Abstract:Interleukin-21 (IL-21) is a new member of the interleukin-2 family. It is mainly synthesized and secreted by the activated of CD4+ T cells and natural killer T cells. IL-21 receptor (IL-21R) is mainly expressed in T cells, B cells, and natural killer (NK) cells. After binding to its receptor, IL-21 can regulate the activation and proliferation of T cells, B cells, and NK cells through activating JAKs-STATs signaling pathways. As a new immunoregulatory factor, IL-21 and its receptor play important roles in the development and progression of various autoimmune diseases. Regulation of the expression levels of IL-21 and IL-21R and blocking of their signal transduction pathways with blockers may be new treatment options for autoimmune diseases.
Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity[J]. Annu Rev Immunol, 2008, 26: 57-79.
[2]
Rosanne S, Leonard WJ. Interleukin-21: a double-edged sword with therapeutic potential[J]. Nat Rev Drug Discov, 2014, 13(5): 379-395.
[3]
Wang T, Diaz-Rosales P, Costa MM, et al. Functional characterization of a nonmammalian IL-21: rainbow trout Oncorhynchus mykiss IL-21 upregulates the expression of the Th cell signature cytokines IFN-γ, IL-10, and IL-22[J]. J Immunol, 2011, 186(2): 708-721.
[4]
Wan CK, Andraski AB, Spolski R, et al. Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells[J]. Proc Nat Acad Sci USA, 2015, 112(30): 9394-9399.
[5]
Moens L, Tangye SG. Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage[J]. Front Immunol, 2014, 5: 65.
[6]
Ye BH, Bi E, Yu JJ, et al. A tumor-suppressive role of the IL-21R/Jak/STAT3 pathway in the germinal center B cell subtype of diffuse large B cell lymphomas[J]. Cancer Res, 2013, 73(8 Supplement): 3041.
[7]
Ding BB, Bi E, Chen H, et al. IL-21 and CD40L synergistically promote plasma cell differentiation through upregulation of Blimp-1 in human B cells[J]. J Immunol, 2013, 190(4): 1827-1836.
[8]
Karnell JL, Ettinger R. The interplay of IL-21 and BAFF in the formation and maintenance of human B cell memory[J]. Front Immunol, 2012, 3(2): 1-9.
[9]
Salzer E, Kansu A, Sic H, et al. Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency[J]. J Allergy Clin Immunol, 2014, 133(6): 1651-1659.
[10]
Kroenke MA, Eto D, Locci M, et al. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell (Tfh) differentiation[J]. J Immunol, 2012, 188(8): 3734-3744.
[11]
Choi YS, Yang JA, Yusuf I, et al. Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory[J]. J Immunol, 2013, 190(8): 4014-4026.
[12]
Bollig N, Brüstle A, Kellner K, et al. Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation [J]. Proc Natl Acad Sci USA, 2012, 109(22): 8664-8669.
[13]
Shane C. Follicular helper CD4 T cells (TFH)[J]. Annu Rev Immunol, 2011, 29: 621-663.
[14]
Sage PT, Alvarez D, Godec J, et al.Circulating T follicular regulatory and helper cells have memory-like properties[J]. J Clin Invest, 2014, 124(12): 5191-5204.
[15]
Zhou L, Ivanov II, Spolski R, et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways[J]. Nat Immunol, 2007, 8(9): 967-974.
[16]
Zhu S, Phatarpekar PV, Denman CJ, et al. Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation[J]. Blood, 2014, 124(3): 403-411.
[17]
Kotlarz D, Ziętara N, Uzel G, et al. Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome[J]. J Exp Med, 2013, 210(3): 433-443.
[18]
Rothwell L, Hu T, Wu Z, et al. Chicken interleukin-21 is costimulatory for T cells and blocks maturation of dendritic cells[J]. Dev Comp Immunol, 2012, 36(2): 475-482.
[19]
Wan CK, Oh J, Li P, et al. The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells[J]. Immunity, 2013, 38(3): 514-527.
[20]
Ferreira RC, Simons HZ, Thompson WS, et al. IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients[J]. Diabetologia, 2015, 58(4): 781-790.
[21]
Sutherland APR, Van Belle T, Wurster AL, et al. Interleukin-21 is required for the development of type 1 diabetes in NOD mice[J]. Diabetes, 2009, 58(5): 1144-1155.
[22]
Chen XL, Bobbala D, Rodriguez GM, et al. Induction of autoimmune diabetes in non-obese diabetic mice requires interleukin-21-dependent activation of autoreactive CD8+ T cells[J]. Clin Exp Immunol, 2013, 173(2): 184-194.
