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

Figures & data

Table 1. Studies related to expression of IL-21/IL-21R in MS patients.

Source of sample	Outcome	Reference
Peripheral blood	Increased expression of IL-21 and IL-21R in CD4^+ T cells from progressive MS	Romme Christensen et al. (2013)
MS lesion	(1) Increased expression of IL-21 only in infiltrating CD4^+ cells in MS lesions (2) IL-21R was broadly distributed on CD4^+, CD19^+ and CD8^+ cells	Tzartos et al. (2011)
CSF	Concentration of IL-21 in CSF of MS patients was not remarkably raised	Wu et al. (2012)
DNA	Association of IL-21R genetic polymorphisms with MS in Nordic population	Nohra et al. (2010)
DNA	No association of IL-21 gene with MS in Swedish population	Linden et al. (2011)
DNA	No association of TENR-IL-2-IL-21 locus on susceptibility or disease progression  in MS in Spanish population	Fedetz et al. (2009)
Serum	No difference of IL-21 in MS patients compared to control subject	Wang et al. (2011a)
Peripheral blood	Increased expression of IL-21 mRNA during MS relapses	Tegla et al. (2013)

CSF, Cerebrospinal Fluid; MS, multiple sclerosis; IL-21R, interleukin-21 receptor.

Table 2. Studies related to the role of IL-21/IL-21R in EAE.

Main claim	Reference
EAE
Diminished EAE disease progression in IL-21 KO mice, which was associated with the expansion of Treg cells	Nurieva et al. (2007)
Administration of IL-21 before initiation of EAE enhanced autoimmune symptoms, which was associated with the expansion of Treg and down-regulation of TH17 cells	Korn et al. (2007)
Treatment of EAE mice with salmonella-CFA/IIC greatly attenuated disease, in part through suppression of IL-17 and IL-21	Ochoa-Reparaz et al. (2008)
Suppressed EAE by DNA vaccination through down-regulation of IL-21	Andersson et al. (2008)
Suppressed EAE induction via LXR agonist T0901317 through inhibition of IL-21	Xu et al. (2009)
Curcumin can attenuate EAE via inhibition of TH17 cells and IL-21 formation	Xie et al. (2009)
Treatment of EAE mice with IFNβ decreases IL-17 and IL-21	Chen et al. (2009)
Decreased TH17/IL-21 and increased Treg cells in E-FABP-deficient EAE mice	Li et al. (2009)
Tolerogenic DC prevent EAE development via down-regulation of RORγt, IL-17A, IL-17F, IL-21 and IL-22	Zhou et al. (2014)
Salmon cartilage Proteoglycans reduce EAE progression via down-regulation of IL-6, IL-21, IL-23R and RORγt and up-regulation of Foxp3	Sashinami et al. (2012)
Blockage of NR4A2 expression inhibits EAE through suppression of IL-21 production and IL-23R expression	Raveney et al. (2013)
Aggravated EAE in BLIMP-1-deficient mice was associated with increased numbers of CNS-infiltrating TH1, TH17, IFNγ^+IL-17A^+ and IL-21^+IL-17A^+ CD4^+ T-cells in brain and spinal cord.	Lin et al. (2014)
IL-21/IL-21R deficient mice are susceptible to EAE	Coquet et al. (2008), Sonderegger et al. (2008)
Inhibition of IL-21 was associated with increased entry of inflammatory cells into the CNS	Piao et al. (2008)
Severe neurological impairment in IL-21R deficient EAE mice	Piao et al. (2008), Liu et al. (2008)

Table 3. Studies related to the role of IL-21/IL-21R in MS.

Main claim	Reference
MS
Simvastatin exerts its anti-inflammatory effects in RR-MS patients, in part through inhibition of TH17 and IL-21	Zhang et al. (2011)
UVB phototherapy down-regulates IL-21 and up-regulates Treg and tolerogenic DC cell levels in MS patients	Peluso et al. (2007)
Increased expression of IL-21, IL-21R and ICOS was observed in CD4^+ T-cells from progressive MS patients. Mitoxantrone decreased TFH and IL-21 in SP-MS patients	Romme Christensen et al. (2013)
Increased IL-21R^+ and IL-21^+CD4^+ T-cells have been observed in the both active and chronic MS lesions	Tzartos et al. (2011), Romme Christensen et al. (2013)
Treatment of MS patients with alemtuzumab led to decreased IL-21 levels	Zhang et al. (2013)
The secondary autoimmunity following treatment with alemtuzumab can be predicted via high baseline levels of IL-21 in MS sera	Costelloe et al. (2012), Jones et al. (2009)

Figure 1. IL-21 can affect various immune cells that are effective in the immunopathogenesis of MS.

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Raveney BJ, Oki S, Yamamura T. 2013. Nuclear receptor NR4A2 orchestrates TH17 cell-mediated autoimmune inflammation via IL-21 signalling. PLoS One 8:e56595.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Costelloe L, Jones J, Coles A. 2012. Secondary autoimmune diseases following alemtu-zumab therapy for multiple sclerosis. Expert Rev Neurother. 12:335–341.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar