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The pathogenicity of Th17 cells in autoimmune diseases

A Correction to this article was published on 29 April 2019

This article has been updated

Abstract

IL-17-producing T helper (Th17) cells have been implicated in the pathogenesis of many inflammatory and autoimmune diseases. Targeting the effector cytokines IL-17 and GM-CSF secreted by autoimmune Th17 cells has been shown to be effective for the treatment of the diseases. Understanding a molecular basis of Th17 differentiation and effector functions is therefore critical for the regulation of the pathogenicity of tissue Th17 cells in chronic inflammation. Here, we discuss the roles of proinflammatory cytokines and environmental stimuli in the control of Th17 differentiation and chronic tissue inflammation by pathogenic Th17 cells in humans and in mouse models of autoimmune diseases. We also highlight recent advances in the regulation of pathogenic Th17 cells by gut microbiota and immunometabolism in autoimmune arthritis.

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Change history

  • 29 April 2019

    Unfortunately, an error occurred in the following passus of the article. The word “receptor” was missing in the sentence “Because T cells do not express GM-CSF receptor [41], GM-CSF affects non-T cells.”

References

  1. Gaffen SL, Jain R, Garg AV, Cua DJ (2014) The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14(9):585–600. https://doi.org/10.1038/nri3707

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6(11):1123–1132. https://doi.org/10.1038/ni1254

    CAS  Article  PubMed  Google Scholar 

  3. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6(11):1133–1141. https://doi.org/10.1038/ni1261

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238. https://doi.org/10.1038/nature04753

    CAS  Article  PubMed  Google Scholar 

  5. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441(7090):231–234. https://doi.org/10.1038/nature04754

    CAS  Article  PubMed  Google Scholar 

  6. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2):179–189. https://doi.org/10.1016/j.immuni.2006.01.001

    CAS  Article  PubMed  Google Scholar 

  7. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8(9):967–974. https://doi.org/10.1038/ni1488

    CAS  Article  PubMed  Google Scholar 

  8. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6):1121–1133. https://doi.org/10.1016/j.cell.2006.07.035

    CAS  Article  PubMed  Google Scholar 

  9. 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 (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28(1):29–39. https://doi.org/10.1016/j.immuni.2007.11.016

    CAS  Article  PubMed  Google Scholar 

  10. Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264(5155):95–98

    CAS  Article  PubMed  Google Scholar 

  11. Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S (1998) Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol 161(9):4652–4660

    CAS  PubMed  Google Scholar 

  12. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282(13):9358–9363. https://doi.org/10.1074/jbc.C600321200

    CAS  Article  PubMed  Google Scholar 

  13. Littman DR, Rudensky AY (2010) Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140(6):845–858. https://doi.org/10.1016/j.cell.2010.02.021

    CAS  Article  PubMed  Google Scholar 

  14. Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A (1998) IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol 28(7):2178–2187. https://doi.org/10.1002/(SICI)1521-4141(199807)28:07<2178::AID-IMMU2178>3.0.CO;2-D

    CAS  Article  PubMed  Google Scholar 

  15. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O'Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467(7318):967–971. https://doi.org/10.1038/nature09447

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O'Shea JJ (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26(3):371–381. https://doi.org/10.1016/j.immuni.2007.02.009

    CAS  Article  PubMed  Google Scholar 

  17. Kim HS, Jang SW, Lee W, Kim K, Sohn H, Hwang SS, Lee GR (2017) PTEN drives Th17 cell differentiation by preventing IL-2 production. J Exp Med 214(11):3381–3398. https://doi.org/10.1084/jem.20170523

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Quintana FJ, Jin H, Burns EJ, Nadeau M, Yeste A, Kumar D, Rangachari M, Zhu C, Xiao S, Seavitt J, Georgopoulos K, Kuchroo VK (2012) Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat Immunol 13(8):770–777. https://doi.org/10.1038/ni.2363

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139(3):485–498. https://doi.org/10.1016/j.cell.2009.09.033

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203(10):2271–2279. https://doi.org/10.1084/jem.20061308

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Hirota K, Turner JE, Villa M, Duarte JH, Demengeot J, Steinmetz OM, Stockinger B (2013) Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol 14(4):372–379. https://doi.org/10.1038/ni.2552

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 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 (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421(6924):744–748. https://doi.org/10.1038/nature01355

    CAS  Article  PubMed  Google Scholar 

  23. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201(2):233–240. https://doi.org/10.1084/jem.20041257

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30(4):576–587. https://doi.org/10.1016/j.immuni.2009.02.007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Schiffenbauer J, Streit WJ, Butfiloski E, LaBow M, Edwards C 3rd, Moldawer LL (2000) The induction of EAE is only partially dependent on TNF receptor signaling but requires the IL-1 type I receptor. Clin Immunol 95(2):117–123. https://doi.org/10.1006/clim.2000.4851

    CAS  Article  PubMed  Google Scholar 

  26. Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203(7):1685–1691. https://doi.org/10.1084/jem.20060285

