Th17 Cells in autoimmune diseases

Abstract

Th17 cells are a new subset of CD4⁺ T cells involved in the clearance of extracellular pathogens and fungi. Accumulating evidence suggests that Th17 cells and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, inflammatory bowel disease, and multiple sclerosis.

Keywords

IL-17 / Th17 cells / RORγt / autoimmune diseases / posttranslational modification / inhibitors

References

[1] Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature2003; 421(6924): 744–748

[2] Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med2003; 198(12): 1951–1957

[3] Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol2005; 6(11): 1133–1141

[4] Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity2008; 28(4): 454–467

[5] Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature2006; 441(7090): 231–234

[6] Bedoya SK, Lam B, Lau K, Larkin J3rd. Th17 cells in immunity and autoimmunity. Clin Dev Immunol2013; 2013: 986789

[7] Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature2006; 441(7090): 235–238

[8] Wei L, Laurence A, Elias KM, O’Shea JJ. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem2007; 282(48): 34605–34610

[9] Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature2008; 453(7198): 1051–1057

[10] Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol2007; 8(9): 942–949

[11] Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, Soumelis V. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol2008; 9(6): 650–657

[12] Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORgt. Nat Immunol2008; 9(6): 641–649

[13] Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgt directs the differentiation program of proinflammatory IL-17⁺ T helper cells. Cell2006; 126(6): 1121–1133

[14] Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M, Takaesu G, Hori S, Yoshimura A, Kobayashi T. Foxp3 inhibits RORgt-mediated IL-17A mRNA transcription through direct interaction with RORgt. J Biol Chem2008; 283(25): 17003–17008

[15] Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORg. Immunity2008; 28(1): 29–39

[16] Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem2007; 282(13): 9358–9363

[17] Brüstle A, Heink S, Huber M, Rosenplänter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol2007; 8(9): 958–966

[18] Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature2008; 453(7191): 65–71

[19] Liu C, Qian W, Qian Y, Giltiay NV, Lu Y, Swaidani S, Misra S, Deng L, Chen ZJ, Li X. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci Signal2009; 2(92): ra63

[20] Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol2012; 13(10): 991–999

[21] Benedetti G, Miossec P. Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis. Eur J Immunol2014; 44(2): 339–347

[22] Metawi SA, Abbas D, Kamal MM, Ibrahim MK. Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA. Clin Rheumatol2011; 30(9): 1201–1207

[23] Suurmond J, Dorjée AL, Boon MR, Knol EF, Huizinga TW, Toes RE, Schuerwegh AJ. Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and-negative rheumatoid arthritis and osteoarthritis synovium. Arthritis Res Ther2011; 13(5): R150

[24] Park JS, Park MK, Lee SY, Oh HJ, Lim MA, Cho WT, Kim EK, Ju JH, Park YW, Park SH, Cho ML, Kim HY. TWEAK promotes the production of interleukin-17 in rheumatoid arthritis. Cytokine2012; 60(1): 143–149

[25] Lubberts E, Koenders MI, van den Berg WB. The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther2005; 7(1): 29–37

[26] Chao CC, Chen SJ, Adamopoulos IE, Davis N, Hong K, Vu A, Kwan S, Fayadat-Dilman L, Asio A, Bowman EP. Anti-IL-17A therapy protects against bone erosion in experimental models of rheumatoid arthritis. Autoimmunity2011; 44(3): 243–252

[27] Kellner H. Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential. Ther Adv Musculoskelet Dis; 5(3): 141–152

[28] Patel DD, Lee DM, Kolbinger F, Antoni C. Effect of IL-17A blockade with secukinumab in autoimmune diseases. Ann Rheum Dis2013; 72(Suppl 2): ii116–ii123

[29] Jain M, Attur M, Furer V, Todd J, Ramirez R, Lock M, Lu QA, Abramson SB, Greenberg JD. Increased plasma IL-17F levels in rheumatoid arthritis patients are responsive to methotrexate, anti-TNF, and T Cell costimulatory modulation. Inflammation2014<month>Sep</month><day>21</day>. [Epub ahead of print]

[30] Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, Iwakura Y, Sakaguchi N, Sakaguchi S. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17⁺ Th cells that cause autoimmune arthritis. J Exp Med2007; 204(1): 41–47

