3,484
Views
28
CrossRef citations to date
0
Altmetric
Review Article

IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis

, , , , , , , , & show all
Pages 274-285 | Received 13 Jul 2015, Accepted 28 Aug 2015, Published online: 28 Oct 2015

References

  • Andersson A, Isaksson M, Wefer J, Norling A, Flores-Morales A, Rorsman F, Kämpe O, Harris RA, Lobell A. 2008. Impaired autoimmune TH17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis. PLoS One 3:e3682.
  • Azizi G, Jadidi‐Niaragh F, Mirshafiey A. 2013. TH17 cells in immunopathogenesis and treatment of rheumatoid arthritis. Intl J Rheum Dis. 16:243–253.
  • Baglio F, Saresella M, Preti MG, Cabinio M, Griffanti L, Marventano I, Piancone F, Calabrese E, Nemni R, Clerici M. 2013. Neuro-inflammation and brain functional disconnection in Alzheimer's disease. Front Aging Neurosci. 5:81.
  • Barker BR, Gladstone MN, Gillard GO, Panas MW, Letvin NL. 2010. Critical role for IL-21 in both primary and memory anti-viral CD8+ T-cell responses. Eur J Immunol. 40:3085–3096.
  • Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, Sharpe AH, Kuchroo VK. 2009. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T-helper cells and TH17 cells. Nat Immunol. 10:167–175.
  • Brady J, Hayakawa Y, Smyth MJ, Nutt SL. 2004. IL-21 induces the functional maturation of murine NK cells. J Immunol. 172:2048–2058.
  • Brandt K, Bulfone-Paus S, Jenckel A, Foster DC, Paus R, Rückert R. 2003. IL-21 inhibits dendritic cell-mediated T-cell activation and induction of contact hypersensitivity in vivo. J Invest Dermatol. 121:1379–1382.
  • Breuer J, Schwab N, Schneider-Hohendorf T, Marziniak M, Mohan H, Bhatia U, Gross CC, Clausen BE, Weishaupt C, Luger TA, et al. 2014. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Ann Neurol. 75:739–758.
  • Brown JW, Coles AJ. 2013. Alemtuzumab: Evidence for its potential in relapsing-remitting multiple sclerosis. Drug Design Devel Ther. 7:131–138.
  • Chanvillard C, Jacolik RF, Infante-Duarte C, Nayak RC. 2013. The role of natural killer cells in multiple sclerosis and their therapeutic implications. Front Immunol. 4:63.
  • Chen M, Chen G, Nie H, Zhang X, Niu X, Zang YC, Skinner SM, Zhang JZ, Killian JM, Hong J. 2009. Regulatory effects of IFNβ on production of osteopontin and IL-17 by CD4+ T-Cells in MS. Eur J Immunol. 39:2525–2536.
  • Cheng W, Chen G. 2014. Chemokines and chemokine receptors in multiple sclerosis. Med Inflamm. 2014:659206.
  • Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, Mackay CR. 2004. T-Follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-TH1/TH2 effector cells that provide help for B-cells. J Immunol. 173:68–78.
  • Clarkson BD, Ling C, Shi Y, Harris MG, Rayasam A, Sun D, Salamat MS, Kuchroo V, Lambris JD, Sandor M, et al. 2014. T-Cell-derived IL-21 promotes brain injury following stroke in mice. J Exp Med. 211:595–604.
  • Collins M, Whitters MJ, Young DA. 2003. IL-21 and IL-21 receptor: A new cytokine pathway modulates innate and adaptive immunity. Immunol Res. 28:131–140.
  • Coquet JM, Chakravarti S, Smyth MJ, Godfrey DI. 2008. Cutting edge: IL-21 is not essential for TH17 differentiation or experimental autoimmune encephalomyelitis. J Immunol. 180:7097–7101.
  • Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, Smyth MJ, Godfrey DI. 2007. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J Immunol. 178:2827–2834.
  • Costelloe L, Jones J, Coles A. 2012. Secondary autoimmune diseases following alemtu-zumab therapy for multiple sclerosis. Expert Rev Neurother. 12:335–341.
  • Croce M, Rigo V, Ferrini S 2015. IL-21: A pleiotropic cytokine with potential applications in oncology. J Immunol Res. 2015:696578.
  • Daga A, Orengo AM, Gangemi RM, Marubbi D, Perera M, Comes A, Ferrini S, Corte G. 2007. Glioma immunotherapy by IL-21 gene-modified cells or by recombinant IL-21 involves antibody responses. Intl J Cancer 121:1756–1763.