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Matsuki T, Nakae S, Sudo K, Horai R, Iwakura Y (2006) Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int Immunol 18(2):399–407. https://doi.org/10.1093/intimm/dxh379

    CAS  Article  PubMed  Google Scholar 

  28. McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O'Shea JJ, Cua DJ (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10(3):314–324. https://doi.org/10.1038/ni.1698

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8(12):1390–1397. https://doi.org/10.1038/ni1539

    CAS  Article  PubMed  Google Scholar 

  30. 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 (2012) Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13(10):991–999. https://doi.org/10.1038/ni.2416

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Gaublomme JT, Yosef N, Lee Y, Gertner RS, Yang LV, Wu C, Pandolfi PP, Mak T, Satija R, Shalek AK, Kuchroo VK, Park H, Regev A (2015) Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell 163(6):1400–1412. https://doi.org/10.1016/j.cell.2015.11.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Wang C, Yosef N, Gaublomme J, Wu C, Lee Y, Clish CB, Kaminski J, Xiao S, Meyer Zu Horste G, Pawlak M, Kishi Y, Joller N, Karwacz K, Zhu C, Ordovas-Montanes M, Madi A, Wortman I, Miyazaki T, Sobel RA, Park H, Regev A, Kuchroo VK (2015) CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163(6):1413–1427. https://doi.org/10.1016/j.cell.2015.10.068

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Carr TM, Wheaton JD, Houtz GM, Ciofani M (2017) JunB promotes Th17 cell identity and restrains alternative CD4(+) T-cell programs during inflammation. Nat Commun 8(1):301. https://doi.org/10.1038/s41467-017-00380-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Hasan Z, Koizumi SI, Sasaki D, Yamada H, Arakaki N, Fujihara Y, Okitsu S, Shirahata H, Ishikawa H (2017) JunB is essential for IL-23-dependent pathogenicity of Th17 cells. Nat Commun 8:15628. https://doi.org/10.1038/ncomms15628

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Basu R, Whitley SK, Bhaumik S, Zindl CL, Schoeb TR, Benveniste EN, Pear WS, Hatton RD, Weaver CT (2015) IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance. Nat Immunol 16(3):286–295. https://doi.org/10.1038/ni.3099

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12(3):255–263. https://doi.org/10.1038/ni.1993

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13(5):715–725

    CAS  Article  PubMed  Google Scholar 

  38. Ichiyama K, Gonzalez-Martin A, Kim BS, Jin HY, Jin W, Xu W, Sabouri-Ghomi M, Xu S, Zheng P, Xiao C, Dong C (2016) The microRNA-183-96-182 cluster promotes T helper 17 cell pathogenicity by negatively regulating transcription factor Foxo1 expression. Immunity 44(6):1284–1298. https://doi.org/10.1016/j.immuni.2016.05.015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Kishi Y, Kondo T, Xiao S, Yosef N, Gaublomme J, Wu C, Wang C, Chihara N, Regev A, Joller N, Kuchroo VK (2016) Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity. J Exp Med 213(11):2489–2501. https://doi.org/10.1084/jem.20151118

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Meyer Zu Horste G, Wu C, Wang C, Cong L, Pawlak M, Lee Y, Elyaman W, Xiao S, Regev A, Kuchroo VK (2016) RBPJ controls development of pathogenic Th17 cells by regulating IL-23 receptor expression. Cell Rep 16(2):392–404. https://doi.org/10.1016/j.celrep.2016.05.088

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang GX, Dittel BN, Rostami A (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12(6):568–575. https://doi.org/10.1038/ni.2031

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Jain R, Chen Y, Kanno Y, Joyce-Shaikh B, Vahedi G, Hirahara K, Blumenschein WM, Sukumar S, Haines CJ, Sadekova S, McClanahan TK, McGeachy MJ, O'Shea JJ, Cua DJ (2016) Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells. Immunity 44(1):131–142. https://doi.org/10.1016/j.immuni.2015.11.009

    CAS  Article  PubMed  Google Scholar 

  43. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453(7191):65–71. https://doi.org/10.1038/nature06880

    CAS  Article  PubMed  Google Scholar 

  44. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191):106–109. https://doi.org/10.1038/nature06881

    CAS  Article  PubMed  Google Scholar 

  45. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784. https://doi.org/10.1016/j.cell.2011.07.033

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376. https://doi.org/10.1084/jem.20110278

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Karmaus PWF, Chen X, Lim SA, Herrada AA, Nguyen TM, Xu B, Dhungana Y, Rankin S, Chen W, Rosencrance C, Yang K, Fan Y, Cheng Y, Easton J, Neale G, Vogel P, Chi H (2018) Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity. Nature. https://doi.org/10.1038/s41586-018-0806-7

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, Regev A, Kuchroo VK (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496(7446):513–517. https://doi.org/10.1038/nature11984

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA (2013) Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496(7446):518–522. https://doi.org/10.1038/nature11868