[31] Leipe J, Schramm MA, Prots I, Schulze-Koops H, Skapenko A. Increased Th17 cell frequency and poor clinical outcome in rheumatoid arthritis are associated with a genetic variant in the IL4R gene, rs1805010. Arthritis Rheum (Munch)2014; 66(5): 1165–1175

[32] Shen H, Goodall JC, Hill Gaston JS. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum2009; 60(6): 1647–1656

[33] van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, Dolhain RJ, Lubberts E. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum2011; 63(1): 73–83

[34] Zhang L, Li YG, Li YH, Qi L, Liu XG, Yuan CZ, Hu NW, Ma DX, Li ZF, Yang Q, Li W, Li JM. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS ONE2012; 7(4): e31000

[35] van Hamburg JP, Corneth OB, Paulissen SM, Davelaar N, Asmawidjaja PS, Mus AM, Lubberts E. IL-17/Th17 mediated synovial inflammation is IL-22 independent. Ann Rheum Dis2013; 72(10): 1700–1707

[36] Kim J, Kang S, Kim J, Kwon G, Koo S. Elevated levels of T helper 17 cells are associated with disease activity in patients with rheumatoid arthritis. Ann Lab Med2013; 33(1): 52–59

[37] Church LD, Filer AD, Hidalgo E, Howlett KA, Thomas AM, Rapecki S, Scheel-Toellner D, Buckley CD, Raza K. Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-α co-expression, but little interleukin-22 and interleukin-23R expression. Arthritis Res Ther2010; 12(5): R184

[38] Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, Evans JG, Cimaz R, Bajaj-Elliott M, Wedderburn LR. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA2010; 107(33): 14751–14756

[39] Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med2006; 203(12): 2673–2682

[40] Hickman-Brecks CL, Racz JL, Meyer DM, LaBranche TP, Allen PM. Th17 cells can provide B cell help in autoantibody induced arthritis. J Autoimmun2011; 36(1): 65–75

[41] Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H. Pathogenic conversion of Foxp3⁺ T cells into TH17 cells in autoimmune arthritis. Nat Med2014; 20(1): 62–68

[42] Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol2001; 1(2): 147–153

[43] Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol2008; 127(3): 385–393

[44] Zhao XF, Pan HF, Yuan H, Zhang WH, Li XP, Wang GH, Wu GC, Su H, Pan FM, Li WX, Li LH, Chen GP, Ye DQ. Increased serum interleukin 17 in patients with systemic lupus erythematosus. Mol Biol Rep2010; 37(1): 81–85

[45] Cheng F, Guo Z, Xu H, Yan D, Li Q. Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis2009; 68(4): 604–606

[46] Vincent FB, Northcott M, Hoi A, Mackay F, Morand EF. Clinical associations of serum interleukin-17 in systemic lupus erythematosus. Arthritis Res Ther2013; 15(4): R97

[47] Amarilyo G, Lourenço EV, Shi FD, La Cava A. IL-17 promotes murine lupus. J Immunol2014; 193(2): 540–543

[48] Xing Q, Wang B, Su H, Cui J, Li J. Elevated Th17 cells are accompanied by FoxP3⁺ Treg cells decrease in patients with lupus nephritis. Rheumatol Int2012; 32(4): 949–958

[49] Kato H, Perl A. Mechanistic target of rapamycin complex 1 expands Th17 and IL-4⁺ CD4^–CD8^– double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J Immunol2014; 192(9): 4134–4144

[50] Crispín JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, Kyttaris VC, Juang YT, Tsokos GC. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol2008; 181(12): 8761–8766

[51] Mizui M, Koga T, Lieberman LA, Beltran J, Yoshida N, Johnson MC, Tisch R, Tsokos GC. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4^–CD8^– IL-17-producing T cells. J Immunol2014; 193(5): 2168–2177

[52] Shah K, Lee WW, Lee SH, Kim SH, Kang SW, Craft J, Kang I. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther2010; 12(2): R53

[53] Yang XY, Wang HY, Zhao XY, Wang LJ, Lv QH, Wang QQ. Th22, but not Th17 might be a good index to predict the tissue involvement of systemic lupus erythematosus. J Clin Immunol2013; 33(4): 767–774