  • Deenick EK, Tangye SG. 2007. Autoimmunity: IL-21: A new player in TH17-cell differentiation. Immunol Cell Biol. 85:503–505.
  • Denic A, Wootla B, Rodriguez M. 2013. CD8+ T-cells in multiple sclerosis. Expert Opin Ther Targets 17:1053–1066.
  • Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, Yusuf I, Crotty S. 2011. IL-21 and IL-6 are critical for different aspects of B-cell immunity and redundantly induce optimal follicular helper CD4 T-cell (TFH) differentiation. PLoS One 6:e17739.
  • Ettinger R, Kuchen S, Lipsky PE. 2008. The role of IL-21 in regulating B-cell function in health and disease. Immunol Rev. 223:60–86.
  • Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, Leonard WJ, Lipsky PE. 2005. IL-21 induces differentiation of human naive and memory B-cells into antibody-secreting plasma cells. J Immunol. 175:7867–7879.
  • Fedetz M, Ndagire D, Fernandez O, Leyva L, Guerrero M, Arnal C, Lucas M, Izquierdo G, Delgado C, Alcina A, et al. 2009. Multiple sclerosis association study with the TENR-IL-2-IL-21 region in a Spanish population. Tissue Antigens 74:244–247.
  • Fernandez O. 2014. Alemtuzumab in the treatment of multiple sclerosis. J Inflamm Res. 7:19–27.
  • Frühlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, Weber J, Marsland BJ, Oxenius A, Kopf M. 2009. IL-21R on T-cells is critical for sustained functionality and control of chronic viral infection. Science 324:1576–1580.
  • Gaby A. 2013. Multiple sclerosis. Global Adv Health Med. 2:50–56.
  • Geri G, Terrier B, Rosenzwajg M, Wechsler B, Touzot M, Seilhean D, Tran TA, Bodaghi B, Musset L, Soumelis V, et al. 2011. Critical role of IL-21 in modulating TH17 and regulatory T-cells in Behçet disease. J Allergy Clin Immunol. 128:655–664.
  • Ghalamfarsa G, Jadidi-Niaragh F, Amiri MM, Razavi SM, Saboor-Yaraghi AA, Shokri F. 2015. All-trans-retinoic Acid differentially regulates proliferation of normal and leukemic B-cells from different subsets of chronic lymphocytic leukemia. Nutr Cancer 67:285–291.
  • Ghalamfarsa G, Jadidi-Niaragh F, Hojjat-Farsangi M, Asgarian-Omran H, Yousefi M, Tahmasebi F, Khoshnoodi J, Razavi SM, Saboor-Yaraghi AA, Rabbani H, et al. 2013. Differential regulation of B-cell proliferation by IL-21 in different subsets of chronic lymphocytic leukemia. Cytokine 62:439–445.
  • Giovannoni G, Baker D, Schmierer K. 2014. Simvastatin in patients with progressive multiple sclerosis. Lancet 384:952.
  • Gol-Ara M, Jadidi-Niaragh F, Sadria R, Azizi G, Mirshafiey A. 2012. The role of different subsets of regulatory T-cells in immunopathogenesis of rheumatoid arthritis. Arthritis. 2012:805875.
  • Hartung HP, Aktas O, Menge T, Kieseier BC. 2014. Immune regulation of multiple sclerosis. Handbook Clin Neurol. 122:3–14.
  • Haugen M, Frederiksen JL, Degn M. 2014. B-Cell follicle-like structures in multiple sclerosis - with focus on the role of B-cell activating factor. J Neuroimmunol. 273:1–7.
  • Hoglund RA, Maghazachi AA. 2014. Multiple sclerosis and the role of immune cells. World J Exp Med. 4:27–37.
  • Jadidi-Niaragh F, Mirshafiey A. 2010. Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis. Neuropharmacology 59:180–189.
  • Jadidi-Niaragh F, Mirshafiey A. 2011a. Regulatory T-cell as orchestra leader in immunosuppression process of multiple sclerosis. Immunopharmacol Immunotoxicol. 33:545–567.
  • Jadidi-Niaragh F, Mirshafiey A. 2011b. TH17 cell, the new player of neuro-inflammatory process in multiple sclerosis. Scand J Immunol. 74:1–13.
  • Jadidi-Niaragh F, Mirshafiey A. 2011c. Therapeutic approach to multiple sclerosis by novel oral drug. Recent Pat Inflamm Allergy Drug Discov. 5:66–80.