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. McQualter JL, Darwiche R, Ewing C, Onuki M, Kay TW, Hamilton JA, Reid HH, Bernard CCA (2001) Granulocyte macrophage colony-stimulating factor. J Exp Med 194(7):873–882. https://doi.org/10.1084/jem.194.7.873

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Sonderegger I, Iezzi G, Maier R, Schmitz N, Kurrer M, Kopf M (2008) GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J Exp Med 205(10):2281–2294. https://doi.org/10.1084/jem.20071119

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12(6):560–567. https://doi.org/10.1038/ni.2027

    CAS  Article  PubMed  Google Scholar 

  53. Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD (2007) Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol 178(8):5245–5252. https://doi.org/10.4049/jimmunol.178.8.5245

    CAS  Article  PubMed  Google Scholar 

  54. Croxford AL, Lanzinger M, Hartmann FJ, Schreiner B, Mair F, Pelczar P, Clausen BE, Jung S, Greter M, Becher B (2015) The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 43(3):502–514. https://doi.org/10.1016/j.immuni.2015.08.010

    CAS  Article  PubMed  Google Scholar 

  55. Ponomarev ED, Shriver LP, Maresz K, Pedras-Vasconcelos J, Verthelyi D, Dittel BN (2006) GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J Immunol 178(1):39–48. https://doi.org/10.4049/jimmunol.178.1.39

    Article  Google Scholar 

  56. Li J, Gran B, Zhang G-X, Ventura ES, Siglienti I, Rostami A, Kamoun M (2003) Differential expression and regulation of IL-23 and IL-12 subunits and receptors in adult mouse microglia. J Neurol Sci 215(1–2):95–103. https://doi.org/10.1016/s0022-510x(03)00203-x

    CAS  Article  PubMed  Google Scholar 

  57. Martinez-Llordella M, Esensten JH, Bailey-Bucktrout SL, Lipsky RH, Marini A, Chen J, Mughal M, Mattson MP, Taub DD, Bluestone JA (2013) CD28-inducible transcription factor DEC1 is required for efficient autoreactive CD4+ T cell response. J Exp Med 210(8):1603–1619. https://doi.org/10.1084/jem.20122387

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Lin CC, Bradstreet TR, Schwarzkopf EA, Jarjour NN, Chou C, Archambault AS, Sim J, Zinselmeyer BH, Carrero JA, Wu GF, Taneja R, Artyomov MN, Russell JH, Edelson BT (2016) IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation. J Exp Med 213(2):251–271. https://doi.org/10.1084/jem.20150568

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Yasuda K, Kitagawa Y, Kawakami R, Isaka Y, Watanabe H, Kondoh G, Kohwi-Shigematsu T, Sakaguchi S, Hirota K (2019) Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation. Nat Commun 10(1):549. https://doi.org/10.1038/s41467-019-08404-w

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8(9):942–949. https://doi.org/10.1038/ni1496

    CAS  Article  PubMed  Google Scholar 

  61. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal MR (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8(9):950–957. https://doi.org/10.1038/ni1497

    CAS  Article  PubMed  Google Scholar 

  62. Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9(6):641–649. https://doi.org/10.1038/ni.1610

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V (2008) A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 9(6):650–657. https://doi.org/10.1038/ni.1613

    CAS  Article  PubMed  Google Scholar 

  64. Chen Z, Tato CM, Muul L, Laurence A, O'Shea JJ (2007) Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum 56(9):2936–2946. https://doi.org/10.1002/art.22866

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H (2007) Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448(7157):1058–1062. https://doi.org/10.1038/nature06096

    CAS  Article  PubMed  Google Scholar 

  66. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE, Douek DC (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452(7188):773–776. https://doi.org/10.1038/nature06764

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8(5):500–508. https://doi.org/10.1038/nm0502-500

    CAS  Article  PubMed  Google Scholar 

  68. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448(7152):484–487. https://doi.org/10.1038/nature05970

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Vaknin-Dembinsky A, Balashov K, Weiner HL (2006) IL-23 is increased in dendritic cells in multiple sclerosis and Down-regulation of IL-23 by antisense Oligos increases dendritic cell IL-10 production. J Immunol 176(12):7768–7774. https://doi.org/10.4049/jimmunol.176.12.7768

    CAS  Article  PubMed  Google Scholar 

  70. Wen SR, Liu GJ, Feng RN, Gong FC, Zhong H, Duan SR, Bi S (2012) Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 244(1–2):94–96. https://doi.org/10.1016/j.jneuroim.2011.12.004

    CAS  Article  PubMed  Google Scholar 

  71. Carrieri PB, Provitera V, De Rosa T, Tartaglia G, Gorga F, Perrella O (1998) Profile of cerebrospinal fluid and serum cytokines in patients with relapsing remitting multiple sclerosis: a correlation with clinical activity. Immunopharmacol Immunotoxicol:373–382

    CAS  Article  PubMed  Google Scholar 

  72. Rasouli J, Ciric B, Imitola J, Gonnella P, Hwang D, Mahajan K, Mari ER, Safavi F, Leist TP, Zhang GX, Rostami A (2015) Expression of GM-CSF in T cells is increased in multiple sclerosis and suppressed by IFN-beta therapy. J Immunol 194(11):5085–5093. https://doi.org/10.4049/jimmunol.1403243