[54] Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X, Wan L, Li M. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum2009; 60(5): 1472–1483

[55] Chen DY, Chen YM, Wen MC, Hsieh TY, Hung WT, Lan JL. The potential role of Th17 cells and Th17-related cytokines in the pathogenesis of lupus nephritis. Lupus2012; 21(13): 1385–1396

[56] Dolff S, Bijl M, Huitema MG, Limburg PC, Kallenberg CG, Abdulahad WH. Disturbed Th1, Th2, Th17 and T(reg) balance in patients with systemic lupus erythematosus. Clin Immunol2011; 141(2): 197–204

[57] Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjögren’s syndrome. Nat Rev Rheumatol2010; 6(9): 529–537

[58] Jonsson R, Vogelsang P, Volchenkov R, Espinosa A, Wahren-Herlenius M, Appel S. The complexity of Sjögren’s syndrome: novel aspects on pathogenesis. Immunol Lett2011; 141(1): 1–9

[59] Singh N, Cohen PL. The T cell in Sjogren’s syndrome: force majeure, not spectateur. J Autoimmun2012; 39(3): 229–233

[60] Fox RI, Adamson TC 3rd, Fong S, Young C, Howell FV. Characterization of the phenotype and function of lymphocytes infiltrating the salivary gland in patients with primary Sjögren syndrome. Diagn Immunol1983; 1(3): 233–239

[61] Lin X, Tian J, Rui K, Ma KY, Ko KH, Wang S, Lu L. The role of T helper 17 cell subsets in Sjögren’s syndrome: similarities and differences between mouse model and humans. Ann Rheum Dis2014; 73(7): e43

[62] Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB. Pathogenic effect of interleukin-17A in induction of Sjögren’s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther2010; 12(6): R220

[63] Ciccia F, Guggino G, Rizzo A, Ferrante A, Raimondo S, Giardina A, Dieli F, Campisi G, Alessandro R, Triolo G. Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjögren’s syndrome. Ann Rheum Dis2012; 71(2): 295–301

[64] Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB. Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjögren’s syndrome: findings in humans and mice. Arthritis Rheum2008; 58(3): 734–743

[65] Sakai A, Sugawara Y, Kuroishi T, Sasano T, Sugawara S. Identification of IL-18 and Th17 cells in salivary glands of patients with Sjögren’s syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J Immunol2008; 181(4): 2898–2906

[66] Katsifis GE, Rekka S, Moutsopoulos NM, Pillemer S, Wahl SM. Systemic and local interleukin-17 and linked cytokines associated with Sjögren’s syndrome immunopathogenesis. Am J Pathol2009; 175(3): 1167–1177

[67] Fei Y, Zhang W, Lin D, Wu C, Li M, Zhao Y, Zeng X, Zhang F. Clinical parameter and Th17 related to lymphocytes infiltrating degree of labial salivary gland in primary Sjögren’s syndrome. Clin Rheumatol2014; 33(4): 523–529

[68] Youinou P, Pers JO. Disturbance of cytokine networks in Sjögren’s syndrome. Arthritis Res Ther2011; 13(4): 227

[69] Alunno A, Bistoni O, Bartoloni E, Caterbi S, Bigerna B, Tabarrini A, Mannucci R, Falini B, Gerli R. IL-17-producing CD4^–CD8^– T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjögren’s syndrome. Ann Rheum Dis2013; 72(2): 286–292

[70] Alunno A, Carubbi F, Bistoni O, Caterbi S, Bartoloni E, Bigerna B, Pacini R, Beghelli D, Cipriani P, Giacomelli R, Gerli R. CD4(-)CD8(-) T-cells in primary Sjögren’s syndrome: association with the extent of glandular involvement. J Autoimmun2014; 51: 38–43

[71] Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol2010; 28(1): 573–621

[72] Di Sabatino A, Biancheri P, Rovedatti L, MacDonald TT, Corazza GR. New pathogenic paradigms in inflammatory bowel disease. Inflamm Bowel Dis2012; 18(2): 368–371

[73] Podolsky DK. Inflammatory bowel disease. N Engl J Med2002; 347(6): 417–429

[74] Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, Bamba T, Fujiyama Y. Increased expression of interleukin 17 in inflammatory bowel disease. Gut2003; 52(1): 65–70