  • Jadidi-Niaragh F, Mirshafiey A. 2012. The deviated balance between regulatory T-cell and TH17 in autoimmunity. Immunopharmacol Immunotoxicol. 34:727–739.
  • Jadidi-Niaragh F, Ghalamfarsa G, Memarian A, Asgarian-Omran H, Razavi SM, Sarrafnejad A, Shokri F. 2013a. Down-regulation of IL-17-producing T-cells is associated with regulatory T-cell expansion and disease progression in chronic lymphocytic leukemia. Tumor Biol. 34:929–940.
  • Jadidi-Niaragh F, Ghalamfarsa G, Yousefi M, Tabrizi MH, Shokri F. 2013b. Regulatory T-cells in chronic lymphocytic leukemia: Implication for immunotherapeutic interventions. Tumor Biol. 34:2031–2039.
  • Jadidi-Niaragh F, Yousefi M, Memarian A, Hojjat-Farsangi M, Khoshnoodi J, Razavi SM, Jeddi-Tehrani M, Shokri F. 2013c. Increased frequency of CD8+ and CD4+ regulatory T-cells in chronic lymphocytic leukemia: Association with disease progression. Cancer Invest. 31:121–131.
  • Janssen EM, Droin NM, Lemmens EE, Pinkoski MJ, Bensinger SJ, Ehst BD, Griffith TS, Green DR, Schoenberger SP. 2005. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434:88–93.
  • Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, Walton A, Sawcer SJ, Compston A, Coles AJ. 2009. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 119:2052–2061.
  • Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, Deng B, Johnson KA, Witek JS, Senices M, Konz RF, et al. 2002. IL-21 limits NK cell responses and promotes antigen-specific T-cell activation: A mediator of the transition from innate to adaptive immunity. Immunity 16:559–569.
  • King C, Tangye SG, Mackay CR. 2008. T-follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol. 26:7417–7466.
  • Klotz L, Meuth SG, Wiendl H. 2012. Immune mechanisms of new therapeutic strategies in multiple sclerosis: A focus on alemtuzumab. Clin Immunol. 142:25–30.
  • Konforte D, Simard N, Paige CJ. 2009. IL-21: An executor of B-cell fate. J Immunol. 182:1781–1787.
  • Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK. 2007. IL-21 initiates an alternative pathway to induce pro-inflammatory TH17 cells. Nature 448:484–487.
  • Krumbholz M, Meinl E. 2014. B-Cells in MS and NMO: Pathogenesis and therapy. Semin Immunopathol. 36:339–350.
  • Leonard WJ, Spolski R. 2005. IL-21: Modulator of lymphoid proliferation, apoptosis, and differentiation. Nat Rev Immunol. 5:688–698.
  • Li B, Reynolds JM, Stout RD, Bernlohr DA, Suttles J. 2009. Regulation of TH17 differentiation by epidermal fatty acid-binding protein. J Immunol. 182:7625–7633.
  • Li Q, Ye LJ, Ren HL, Huyan T, Li J, Shi JL, Huang QS. 2015. Multiple effects of IL-21 on human NK cells in ex vivo expansion. Immunobiology 220:876–888.
  • Liu J, Cen H, Ni J, Zhang M, Li P, Yang XK, Leng RX, Pan HF, Ye DQ. 2015. Association of IL-21 polymorphisms (rs907715, rs2221903) with susceptibility to multiple autoimmune diseases: A meta-analysis. Autoimmunity 48:108–116.
  • Lin MH, Yeh LT, Chen SJ, Chiou HY, Chu CC, Yen LB, Lin KI, Chang DM, Sytwu HK. 2014. T-Cell-specific BLIMP-1 deficiency exacerbates experimental autoimmune encephalomyelitis in nonobese diabetic mice by increasing TH1 and TH17 cells. Clin Immunol. 151:101–113.
  • Linden M, Nohra R, Sundqvist E, Khademi M, Hillert J, Alfredsson L, Olsson T, Kockum I. 2011. No evidence of IL-21 association with multiple sclerosis in a Swedish population. Tissue Antigens 78:271–274.
  • Linhares UC, Schiavoni PB, Barros PO, Kasahara TM, Teixeira B, Ferreira TB, Alvarenga R, Hygino J, Vieira MM, Bittencourt VC, et al. 2013. 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.