    CAS  Article  PubMed  Google Scholar 

  73. Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. Lancet 388(10055):2023–2038. https://doi.org/10.1016/S0140-6736(16)30173-8

    CAS  Article  PubMed  Google Scholar 

  74. Gregersen PK, Silver J, Winchester RJ (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30(11):1205–1213

    CAS  Article  PubMed  Google Scholar 

  75. Gonzalez-Gay MA, Garcia-Porrua C, Hajeer AH (2002) Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis. Semin Arthritis Rheum 31(6):355–360

    CAS  Article  PubMed  Google Scholar 

  76. Lundy SK, Sarkar S, Tesmer LA, Fox DA (2007) Cells of the synovium in rheumatoid arthritis. T lymphocytes. Arthritis Res Ther 9(1):202. https://doi.org/10.1186/ar2107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Firestein GS, Zvaifler NJ (1987) Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. II Low levels of synovial fluid and synovial tissue interferon suggest that gamma-interferon is not the primary macrophage activating factor. Arthritis Rheum 30(8):864–871

    CAS  Article  PubMed  Google Scholar 

  78. Firestein GS, Zvaifler NJ (1990) How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 33(6):768–773

    CAS  Article  PubMed  Google Scholar 

  79. Courtenay JS, Dallman MJ, Dayan AD, Martin A, Mosedale B (1980) Immunisation against heterologous type II collagen induces arthritis in mice. Nature 283(5748):666–668

    CAS  Article  PubMed  Google Scholar 

  80. Matsumoto I, Staub A, Benoist C, Mathis D (1999) Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 286(5445):1732–1735

    CAS  Article  PubMed  Google Scholar 

  81. Ito Y, Usui T, Kobayashi S, Iguchi-Hashimoto M, Ito H, Yoshitomi H, Nakamura T, Shimizu M, Kawabata D, Yukawa N, Hashimoto M, Sakaguchi N, Sakaguchi S, Yoshifuji H, Nojima T, Ohmura K, Fujii T, Mimori T (2009) Gamma/delta T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis. Arthritis Rheum 60(8):2294–2303. https://doi.org/10.1002/art.24687

    CAS  Article  PubMed  Google Scholar 

  82. Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, Iwakura Y, Sakaguchi N, Sakaguchi S (2007) T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med 204(1):41–47. https://doi.org/10.1084/jem.20062259

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Iwanami K, Matsumoto I, Tanaka-Watanabe Y, Inoue A, Mihara M, Ohsugi Y, Mamura M, Goto D, Ito S, Tsutsumi A, Kishimoto T, Sumida T (2008) Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. Arthritis Rheum 58(3):754–763. https://doi.org/10.1002/art.23222

    CAS  Article  PubMed  Google Scholar 

  84. Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S (2003) Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426(6965):454–460. https://doi.org/10.1038/nature02119

    CAS  Article  PubMed  Google Scholar 

  85. Hata H, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K, Azuma Y, Kanai C, Moriizumi E, Nomura T, Nakamura T, Sakaguchi S (2004) Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J Clin Invest 114(4):582–588. https://doi.org/10.1172/JCI21795

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Tanaka S, Maeda S, Hashimoto M, Fujimori C, Ito Y, Teradaira S, Hirota K, Yoshitomi H, Katakai T, Shimizu A, Nomura T, Sakaguchi N, Sakaguchi S (2010) Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. J Immunol 185(4):2295–2305. https://doi.org/10.4049/jimmunol.1000848

    CAS  Article  PubMed  Google Scholar 

  87. Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, Hirota K, Tanaka S, Nomura T, Miki I, Gordon S, Akira S, Nakamura T, Sakaguchi S (2005) A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med 201(6):949–960. https://doi.org/10.1084/jem.20041758

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Hashimoto M, Hirota K, Yoshitomi H, Maeda S, Teradaira S, Akizuki S, Prieto-Martin P, Nomura T, Sakaguchi N, Kohl J, Heyman B, Takahashi M, Fujita T, Mimori T, Sakaguchi S (2010) Complement drives Th17 cell differentiation and triggers autoimmune arthritis. J Exp Med 207(6):1135–1143. https://doi.org/10.1084/jem.20092301

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Ito Y, Hashimoto M, Hirota K, Ohkura N, Morikawa H, Nishikawa H, Tanaka A, Furu M, Ito H, Fujii T, Nomura T, Yamazaki S, Morita A, Vignali DA, Kappler JW, Matsuda S, Mimori T, Sakaguchi N, Sakaguchi S (2014) Detection of T cell responses to a ubiquitous cellular protein in autoimmune disease. Science 346(6207):363–368. https://doi.org/10.1126/science.1259077

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, Yamaguchi T, Nomura T, Ito H, Nakamura T, Sakaguchi N, Sakaguchi S (2007) Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med 204(12):2803–2812. https://doi.org/10.1084/jem.20071397

