés chez des patients atteints de NMO. Cependant, la concentration d'IL-21 dans le liquide céphalo-rachidien (LCR) de patients atteints de SP ou de NMO demeure inconnue.


Le but de l'étude était de déterminer la concentration d'IL-21 dans le LCR de patients atteints de NMO ou de SP et d'évaluer sa relation à l'activité de la maladie, particulièrement en ce qui a trait à son impact sur l'activité immunitaire humorale.


L'IL-21 dans le LCR a été identifié par ELISA chez 21 patients atteints de NMO, 20 patients atteints de SP et 16 sujets témoins.


La concentration d'IL-21 dans le LCR était sensiblement élevée chez les patients atteints de NMO (p = 0,012) et limite chez les patients atteints de SP (p = 0,115). De plus, ceci était associé à une activité immunitaire humorale comme le démontre la corrélation entre IL-21 et le complément dans la cohorte de patients atteints de NMO (p = 0,023) et un niveau élevé d'IL-21 dans le sous-groupe de patients possédant des autoanticorps (p = 0,027).


La concentration d'IL-21 dans le LCR était sensiblement élevée chez les patients atteints de NMO et pourrait avoir une corrélation positive avec l'activité immunitaire humorale.

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Corresponding author

Multiple Sclerosis Center, Department of Neurology, The Third Affiliated Hospital of Sun yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China. email:


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1. Matà, S, Lolli, F. Neuromyelitis optica: an update. J Neurol Sci. 2011;303(1–2):1321.
2. Fletcher, JM, Lalor, SJ, Sweeney, CM, et al. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010;162(1):111.
3. Li, Y, Wang, H, Long, Y, et al. Increased memory Th17cells in patients with neuromyelitis optica and multiple sclerosis. J Neuroimmunol. 2011;234(1–2):15560.
4. Link, H, Tibbling, G. Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. Scand J Clin Lab Invest. 1977;37(5):397401.
5. Archelos, JJ, Storch, MK, Hartung, HP. The role of B cells and autoantibodies in multiple sclerosis. Ann Neurol. 2000;47(6): 694706.
6. Lennon, V.A, Wingerchuk, DM, Kryzer, TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):210612.
7. Watanabe, S, Nakashima, I, Misu, T, et al. Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica. Mult Scler. 2007;13(1):12832.
8. Bakker, J, Metz, L. Devic’s neuromyelitis optica treated with intravenous gamma globulin (IVIG). Can J Neurol Sci. 2004;31 (2):2657.
9. Cree, BA, Lamb, S, Morgan, K, et al. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005;64 (7):12702.
10. Bedi, GS, Brown, AD, Delgado, SR, et al. Impact of rituximab on relapse rate and disability in neuromyelitis optica. Mult Scler. 2011;17(10):122530.
11. Pellkofer, HL, Krumbholz, M, Berthele, A, et al. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology. 2011;76(15):13105.
12. Ozaki, K, Kikly, K, Michalovich, D, et al. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Natl Acad Sci USA. 2000;97(21):1143944.
13. Parrish-Novak, J, Dillon, SR, Nelson, A, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408(6808):5763.
14. Spolski, R, Leonard, WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 2008:26:5779.
15. Monteleone, G, Caruso, R, Fina, D, et al. Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut. 2006;55(12):177480.
16. Monteleone, G, Pallone, F, Macdonald, TT. Interleukin-21 as a new therapeutic target for immune-mediated diseases. Trends Pharmacol Sci. 2009;30(8):4417.
17. Deenick, EK, Tangye, SG. Autoimmunity: IL-21: a new player in Th17-cell differentiation. Immunol Cell Biol. 2007;85(7):5035.
18. Monteleone, G, Pallone, F, Macdonald, TT. Interleukin-21 (IL-21)-mediated pathways in T cell-mediated disease. Cytokine Growth Factor Rev. 2009;20(2):18591.
19. Konforte, D, Simard, N, Paige, CJ. IL-21: an executor of B cell fate. J Immunol 2009;182(4):17817.
20. Ettinger, R, Kuchen, S, Lipsky, PE. Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis. 2008;67 Suppl 3:iii836.
21. Ettinger, R, Kuchen, S, Lipsky, PE. The role of IL-21 inregulating B-cell functionin health and disease. Immunol Rev. 2008;223: 6086.
22. Wang, HH, Dai, YQ, Qiu, W, et al. Interleukin-17-secreting T cells in neuromyelitis optica and multiple sclerosis during relapse. J Clin Neurosci. 2011;18(10):13137.
23. Wingerchuk, DM, Lennon, VA, Pittock, SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10): 14859.
24. Polman, CH, Reingold, SC, Banwell, B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292302.
25. Vollmer, TL, Liu, R, Price, M, et al. Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen. J Immunol. 2005;174(5):2696701.
26. Chen, M, Chen, G, Nie, H, et al. Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T Cells in MS. Eur J Immunol. 2009;39(9):252536.
27. Zhang, X, Tao, Y, Troiani, L, et al. Simvastatin inhibits IFN regulatory factor 4 expression and Th17 cell differentiation in CD4+ T cells derived from patients with multiple sclerosis. J Immunol. 2011;187(6):34317.
28. Xie, L, Li, XK, Funeshima-Fuji, N, et al. Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. Int Immunopharmacol. 2009;9(5):57581.
29. Andersson, A, Isaksson, M, Wefer, J, et al. Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis. PLoS One. 2008;3(11):e3682.
30. Kwok, SK, Cho, ML, Park, MK, et al. Interleukin-21 promotes osteoclasto genesis in rheumatoid arthritis in humans and mice. Arthritis Rheum. 2012;64(3):74051
31. Kang, KY, Kim, HO, Kwok, SK, et al. Impact of interleukin-21 in the pathogenesis of primary Sjogren’s syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands. Arthritis Res Ther. 2011;13(5):R179.
32. Tüzün, E, Kürtüncü, M, Türkoğlu, R, et al. Enhanced complement consumption in neuromyelitis optica and Behçet’s disease patients. J Neuroimmunol. 2011;233(–1–2):2115.
33. Doi, H, Matsushita, T, Isobe, N, et al. Hypercomplementemia at relapse in patients with anti-aquaporin-4 antibody. Mult Scler. 2009;15(3):30410.
34. Bradl, M, Misu, T, Takahashi, T, et al. Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol. 2009;66(5):63043.
35. Jarius, S, Paul, F, Franciotta, D, et al. Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica. Nat Clin Pract Neurol. 2008;4(4): 20214.
36. Fedetz, M, Ndagire, D, Fernandez, O, et al. Multiple sclerosis association study with the TENR-IL2-IL21 region in a Spanish population. Tissue Antigens. 2009;74(3):2447.
37. Lindén, M, Nohra, R, Sundqvist, E, et al. No evidence of IL21 association with multiple sclerosis in a Swedish population. Tissue Antigens. 2011;78(4):2714.
38. Tzartos, JS, Craner, MJ, Friese, MA, et al. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am J Pathol. 2011;178(2):794802.


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