  • Liu R, Bai Y, Vollmer TL, Bai XF, Jee Y, Tang YY, Campagnolo DI, Collins M, Young DA, La Cava A, et al. 2008. IL-21 receptor expression determines the temporal phases of experimental autoimmune encephalomyelitis. Exp Neurol. 211:14–24.
  • Mehta DS, Wurster AL, Grusby MJ. 2004. Biology of IL-21 and the IL-21 receptor. Immunol Rev. 202:84–95.
  • Metcalf TU, Baxter VK, Nilaratanakul V, Griffin DE. 2013. Recruitment and retention of B-cells in the central nervous system in response to alphavirus encephalomyelitis. J Virol. 87:2420–2429.
  • Mirshafiey A, Jadidi-Niaragh F. 2010a. Immunopharmacological role of the leukotriene receptor antagonists and inhibitors of leukotrienes generating enzymes in multiple sclerosis. Immunopharmacol Immunotoxicol. 32:219–227.
  • Mirshafiey A, Jadidi-Niaragh F. 2010b. Prostaglandins in pathogenesis and treatment of multiple sclerosis. Immunopharmacol Immunotoxicol. 32:543–554.
  • Mirshafiey A, Asghari B, Ghalamfarsa G, Jadidi-Niaragh F, Azizi G. 2014. The significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis. Sultan Qaboos Univ Med J. 14:e13–25.
  • Monteleone G, Pallone F, Macdonald TT. 2009. IL-21 as a new therapeutic target for immune-mediated diseases. Trends Pharmacol Sci. 30:441–447.
  • Nohra R, Beyeen AD, Guo JP, Khademi M, Sundqvist E, Hedreul MT, Sellebjerg F, Smestad C, Oturai AB, Harbo HF, et al. 2010. RGMA and IL-21R show association with experimental inflammation and multiple sclerosis. Genes Immun. 11:279–293.
  • Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, et al. 2007. Essential autocrine regulation by IL-21 in the generation of inflammatory T-cells. Nature 448:480–483.
  • Ochoa-Reparaz J, Rynda A, Ascon MA, Yang X, Kochetkova I, Riccardi C, Callis G, Trunkle T, Pascual DW. 2008. IL-13 production by regulatory T-cells protects against experimental autoimmune encephalomyelitis independently of autoantigen. J Immunol. 181:954–968.
  • Ortiz GG, Pacheco-Moisés FP, Macías-Islas MÁ, Flores-Alvarado LJ, Mireles-Ramírez MA, González-Renovato ED, Hernández-Navarro VE, Sánchez-López AL, Alatorre-Jiménez MA. 2014. Role of the blood-brain barrier in multiple sclerosis. Arch Med Res. 45:687–697.
  • Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, et al. 2000. IL 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63.
  • Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, Pallone F, Monteleone G. 2007. IL-21 counteracts the regulatory T-cell-mediated suppression of human CD4+ T-lymphocytes. J Immunol. 178:732–739.
  • Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF Jr, Cheever AW, Young DA, Collins M, Grusby MJ, Wynn TA. 2006. The IL-21 receptor augments TH2 effector function and alternative macrophage activation. J Clin Invest. 116:2044–2055.
  • Petrelli A, Carvello M, Vergani A, Lee KM, Tezza S, Du M, Kleffel S, Chengwen L, Mfarrej BG, Hwu P, et al. 2011. IL-21 is an anti-tolerogenic cytokine of the late-phase alloimmune response. Diabetes 60:3223–3234.
  • Phares TW, Disano KD, Hinton DR, Hwang M, Zajac AJ, Stohlman SA, Bergmann CC. 2013. IL-21 optimizes T-cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol. 263:43–54.
  • Phares TW, Marques CP, Stohlman SA, Hinton DR, Bergmann CC. 2011. Factors supporting intrathecal humoral responses following viral encephalomyelitis. J Virol. 85:2589–2598.
  • Phares TW, Stohlman SA, Hwang M, Min B, Hinton DR, Bergmann CC. 2012. CD4 T-cells promote CD8 T-cell immunity at the priming and effector site during viral encephalitis. J Virol. 86:2416–2427.
  • Piao WH, Jee YH, Liu RL, Coons SW, Kala M, Collins M, Young DA, Campagnolo DI, Vollmer TL, Bai XF, et al. 2008. IL-21 modulates CD4+CD25+ regulatory T-cell homeostasis in experimental autoimmune encephalomyelitis. Scand J Immunol. 67:37–46.