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Kochi Y, Okada Y, Suzuki A, Ikari K, Terao C, Takahashi A, Yamazaki K, Hosono N, Myouzen K, Tsunoda T, Kamatani N, Furuichi T, Ikegawa S, Ohmura K, Mimori T, Matsuda F, Iwamoto T, Momohara S, Yamanaka H, Yamada R, Kubo M, Nakamura Y, Yamamoto K (2010) A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat Genet 42(6):515–519. https://doi.org/10.1038/ng.583

    CAS  Article  PubMed  Google Scholar 

  92. Gasson JC (1991) Molecular physiology of granulocyte-macrophage colony-stimulating factor. Blood 77(6):1131–1145

    CAS  Article  PubMed  Google Scholar 

  93. Alvaro-Gracia JM, Zvaifler NJ, Brown CB, Kaushansky K, Firestein GS (1991) Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. J Immunol 146(10):3365–3371

    CAS  PubMed  Google Scholar 

  94. Wright HL, Bucknall RC, Moots RJ, Edwards SW (2012) Analysis of SF and plasma cytokines provides insights into the mechanisms of inflammatory arthritis and may predict response to therapy. Rheumatology (Oxford) 51(3):451–459. https://doi.org/10.1093/rheumatology/ker338

    CAS  Article  Google Scholar 

  95. Hirota K, Hashimoto M, Ito Y, Matsuura M, Ito H, Tanaka M, Watanabe H, Kondoh G, Tanaka A, Yasuda K, Kopf M, Potocnik AJ, Stockinger B, Sakaguchi N, Sakaguchi S (2018) Autoimmune Th17 cells induced synovial stromal and innate lymphoid cell secretion of the cytokine GM-CSF to initiate and augment autoimmune arthritis. Immunity 48(6):1220–1232 e1225. https://doi.org/10.1016/j.immuni.2018.04.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. Terao C, Raychaudhuri S, Gregersen PK (2016) Recent advances in defining the genetic basis of rheumatoid arthritis. Annu Rev Genomics Hum Genet 17:273–301. https://doi.org/10.1146/annurev-genom-090314-045919

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Kim K, Bang SY, Lee HS, Bae SC (2017) Update on the genetic architecture of rheumatoid arthritis. Nat Rev Rheumatol 13(1):13–24. https://doi.org/10.1038/nrrheum.2016.176

    CAS  Article  PubMed  Google Scholar 

  98. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD, Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su DF, Yang J, Xie G, Keystone E, Westra HJ, Esko T, Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA, Diogo D, Cui J, Liao K, Guo MH, Myouzen K, Kawaguchi T, Coenen MJ, van Riel PL, van de Laar MA, Guchelaar HJ, Huizinga TW, Dieude P, Mariette X, Bridges SL Jr, Zhernakova A, Toes RE, Tak PP, Miceli-Richard C, Bang SY, Lee HS, Martin J, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Rantapaa-Dahlqvist S, Arlestig L, Choi HK, Kamatani Y, Galan P, Lathrop M, consortium R, consortium G, Eyre S, Bowes J, Barton A, de Vries N, Moreland LW, Criswell LA, Karlson EW, Taniguchi A, Yamada R, Kubo M, Liu JS, Bae SC, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Raychaudhuri S, Stranger BE, De Jager PL, Franke L, Visscher PM, Brown MA, Yamanaka H, Mimori T, Takahashi A, Xu H, Behrens TW, Siminovitch KA, Momohara S, Matsuda F, Yamamoto K, Plenge RM (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506(7488):376–381. https://doi.org/10.1038/nature12873

    CAS  Article  PubMed  Google Scholar 

  99. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG, Consortium B, Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, Criswell LA, Crusius JB, Cui J, de Bakker PI, De Jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Lee AT, Liu X, Martin P, Morgan AW, Padyukov L, Posthumus MD, Radstake TR, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, van der Helm-van Mil AH, van der Horst-Bruinsma IE, van der Schoot CE, van Riel PL, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth BP, Consortium Y, Wijmenga C, Karlson EW, Toes RE, de Vries N, Begovich AB, Worthington J, Siminovitch KA, Gregersen PK, Klareskog L, Plenge RM (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42(6):508–514. https://doi.org/10.1038/ng.582

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, Amos CI, Padyukov L, Toes RE, Huizinga TW, Wijmenga C, Trynka G, Franke L, Westra HJ, Alfredsson L, Hu X, Sandor C, de Bakker PI, Davila S, Khor CC, Heng KK, Andrews R, Edkins S, Hunt SE, Langford C, Symmons D, Biologics in Rheumatoid Arthritis G, Genomics Study S, Wellcome Trust Case Control C, Concannon P, Onengut-Gumuscu S, Rich SS, Deloukas P, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Arlsetig L, Martin J, Rantapaa-Dahlqvist S, Plenge RM, Raychaudhuri S, Klareskog L, Gregersen PK, Worthington J (2012) High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet 44(12):1336–1340. https://doi.org/10.1038/ng.2462