[75] Seiderer J, Elben I, Diegelmann J, Glas J, Stallhofer J, Tillack C, Pfennig S, Jürgens M, Schmechel S, Konrad A, Göke B, Ochsenkühn T, Müller-Myhsok B, Lohse P, Brand S. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn’s disease and analysis of the IL17F p. His161Arg polymorphism in IBD. Inflamm Bowel Dis2008; 14(4): 437–445

[76] Zenewicz LA, Antov A, Flavell RA. CD4 T-cell differentiation and inflammatory bowel disease. Trends Mol Med 2009; 15(5): 199–207

[77] Feng T, Qin H, Wang L, Benveniste EN, Elson CO, Cong Y. Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production. J Immunol2011; 186(11): 6313–6318

[78] Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut 2011; 60(12): 1739–1753

[79] Caprioli F, Bosè F, Rossi RL, Petti L, Viganò C, Ciafardini C, Raeli L, Basilisco G, Ferrero S, Pagani M, Conte D, Altomare G, Monteleone G, Abrignani S, Reali E. Reduction of CD68⁺ macrophages and decreased IL-17 expression in intestinal mucosa of patients with inflammatory bowel disease strongly correlate with endoscopic response and mucosal healing following infliximab therapy. Inflamm Bowel Dis2013; 19(4): 729–739

[80] Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev2014; 13(1): 3–10

[81] Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L, Wang YH, Schluns KS, Broaddus RR, Zhu Z, Dong C. Regulation of inflammatory responses by IL-17F. J Exp Med2008; 205(5): 1063–1075

[82] O’Connor W Jr, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, Kolls JK, Flavell RA. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol2009; 10(6): 603–609

[83] Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis2006; 12(5): 382–388

[84] Troncone E, Marafini I, Pallone F, Monteleone G. Th17 cytokines in inflammatory bowel diseases: discerning the good from the bad. Int Rev Immunol2013; 32(5–6): 526–533

[85] Sarra M, Pallone F, Macdonald TT, Monteleone G. IL-23/IL-17 axis in IBD. Inflamm Bowel Dis2010; 16(10): 1808–1813

[86] Morrison PJ, Bending D, Fouser LA, Wright JF, Stockinger B, Cooke A, Kullberg MC. Th17-cell plasticity in Helicobacter hepaticus-induced intestinal inflammation. Mucosal Immunol2013; 6(6): 1143–1156

[87] Morrison PJ, Ballantyne SJ, Kullberg MC. Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity. Immunology2011; 133(4): 397–408

[88] Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, Wehkamp J, Feagan BG, Yao MD, Karczewski M, Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei M, Bertolino AP, Tougas G, Travis SP; Secukinumab in Crohn’s Disease Study Group. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut2012; 61(12): 1693–1700

[89] McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol2007; 8(9): 913–919

[90] Voskuhl RR, Martin R, Bergman C, Dalal M, Ruddle NH, McFarland HF. T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes. Autoimmunity1993; 15(2): 137–143

[91] Kroenke MA, Chensue SW, Segal BM. EAE mediated by a non-IFN-γ/non-IL-17 pathway. Eur J Immunol2010; 40(8): 2340–2348

[92] Jäger A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol2009; 183(11): 7169–7177

[93] Romme Christensen J, Börnsen L, Ratzer R, Piehl F, Khademi M, Olsson T, Sørensen PS, Sellebjerg F. Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. PLoS ONE2013; 8(3): e57820

[94] Tao Y, Zhang X, Chopra M, Kim MJ, Buch KR, Kong D, Jin J, Tang Y, Zhu H, Jewells V, Markovic-Plese S. The role of endogenous IFN-β in the regulation of Th17 responses in patients with relapsing-remitting multiple sclerosis. J Immunol2014; 192(12): 5610–5617

[95] Coquet JM, Middendorp S, van der Horst G, Kind J, Veraar EA, Xiao Y, Jacobs H, Borst J. The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity. Immunity2013; 38(1): 53–65

[96] Haak S, Croxford AL, Kreymborg K, Heppner FL, Pouly S, Becher B, Waisman A. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest2009; 119(1): 61–69