  • Plantone D, Marti A, Frisullo G, Iorio R, Damato V, Nociti V, Patanella AK, Bianco A, Mirabella M, Batocchi AP. 2013. Circulating CD56dim NK cells expressing perforin are increased in progressive multiple sclerosis. J Neuroimmunol. 265:124–127.
  • Raveney BJ, Oki S, Yamamura T. 2013. Nuclear receptor NR4A2 orchestrates TH17 cell-mediated autoimmune inflammation via IL-21 signalling. PLoS One 8:e56595.
  • Romme Christensen J, Bornsen L, Ratzer R, Piehl F, Khademi M, Olsson T, Sorensen PS, Sellebjerg F. 2013. Systemic inflammation in progressive multiple sclerosis involves follicular TH, TH17, and activated B-cells and correlates with progression. PLoS One 8:e57820.
  • Roozbeh M, Mohammadpour H, Azizi G, Ghobadzadeh S, Mirshafiey A. 2014. The potential role of iNKT cells in experimental allergic encephalitis and multiple sclerosis. Immunopharmacol Immunotoxicol. 36:105–113.
  • Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Alberoni M, Nemni R, Clerici M. 2011. Increased activity of TH17 and TH9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer's disease. Brain Behav Immun. 25:539–547.
  • Sashinami H, Asano K, Yoshimura S, Mori F, Wakabayashi K, Nakane A. 2012. Salmon proteoglycan suppresses progression of mouse experimental autoimmune encephalo-myelitis via regulation of TH17 and Foxp3+ regulatory T-cells. Life Sci. 91:1263–1269.
  • Shekhar S, Yang X. 2012. The darker side of follicular helper T-cells: From autoimmunity to immunodeficiency. Cell Mol Immunol. 9:380–385.
  • Sitati EM, Diamond MS. 2006. CD4+ T-cell responses are required for clearance of West Nile virus from the central nervous system. J Virol. 80:12060–12069.
  • Smyth MJ, Wallace ME, Nutt SL, Yagita H, Godfrey DI, Hayakawa Y. 2005. Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. J Exp Med. 201:1973–1985.
  • Sonderegger I, Kisielow J, Meier R, King C, Kopf M. 2008. IL-21 and IL-21R are not required for development of TH17 cells and autoimmunity in vivo. Eur J Immunol. 38:1833–1838.
  • Spolski R, Leonard WJ. 2008. IL-21: Basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 26:57–79.
  • Spolski R, Leonard WJ. 2014. IL-21: A double-edged sword with therapeutic potential. Nat Rev Drug Discov. 13:379–395.
  • Stohlman SA, Bergmann CC, Lin MT, Cua DJ, Hinton DR. 1998. CTL effector function within the central nervous system requires CD4+ T-cells. J Immunol. 160:2896–2904.
  • Strengell M, Lehtonen A, Matikainen S, Julkunen I. 2006. IL-21 enhances SOCS gene expression and inhibits LPS-induced cytokine production in human monocyte-derived dendritic cells. J Leukocyte Biol. 79:1279–1285.
  • Strengell M, Matikainen S, Sirén J, Lehtonen A, Foster D, Julkunen I, Sareneva T. 2003. IL-21 in synergy with IL-15 or IL-18 enhances IFNγ production in human NK and T-cells. J Immunol. 170:5464–5469.
  • Stumhofer JS, Silver JS, Hunter CA. 2013. IL-21 is required for optimal antibody production and T-cell responses during chronic Toxoplasma gondii infection. PLoS One 8:e62889.
  • Suto A, Kashiwakuma D, Kagami SI, Hirose K, Watanabe N, Yokote K, Saito Y, Nakayama T, Grusby MJ, Iwamoto I. 2008. Development and characterization of IL-21-producing CD4+ T-cells. J Exp Med. 205:1369–1379.
  • Tangye SG. 2015. Advances in IL-21 biology - enhancing our understanding of human disease. Curr Opin Immunol. 34:107–115.
  • Tao Y, Zhang X, Chopra M, Kim MJ, Buch KR, Kong D, Jin J, Tang Y, Zhu H, Jewells V, et al. 2014. The role of endogenous IFNβ in the regulation of TH17 responses in patients with relapsing-remitting multiple sclerosis. J Immunol. 192:5610–5617.
  • Tedder TF, Leonard WJ. 2014. Autoimmunity: Regulatory B-cells - IL-35 and IL-21 regulate the regulators. Nat Rev Rheumatol. 10:452–453.