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P (1999) Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42(5):963–970. https://doi.org/10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO;2-E

    CAS  Article  PubMed  Google Scholar 

  102. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103(9):1345–1352. https://doi.org/10.1172/JCI5703

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, Maslinski W (2000) High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol 164(5):2832–2838

    CAS  Article  PubMed  Google Scholar 

  104. Shahrara S, Huang Q, Mandelin AM 2nd, Pope RM (2008) TH-17 cells in rheumatoid arthritis. Arthritis Res Ther 10(4):R93. https://doi.org/10.1186/ar2477

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Kirkham BW, Lassere MN, Edmonds JP, Juhasz KM, Bird PA, Lee CS, Shnier R, Portek IJ (2006) Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 54(4):1122–1131. https://doi.org/10.1002/art.21749

    CAS  Article  PubMed  Google Scholar 

  106. Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, Skapenko A (2010) Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 62(10):2876–2885. https://doi.org/10.1002/art.27622

    CAS  Article  PubMed  Google Scholar 

  107. Penatti A, Facciotti F, De Matteis R, Larghi P, Paroni M, Murgo A, De Lucia O, Pagani M, Pierannunzii L, Truzzi M, Ioan-Facsinay A, Abrignani S, Geginat J, Meroni PL (2017) Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 19(1):103. https://doi.org/10.1186/s13075-017-1305-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, Dolhain RJ, Lubberts E (2011) 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 Rheum 63(1):73–83. https://doi.org/10.1002/art.30093

    CAS  Article  PubMed  Google Scholar 

  109. Jandus C, Bioley G, Rivals JP, Dudler J, Speiser D, Romero P (2008) Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum 58(8):2307–2317. https://doi.org/10.1002/art.23655

    Article  PubMed  Google Scholar 

  110. Yamada H, Nakashima Y, Okazaki K, Mawatari T, Fukushi JI, Kaibara N, Hori A, Iwamoto Y, Yoshikai Y (2008) Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis. Ann Rheum Dis 67(9):1299–1304. https://doi.org/10.1136/ard.2007.080341

    CAS  Article  PubMed  Google Scholar 

  111. Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, Melendez AJ, McInnes IB (2010) Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol 184(7):3336–3340. https://doi.org/10.4049/jimmunol.0903566

    CAS  Article  PubMed  Google Scholar 

  112. Kan J, Mishima S, Kashiwakura J, Sasaki-Sakamoto T, Seki M, Saito S, Ra C, Tokuhashi Y, Okayama Y (2016) Interleukin-17A expression in human synovial mast cells in rheumatoid arthritis and osteoarthritis. Allergol Int 65(Suppl):S11–S16. https://doi.org/10.1016/j.alit.2016.04.007

    Article  PubMed  Google Scholar 

  113. Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, Evans JG, Cimaz R, Bajaj-Elliott M, Wedderburn LR (2010) Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A 107(33):14751–14756. https://doi.org/10.1073/pnas.1003852107

    Article  PubMed  PubMed Central  Google Scholar 

  114. Basdeo SA, Cluxton D, Sulaimani J, Moran B, Canavan M, Orr C, Veale DJ, Fearon U, Fletcher JM (2017) Ex-Th17 (nonclassical Th1) cells are functionally distinct from classical Th1 and Th17 cells and are not constrained by regulatory T cells. J Immunol 198(6):2249–2259. https://doi.org/10.4049/jimmunol.1600737

    CAS  Article  PubMed  Google Scholar 

  115. Cosmi L, Cimaz R, Maggi L, Santarlasci V, Capone M, Borriello F, Frosali F, Querci V, Simonini G, Barra G, Piccinni MP, Liotta F, De Palma R, Maggi E, Romagnani S, Annunziato F (2011) Evidence of the transient nature of the Th17 phenotype of CD4+CD161+ T cells in the synovial fluid of patients with juvenile idiopathic arthritis. Arthritis Rheum 63(8):2504–2515. https://doi.org/10.1002/art.30332

    CAS  Article  PubMed  Google Scholar 

  116. Yamada H, Haraguchi A, Sakuraba K, Okazaki K, Fukushi JI, Mizu-Uchi H, Akasaki Y, Esaki Y, Kamura S, Fujimura K, Kondo M, Miyahara H, Nakashima Y, Yoshikai Y (2017) Th1 is the predominant helper T cell subset that produces GM-CSF in the joint of rheumatoid arthritis. RMD Open 3(1):e000487. https://doi.org/10.1136/rmdopen-2017-000487

    Article  PubMed  PubMed Central  Google Scholar 

  117. Piper C, Pesenacker AM, Bending D, Thirugnanabalan B, Varsani H, Wedderburn LR, Nistala K (2014) T cell expression of granulocyte-macrophage colony-stimulating factor in juvenile arthritis is contingent upon Th17 plasticity. Arthritis Rheum 66(7):1955–1960. https://doi.org/10.1002/art.38647