[97] Kreymborg K, Etzensperger R, Dumoutier L, Haak S, Rebollo A, Buch T, Heppner FL, Renauld JC, Becher B. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J Immunol2007; 179(12): 8098–8104

[98] Sonderegger I, Kisielow J, Meier R, King C, Kopf M. IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo. Eur J Immunol2008; 38(7): 1833–1838

[99] Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol2011; 12(6): 560–567

[100] El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang GX, Dittel BN, Rostami A. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol2011; 12(6): 568–575

[101] Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature2013; 496(7446): 518–522

[102] Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol2009; 10(5): 514–523

[103] Maddur MS, Miossec P, Kaveri SV, Bayry J. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol2012; 181(1): 8–18

[104] Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, Dooley LT, Lebwohl M; CNTO 1275 Psoriasis Study Group. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med2007; 356(6): 580–592

[105] Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, Blank M, Rutgeerts P; Ustekinumab Crohn’s Disease Study Group.A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology2008; 135(4): 1130–1141

[106] Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH; Psoriasis Study Group, Durez P, Tak PP, Gomez-Reino JJ; Rheumatoid Arthritis Study Group, Foster CS, Kim RY, Samson CM, Falk NS, Chu DS, Callanan D, Nguyen QD; Uveitis Study Group, Rose K, Haider A, Di Padova F. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med2010; 2(52): 52ra72

[107] Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P, Sloan-Lancaster J. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum2010; 62(4): 929–939

[108] Huh JR, Littman DR. Small molecule inhibitors of RORγt: targeting Th17 cells and other applications. Eur J Immunol2012; 42(9): 2232–2237

[109] Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR, Chow J, Manel N, Ciofani M, Kim SV, Cuesta A, Santori FR, Lafaille JJ, Xu HE, Gin DY, Rastinejad F, Littman DR. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature2011; 472(7344): 486–490

[110] Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidović D, Schürer SC, Xu J, Wagoner G, Drew PD, Griffin PR, Burris TP. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature2011; 472(7344): 491–494

[111] Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgt protein. J Biol Chem2011; 286(26): 22707–22710

[112] Cascão R, Vidal B, Raquel H, Neves-Costa A, Figueiredo N, Gupta V, Fonseca JE, Moita LF. Effective treatment of rat adjuvant-induced arthritis by celastrol. Autoimmun Rev2012; 11(12): 856–862

[113] Xiao S, Yosef N, Yang J, Wang Y, Zhou L, Zhu C, Wu C, Baloglu E, Schmidt D, Ramesh R, Lobera M, Sundrud MS, Tsai PY, Xiang Z, Wang J, Xu Y, Lin X, Kretschmer K, Rahl PB, Young RA, Zhong Z, Hafler DA, Regev A, Ghosh S, Marson A, Kuchroo VK. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity2014; 40(4): 477–489

[114] Xie L, Chen J, McMickle A, Awar N, Nady S, Sredni B, Drew PD, Yu S. The immunomodulator AS101 suppresses production of inflammatory cytokines and ameliorates the pathogenesis of experimental autoimmune encephalomyelitis. J Neuroimmunol2014; 273(1–2): 31–41

[115] Zhong B, Liu X, Wang X, Chang SH, Liu X, Wang A, Reynolds JM, Dong C. Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25. Nat Immunol2012; 13(11): 1110–1117

[116] Han L, Yang J, Wang X, Wu Q, Yin S, Li Z, Zhang J, Xing Y, Chen Z, Tsun A, Li D, Piccioni M, Zhang Y, Guo Q, Jiang L, Bao L, Lv L, Li B. The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor γt (RORγt) in Th17 cells. J Biol Chem2014; 289(37): 25546–25555

[117] Pal A, Young MA, Donato NJ. Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. Cancer Res2014; 74(18): 4955–4966

Acknowledgements

Our research is supported by the National Basic Research Program of China (2014CB541803, 2014CB541903), National Natural Science Foundation of China (81330072, 31370863, 31200647, 81271835), National Science and Technology Major Project (2012ZX10002007-003), and STCSM project (14JC1406100).

Lei Han, Jing Yang, Xiuwen Wang, Dan Li, Ling Lv, and Bin Li declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol that requires approval by a relevant institutional review board or ethics committee.

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2014 Higher Education Press and Springer-Verlag Berlin Heidelberg