  • Tegla CA, Cudrici CD, Azimzadeh P, Singh AK, Trippe R, Khan A, Chen H, Andrian-Albescu M, Royal W, Bever C, et al. 2013. Dual role of response gene to complement-32 in multiple sclerosis. Exp Mol Pathol. 94:17–28.
  • Tzartos JS, Craner MJ, Friese MA, Jakobsen KB, Newcombe J, Esiri MM, Fugger L. 2011. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am J Pathol. 178:794–802.
  • Vollmer TL, Liu R, Price M, Rhodes S, La Cava A, Shi FD. 2005. Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen. J Immunol. 174:2696–2701.
  • Wan CK, Oh J, Li P, West EE, Wong EA, Andraski AB, Spolski R, Yu ZX, He J, Kelsall BL, et al. 2013. The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells. Immunity 38:514–527.
  • Wang HH, Dai YQ, Qiu W, Lu ZQ, Peng FH, Wang YG, Bao J, Li Y, Hu XQ. 2011a. IL-17-secreting T-cells in neuromyelitis optica and multiple sclerosis during relapse. J Clin Neurosci. 18:1313–1317.
  • Wang L, Yu CR, Kim HP, Liao W, Telford WG, Egwuagu CE, Leonard WJ. 2011b. Key role for IL-21 in experimental autoimmune uveitis. Proc Natl Acad Sci USA 108:9542–9547.
  • Wei L, Laurence A, Elias KM, O'Shea JJ. 2007. IL-21 is produced by TH17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem. 282:34605–34610.
  • Wu A, Zhong X, Wang H, Xu W, Cheng C, Dai Y, Bao J, Qiu W, Lu Z, Hu X. 2012. Cerebrospinal fluid IL-21 levels in neuromyelitis optica and multiple sclerosis. Can J Neurol Sci. 39:813–820.
  • Xie L, Li X, Funeshima-Fuji N, Kimura H, Matsumoto Y, Isaka Y, Takahara S. 2009. Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. Intl Immunopharmacol. 9:575–581.
  • Xu J, Wagoner G, Douglas JC, Drew PD. 2009. Liver X receptor agonist regulation of TH17 lymphocyte function in autoimmunity. J Leukocyte Biol. 86:401–409.
  • Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF. 2008. A regulatory B-cell subset with a unique CD1dhiCD5+ phenotype controls T-cell-dependent inflammatory responses. Immunity 28:639–650.
  • Yanaba K, Bouaziz JD, Matsushita T, Tsubata T, Tedder TF. 2009. The development and function of regulatory B-cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol. 182:7459–7472.
  • Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, et al. 2008. Molecular antagonism and plasticity of regulatory and inflammatory T-cell programs. Immunity 29:44–56.
  • Yoo JK, Braciale TJ. 2014. IL-21 promotes late activator APC-mediated T-follicular helper cell differentiation in experimental pulmonary virus infection. PLoS One 9:e105872.
  • Yoshizaki A, Miyagaki T, Dilillo DJ, Matsushita T, Horikawa M, Kountikov EI, Spolski R, Poe JC, Leonard WJ, Tedder TF. 2012. Regulatory B-cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491:264–268.
  • Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, Chen W, Scher JU, Mo R, Depoil D, Rao N, Liu B, Wei J, et al. 2014. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T-cells via STAT3-dependent mechanism. Proc Natl Acad Sci USA 111:16814–16819.
  • Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, Pise-Masison CA, Radonovich MF, Brady JN, Restifo NP, et al. 2005. Synergy of IL-21 and IL-15 in regulating CD8+ T-cell expansion and function. J Exp Med. 201:139–148.
  • Zhang X, Tao Y, Chopra M, Ahn M, Marcus KL, Choudhary N, Zhu H, Markovic-Plese S. 2013. Differential reconstitution of T-cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol. 191:5867–5874.
  • Zhang X, Tao Y, Troiani L, Markovic-Plese S. 2011. Simvastatin inhibits IFN regulatory factor-4 expression and TH17 cell differentiation in CD4+ T-cells derived from patients with multiple sclerosis. J Immunol. 187:3431–3437.
  • Zhou F, Ciric B, Zhang GX, Rostami A. 2014. Immunotherapy using lipopolysaccharide-stimulated bone marrow-derived dendritic cells to treat experimental autoimmune encephalomyelitis. Clin Exp Immunol. 178:447–458.
  • Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. 2007. IL-6 programs TH17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 8:967–974.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.