    CAS  Article  Google Scholar 

  118. Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Mazurov V, Aelion JA, Lee SH, Codding CE, Kellner H, Ikawa T, Hugot S, Mpofu S (2013) Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 72(6):863–869. https://doi.org/10.1136/annrheumdis-2012-201601

    CAS  Article  PubMed  Google Scholar 

  119. Genovese MC, Greenwald M, Cho CS, Berman A, Jin L, Cameron GS, Benichou O, Xie L, Braun D, Berclaz PY, Banerjee S (2014) A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors. Arthritis Rheum 66(7):1693–1704. https://doi.org/10.1002/art.38617

    CAS  Article  Google Scholar 

  120. Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Aelion JA, Lee SH, Codding CE, Kellner H, Ikawa T, Hugot S, Ligozio G, Mpofu S (2014) One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study. J Rheumatol 41(3):414–421. https://doi.org/10.3899/jrheum.130637

    CAS  Article  PubMed  Google Scholar 

  121. Genovese MC, Braun DK, Erickson JS, Berclaz PY, Banerjee S, Heffernan MP, Carlier H (2016) Safety and efficacy of open-label subcutaneous Ixekizumab treatment for 48 weeks in a phase II study in biologic-naive and TNF-IR patients with rheumatoid arthritis. J Rheumatol 43(2):289–297. https://doi.org/10.3899/jrheum.140831

    CAS  Article  PubMed  Google Scholar 

  122. Blanco FJ, Moricke R, Dokoupilova E, Codding C, Neal J, Andersson M, Rohrer S, Richards H (2017) Secukinumab in active rheumatoid arthritis: a phase III randomized, double-blind, active comparator- and placebo-controlled study. Arthritis Rheum 69(6):1144–1153. https://doi.org/10.1002/art.40070

    CAS  Article  Google Scholar 

  123. Dokoupilova E, Aelion J, Takeuchi T, Malavolta N, Sfikakis PP, Wang Y, Rohrer S, Richards HB (2018) Secukinumab after anti-tumour necrosis factor-alpha therapy: a phase III study in active rheumatoid arthritis. Scand J Rheumatol 47(4):276–281. https://doi.org/10.1080/03009742.2017.1390605

    CAS  Article  PubMed  Google Scholar 

  124. Raza K, Falciani F, Curnow SJ, Ross EJ, Lee CY, Akbar AN, Lord JM, Gordon C, Buckley CD, Salmon M (2005) Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther 7(4):R784–R795. https://doi.org/10.1186/ar1733

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. Kokkonen H, Soderstrom I, Rocklov J, Hallmans G, Lejon K, Rantapaa Dahlqvist S (2010) Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum 62(2):383–391. https://doi.org/10.1002/art.27186

    CAS  Article  PubMed  Google Scholar 

  126. Behrens F, Tak PP, Ostergaard M, Stoilov R, Wiland P, Huizinga TW, Berenfus VY, Vladeva S, Rech J, Rubbert-Roth A, Korkosz M, Rekalov D, Zupanets IA, Ejbjerg BJ, Geiseler J, Fresenius J, Korolkiewicz RP, Schottelius AJ, Burkhardt H (2015) MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial. Ann Rheum Dis 74(6):1058–1064. https://doi.org/10.1136/annrheumdis-2013-204816

    CAS  Article  PubMed  Google Scholar 

  127. Burmester GR, Weinblatt ME, IB MI, Porter D, Barbarash O, Vatutin M, Szombati I, Esfandiari E, Sleeman MA, Kane CD, Cavet G, Wang B, Godwood A, Magrini F, Group ES (2013) Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann Rheum Dis 72(9):1445–1452. https://doi.org/10.1136/annrheumdis-2012-202450

    CAS  Article  PubMed  Google Scholar 

  128. Burmester GR, McInnes IB, Kremer J, Miranda P, Korkosz M, Vencovsky J, Rubbert-Roth A, Mysler E, Sleeman MA, Godwood A, Sinibaldi D, Guo X, White WI, Wang B, Wu CY, Ryan PC, Close D, Weinblatt ME, investigators EEs (2017) A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis 76(6):1020–1030. https://doi.org/10.1136/annrheumdis-2016-210624

    CAS  Article  PubMed  Google Scholar 

  129. Weinblatt ME, McInnes IB, Kremer JM, Miranda P, Vencovsky J, Guo X, White WI, Ryan PC, Godwood A, Albulescu M, Close D, Burmester GR (2018) A randomized phase IIb study of Mavrilimumab and Golimumab in rheumatoid arthritis. Arthritis Rheum 70(1):49–59. https://doi.org/10.1002/art.40323

    CAS  Article  Google Scholar 

  130. Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C, Group ES, Group FS (2014) Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med 371(4):326–338. https://doi.org/10.1056/NEJMoa1314258

