Abstract
Neuromyelitis optica (NMO), also known as Devic’s disease, is an autoimmune, inflammatory disorder of the central nervous system (CNS) in which the immune system attacks myelin of the neurons located at the optic nerves and spinal cord, thus producing a simultaneous or sequential optic neuritis and myelitis. The objective of this study was evaluated the background T-cell function of patients suffering from neuromyelitis optica (NMO), an autoimmune disorder of the central nervous system. In our study, the in vitro T cell proliferation and the production of Th1 cytokines were significantly lower in cell cultures from NMO patients, as compared with healthy individuals. In contrast, a dominant Th17-like phenotype, associate with higher IL-23 and IL-6 production by LPS-activated monocytes, was observed among NMO patients. The release of IL-21 and IL-6 by polyclonaly activated CD4+ T cells was directly correlated to neurological disability. In addition, the in vitro release of IL-21, IL-6 and IL-17 was significantly more resistant to glucocorticoid inhibition in NMO patients. In conclusion, the results indicate dominate Th17-related response in NMO patients that was directly proportional to neurological disability. Furthermore, our results can help to explain why NMO patients trend to be more refractory to corticoid treatment.
Similar content being viewed by others
References
Wingerchuk D, Lennon V, Lucchinetti C, Pittock S, Weinchenker B. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6:805–15.
Devic E. Myélite aiguë dorse-lombaire de névrite optique, autopsie. Congress Français de méd. Premiere Seance. 1984;9:434–9.
Mandler RN, Davis LE, Jeffery DR, Kornfeld M. Devic’s neuromyelitis optica: a clinicopathological study of 8 patients. Ann Neurol. 1993;34:162–8.
Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 1999;53:1107–14.
Mandler R, Ahmed W, Dencoff J. Devic’s neuromyelitis optica: a prospective study of seven pacients treated with prednisone and azathioprine. Neurology. 1998;51:1219–20.
Weeinshenker BG. Plasma exchange for severe attacks of inflammatory demyelinating diseases of the central nervous system. J Clin Apheresis. 2001;16:39–42.
Lennon VA, Wingerchuch DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara CF, et al. Serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364:2106–12.
Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high Aquaporin 4 expression. Arch Neuro. 2006;63:964–8.
Kira J, Yamasaki K, Horiuchi I, Ohyagi Y, Taniwaki T, Kawano Y. Changes in the clinical phenotypes of Multiple Sclerosis during the past 50 years in Japan. J Neurol Sci. 1999;166:53–7.
Cabrera-Gomez JA, Kurtzke JF, Gonzalez-Quevedo A, Lara-Rodriguez R. An epidemiological study of neuromyelitis optica in cuba. J Neurol. 2009;256(256):35–44.
Papais-Alvarenga RM, Miranda-Santos CM, Puccioni-Sohler M, de Almeida AM, Oliveira S, Basílio de Oliveira CA, Alvarenga H, Poser CM. Optic neuromyelitis syndrome in Brazilian patients. J Neurol Neurosurg Psychiatry. 2002;73:429–35.
Kurtzke JF. Rating neurologyc impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52.
Papais-Alvarenga RM, Carellos SC, Alvareng MP, Holander C, Bichara RP, Thuler LCS. Clinical course of optic neuritis in patients with relapsing neuromyelitis optica. Arch Ophthalmol. 2008;126:12–6.
Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66:1485–9.
Argyriou AA, Makris N. Neuromyelitis optica: a distinct demyelinating disease of the central nervous system. Acta Neurol Scand. 2008;118:209–17.
Wingerchuk DM, Hogancamp WF, O’brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 1999;53:1107–14.
Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain. 2002;125:1450–61.
Lefkowitz D, Angelo JN. Neuromyelitis optica with unusual vascular changes. Arch Neurol. 1984;41:1103–5.
Roemer SF, Parisi JE, Lennon VA, et al. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain. 2007;130:1194–205.
Sinclair C, Kirk J, Herron B, Fitzgerald U, Mcquaid S. Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol (Berl). 2007;113:187–94.
Krishnamoorthy G, Lassmann H, Wekerle H, Holz A. Spontaneous opticaspinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J Clin Invest. 2006;116:2385.
Matsuya N, Komori M, Nomura K, Nakane S, Fukudome T, Goto H, et al. Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica. Internat Immunol. 2011;23:565–73.
Ishizu T, Osoegawa M, Mei F-J, Kikuchi H, Tanaka M, Takakura Y, et al. Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain. 2005;128:988–1002.
Uzawa A, Mori M, Arai K, Sato Y, Hayakawa S, Masuda S, et al. Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6. Multiple Sclerosis. 2010;16:1443–52.
Wang HH, Dai YQ, Qiu W, Lu ZQ, Peng FH, Wang YG, et al. Interleukin-17-secreting T cells in neuromyelitis optica and multiple sclerosis during relapse. J Clin Neuroscience. 2011;18:1313–7.