[23]
Lin X, Hamilton-Williams EE, Rainbow DB, et al. Genetic interactions amongIdd3, Idd5.1, Idd5.2 and Idd5.3 protective loci in the NOD mouse model of type 1 diabetes[J]. J Immunol, 2013, 190(7): 3109-3120.
[24]
Spolski R, Leonard WJ. The Yin and Yang of Interleukin-21 in allergy, autoimmunity and cancer[J]. Curr Opin Immunol, 2008, 20(3): 295-301.
[25]
Liu R, Wu Q, Su D, et al. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis[J]. Arthritis Res Ther, 2012, 14(6): R255.
[26]
Young DA, Hegen M, Ma HLM, et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis[J]. Arthritis Rheum, 2007, 56(4): 1152-1163.
[27]
Nakou M, Papadimitraki ED, Fanouriakis A, et al. Interleukin-21 is increased in active systemic lupus erythematosus patients and contributes to the generation of plasma B cells[J]. Clin Exp Rheumatol, 2013, 31(2): 172-179.
[28]
Lee J, Shin EK, Lee SY, et al. Oestrogen up-regulates interleukin-21 production by CD4+ T lymphocytes in patients with systemic lupus erythematosus[J]. Immunology, 2014, 142(4): 573-580.
[29]
Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: the MRL-lpr mouse strain as a model[J]. Autoimmun Rev, 2014, 13(9): 963-973.
[30]
Bubier JA, Sproule TJ, Foreman O, et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice[J]. Proc Nat Aca Sci USA, 2009, 106(5): 1518-1523.
[31]
Herber D, Brown TP, Liang S, et al. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R. Fc reduces disease progression[J]. J Immunol, 2007, 178(6): 3822-3830.
[32]
Rankin A L, Guay H, Herber D, et al. IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Faslpr/lpr/J mice[J]. J Immunol, 2012, 188(4): 1656-1667.
[33]
Hughes T, Kim-Howard X, Kelly JA, et al. Fine mapping and trans-ethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21[J]. Arthritis Rheumatol, 2011, 63(6): 1689-1697.
[34]
Lan Y, Luo B, Wang JL, et al. The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk of systemic lupus erythematosus[J]. Gene, 2014, 538(1): 94-98.
[35]
Dong L, Chen Y, Masaki Y, et al. Possible mechanisms of lymphoma development in Sjögren's syndrome[J]. Curr Immunol Rev, 2013, 9(1): 13-22.
[36]
Kang KY, Kim HO, Kwok SK, et al. Impact of interleukin-21 in the pathogenesis of primary Sjögren's syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands[J]. Arthritis Res Ther, 2011, 13(5): R179.
Hundorfean G, Neurath M F, Mudter J. Functional relevance of T helper 17 (Th17) cells and the IL-17 cytokine family in inflammatory bowel disease[J]. Inflamm Bowel Dis, 2012, 18(1): 180-186.
[39]
司方明. IL-21 及其受体表达与溃疡性结肠炎分级的相关性
[J]
军医进修学院学报, 2009, 30(4): 479-480.
[40]
De Nitto D, Sarra M, Pallone F, et al. Interleukin-21 triggers effector cell responses in the gut[J]. World J Gastroenterol, 2010, 16(29): 3638-3641.
Shi J, Zhou L, Zhernakova A, et al. Haplotype-based analysis of ulcerative colitis risk loci identifies both IL2 and IL21 as susceptibility genes in Han Chinese[J]. Inflamm Bowel Dis, 2011, 17(12): 2472-2479.
[44]
Li Y, Rauniyar VK, Yin WF, et al. Serum IL-21 levels decrease with glucocorticoid treatment in myasthenia gravis[J]. Neurol Sci, 2014, 35(1): 29-34.
Yi JS, Guidon A, Sparks S, et al. Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis[J]. J Autoimmun, 2014, 52: 130-138.
[47]
Kong Q, Sun B, Bai S, et al. Administration of bone marrow stromal cells ameliorates experimental autoimmune myasthenia gravis by altering the balance of Th1/Th2/Th17/Treg cell subsets through the secretion of TGF-β[J]. J Neuroimmunol, 2009, 207(1): 83-91.
[48]
Liu W, Dienz O, Roberts B, et al. IL-21R expression on CD8+ T cells promotes CD8+ T cell activation in coxsackievirus B3 induced myocarditis[J]. Exp Molec Pathol, 2012, 92(3): 327-333.