    CAS  Article  PubMed  Google Scholar 

  131. Gordon KB, Leonardi CL, Lebwohl M, Blauvelt A, Cameron GS, Braun D, Erickson J, Heffernan M (2014) A 52-week, open-label study of the efficacy and safety of ixekizumab, an anti-interleukin-17A monoclonal antibody, in patients with chronic plaque psoriasis. J Am Acad Dermatol 71(6):1176–1182. https://doi.org/10.1016/j.jaad.2014.07.048

    CAS  Article  PubMed  Google Scholar 

  132. IB MI, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, Rahman P, van der Heijde D, Landewe R, Conaghan PG, Gottlieb AB, Richards H, Pricop L, Ligozio G, Patekar M, Mpofu S, Group FS (2015) Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386(9999):1137–1146. https://doi.org/10.1016/S0140-6736(15)61134-5

    CAS  Article  Google Scholar 

  133. Mease P, van der Heijde D, Landewe R, Mpofu S, Rahman P, Tahir H, Singhal A, Boettcher E, Navarra S, Meiser K, Readie A, Pricop L, Abrams K (2018) Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study. Ann Rheum Dis 77(6):890–897. https://doi.org/10.1136/annrheumdis-2017-212687

    CAS  Article  PubMed  Google Scholar 

  134. Pavelka K, Kivitz A, Dokoupilova E, Blanco R, Maradiaga M, Tahir H, Pricop L, Andersson M, Readie A, Porter B (2017) Efficacy, safety, and tolerability of secukinumab in patients with active ankylosing spondylitis: a randomized, double-blind phase 3 study, MEASURE 3. Arthritis Res Ther 19(1):285. https://doi.org/10.1186/s13075-017-1490-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. Needell JC, Zipris D (2016) The role of the intestinal microbiome in type 1 diabetes pathogenesis. Curr Diab Rep 16(10):89. https://doi.org/10.1007/s11892-016-0781-z

    CAS  Article  PubMed  Google Scholar 

  136. Miyake S, Kim S, Suda W, Oshima K, Nakamura M, Matsuoka T, Chihara N, Tomita A, Sato W, Kim SW, Morita H, Hattori M, Yamamura T (2015) Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to clostridia XIVa and IV clusters. PLoS One 10(9):e0137429. https://doi.org/10.1371/journal.pone.0137429

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T, Cerundolo V, Pamer EG, Abramson SB, Huttenhower C, Littman DR (2013) Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2:e01202. https://doi.org/10.7554/eLife.01202

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K, Hirota K, Matsushita M, Furuta Y, Narazaki M, Sakaguchi N, Kayama H, Nakamura S, Iida T, Saeki Y, Kumanogoh A, Sakaguchi S, Takeda K (2016) Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheum 68(11):2646–2661. https://doi.org/10.1002/art.39783

    CAS  Article  Google Scholar 

  139. Vaahtovuo J, Munukka E, Korkeamaki M, Luukkainen R, Toivanen P (2008) Fecal microbiota in early rheumatoid arthritis. J Rheumatol 35(8):1500–1505

    CAS  PubMed  Google Scholar 

  140. Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J (2015) The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 21(8):895–905. https://doi.org/10.1038/nm.3914

    CAS  Article  PubMed  Google Scholar 

  141. Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32(6):815–827. https://doi.org/10.1016/j.immuni.2010.06.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. Marietta EV, Murray JA, Luckey DH, Jeraldo PR, Lamba A, Patel R, Luthra HS, Mangalam A, Taneja V (2016) Suppression of inflammatory arthritis by human gut-derived Prevotella histicola in humanized mice. Arthritis Rheum 68(12):2878–2888. https://doi.org/10.1002/art.39785

    CAS  Article  Google Scholar 

  143. Yang Z, Fujii H, Mohan SV, Goronzy JJ, Weyand CM (2013) Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J Exp Med 210(10):2119–2134. https://doi.org/10.1084/jem.20130252

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. Shen Y, Wen Z, Li Y, Matteson EL, Hong J, Goronzy JJ, Weyand CM (2017) Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat Immunol 18(9):1025–1034. https://doi.org/10.1038/ni.3808

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. Yang Z, Shen Y, Oishi H, Matteson EL, Tian L, Goronzy JJ, Weyand CM (2016) Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci Transl Med 8(331):331ra338. https://doi.org/10.1126/scitranslmed.aad7151

    Article  Google Scholar 

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Funding

This work was supported by the JSPS Grants-in-Aid for Scientific Research (K.H.).

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Correspondence to Keiji Hirota.

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This article is a contribution to the special issue on The Pathogenicity of Acquired Immunity in Human Diseases - Guest Editor: Kiyoshi Hirahara

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The original version of this article was revised: The word “receptor” was missing in the sentence “Because T cells do not express GM-CSF receptor [41], GM-CSF affects non-T cells.” . Full information regarding the corrections made can be found in the erratum/correction for this article.

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Yasuda, K., Takeuchi, Y. & Hirota, K. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol 41, 283–297 (2019). https://doi.org/10.1007/s00281-019-00733-8

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Keywords

  • IL-17
  • GM-CSF
  • Th17 cells
  • Autoimmune arthritis
  • EAE
  • Rheumatoid arthritis