Li Y, Wang H, Long Y, Lu Z, Hu X. Increased memory Th7 cells in patients with neuromyelitis optica and multiple sclerosis. J Neuroimmunol. 2011;234:155–60.
Gutcher I, Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest. 2007;117:1119–25.
Crozat K, Vivier E, Dalod M. Crosstalk between components of the innate immune system: promoting anti-microbial defenses and avoiding immunopathologies. Immunol Rev. 2009;227:129–49.
Ekkens MJ, Liu Z, Liu Q, Whitmire J, Xiao S, Foster A, et al. The role of OX40 ligand interactions in the development of the Th2 response to the gastrointestinal nematode parasite Heligmosomoides polygyrus. J Immunol. 2003;170:384–93.
Andoh A, Takaya H, Makino J, Sato H, Bamba S, Araki Y, et al. Cooperation of interleukin-17 and interferon-gamma on chemokine secretion in human fetal intestinal epithelial cells. Clin Exp Immunol. 2001;125:56–63.
Matsuzaki G, Umemura M. IL-17 as an effetor molecule of innate and acquired immunity against infections. Microbiol Immunonol. 2007;51:1139–47.
Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol. 1998;160:3513–21.
Lovett-Racke AE, Yang Y, Racke MK. Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis. Biochimica et Biophysica Acta. 1812;2011:246–51.
Miossec P. IL-17 and Th17 cells in human inflammatory diseases. Microb Infect. 2009;11:625–30.
Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–32.
Shevach EM. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30:636–45.
Maynard CL, Harrington LE, Janowski KM, Oliver JR, Zindl CL, Rudensky AY. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3-precursor cells in the absence of interleukin 10 Nat. Immunol. 2007;8:931–41.
Kitani A, Fuss I, Nakamura K, Kumaki F, Usui T, Strober W. Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. J Exp Med. 2003;198:1179–88.
McGeachy MJ, Stephens LA, Anderton SM. Natural recovery and protection from autoimmune encephalomyelitis: Contribution of CD4 + CD25+ regulatory T cells within the central nervous system. J Immunol. 2005;175:3025–32.
Belkaid Y. Regulatory T, cells and infection: a dangerous necessity. Nat Rev Immunol. 2007;7:875–88.
Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforming growth factor-b and interleukin-10. Immunity. 2008;8:468–76.
Agarwal SK, Marshall SGD. Glucocorticoid-induced type 1/type 2 cytokine alterations in humans: a model for stress-related immune dysfunction. J Interferon Cytokine Res. 1998;18:1059–68.
Zygmunt B, Veldhoen M. T helper cell differentiation more than just cytokines. Adv Immunol. 2011;109:159–96.
Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SH. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202:473–7.
Merrill JE, Mohlstrom C, Uittenbogaart C, Kermaniarab V, Ellison GW, Myers LW. Response to and production of interleukin 2 by peripheral blood and cerebrospinal fluid lymphocytes of patients with multiple sclerosis. JImmunol. 1984;133:1931–7.
Killestein J, Hintzen RQ, Uitdehaag BM, Baars PA, Roos MT, van Lier RA, et al. Baseline T cell reactivity in multiple sclerosis is correlated to efficacy of interferon-beta. J Neuroimmunol. 2002;133:217–24.
Méndez-Samperio P. Role of interleukin-12 family cytokines in the cellular response to mycobacterial disease. Int J Infect Dis. 2010;14:e366–71.
Akkoc T, Koning PJ, Rückert B, Barlan I, Akdis M, Akdis CA. Increased activation-induced cell death of high IFN-gamma-producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases. J Allergy Clin Immunol. 2008;121:652–8.
Costa VS, Mattana TC, da Silva ME. Unregulated IL-23/IL-17 immune response in autoimmune diseases. Diabetes Res Clin Pract. 2010;88:222–6.
Morrison PJ, Ballantyne MC. Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity. Immunology. 2011;133:397–408.
Kira J-I. Neuromyelitis optica and opticospinal multiple sclerosis: mechanisms and pathogenesis. Pathophysiology. 2011;18:69–79.
Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2012;122:143–59.
Matiello M, Jacob A, Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Opin Neurol. 2007;20:255–60.
Spolski R, Leonard WJ. IL-21 and T follicular helper cells. Int Immunol. 2009;22:7–12.
Matsuya N, Komori M, Nomura K, Nakane S, Fukudome T, Goto H, Shiraishi H, Wandinger KP, Matsuo H, Kondo T. Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica. Int Immunol. 2011;23(9):565–73.
Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10:849–59.
Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function. Annu Rev Immunol. 2000;18:309–41.
Conflict of interest statement
All authors declare that there are no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by Fundação Carlos Chagas Filho de amparo à pesquisa do estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
Rights and permissions
About this article
Cite this article
Linhares, U.C., Schiavoni, P.B., Barros, P.O. et al. The Ex Vivo Production of IL-6 and IL-21 by CD4+ T Cells is Directly Associated with Neurological Disability in Neuromyelitis Optica Patients. J Clin Immunol 33, 179–189 (2013). https://doi.org/10.1007/s10875-012-9780-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-012-9780-2