Seminars in Immunopathology

, Volume 39, Issue 4, pp 469–486 | Cite as

Arthritis models: usefulness and interpretation

  • Natacha Bessis
  • Patrice Decker
  • Eric Assier
  • Luca Semerano
  • Marie-Christophe Boissier


Animal models of arthritis are used to better understand pathophysiology of a disease or to seek potential therapeutic targets or strategies. Focusing on models currently used for studying rheumatoid arthritis, we show here in which extent models were invaluable to enlighten different mechanisms such as the role of innate immunity, T and B cells, vessels, or microbiota. Moreover, models were the starting point of in vivo application of cytokine-blocking strategies such as anti-TNF or anti-IL-6 treatments. The most popular models are the different types of collagen-induced arthritis and arthritis in KBN mice. As spontaneous arthritides, human TNF-α transgenic mice are a reliable model. It is mandatory to use animal models in the respect of ethical procedure, particularly regarding the number of animals and the control of pain. Moreover, design of experiments should be of the highest level, animal models of arthritis being dedicated to exploration of well-based novelties, and never used for confirmation or replication of already proven concepts. The best interpretations of data in animal models of arthritis suppose integrated research, including translational studies from animals to humans.


Arthritis models Collagen-induced arthritis Rheumatoid arthritis Inflammation 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Bernard C (1865) Introduction à l‘étude de la médecine expérimentale, vol 1. JB Baillère et Fils, ParisGoogle Scholar
  2. 2.
    Webb DR (2014) Animal models of human disease: inflammation. Biochem Pharmacol 87:121–130. doi: 10.1016/j.bcp.2013.06.014 PubMedCrossRefGoogle Scholar
  3. 3.
    Takao K, Miyakawa T (2015) Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 112:1167–1172. doi: 10.1073/pnas.1401965111 PubMedCrossRefGoogle Scholar
  4. 4.
    Stoerk H (1954) Chronic polyarthritis in rats injected with spleen in adjuvants. 30:616–621Google Scholar
  5. 5.
    Pearson CM (1956) Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol Med Soc Exp Biol Med N Y N 91:95–101CrossRefGoogle Scholar
  6. 6.
    Seok J, Warren HS, Cuenca AG et al (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 110:3507–3512. doi: 10.1073/pnas.1222878110 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Pound P, Bracken MB (2014) Is animal research sufficiently evidence based to be a cornerstone of biomedical research? BMJ 348:g3387PubMedCrossRefGoogle Scholar
  8. 8.
    Segura E, Touzot M, Bohineust A et al (2013) Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity 38:336–348PubMedCrossRefGoogle Scholar
  9. 9.
    Narendra SC, Chalise JP, Hook N, Magnusson M (2014) Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling. J Leukoc Biol 95:661–666PubMedCrossRefGoogle Scholar
  10. 10.
    Hoffmann MH, Skriner K, Herman S et al (2011) Nucleic acid-stimulated antigen-presenting cells trigger T cells to induce disease in a rat transfer model of inflammatory arthritis. J Autoimmun 36:288–300PubMedCrossRefGoogle Scholar
  11. 11.
    Tak PP, Smeets TJ, Daha MR et al (1997) Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 40:217–225PubMedCrossRefGoogle Scholar
  12. 12.
    Joosten LA, Helsen MM, van de Loo FA, van den Berg WB (1996) Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. A comparative study using anti-TNF alpha, anti-IL-1 alpha/beta, and IL-1Ra. Arthritis Rheum 39:797–809PubMedCrossRefGoogle Scholar
  13. 13.
    Zhu W, Li X, Fang S et al (2015) Anti-citrullinated protein antibodies induce macrophage subset disequilibrium in RA patients. Inflammation 38:2067–2075PubMedCrossRefGoogle Scholar
  14. 14.
    Misharin AV, Cuda CM, Saber R et al (2014) Nonclassical Ly6C(−) monocytes drive the development of inflammatory arthritis in mice. Cell Rep 9:591–604PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Li J, Hsu HC, Ding Y et al (2014) Inhibition of fucosylation reshapes inflammatory macrophages and suppresses type II collagen-induced arthritis. Arthritis Rheumatol 66:2368–2379PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Shimizu K, Nakajima A, Sudo K et al (2015) IL-1 receptor type 2 suppresses collagen-induced arthritis by inhibiting IL-1 signal on macrophages. JImmunol 194:3156–3168CrossRefGoogle Scholar
  17. 17.
    Cook AD, Braine EL, Campbell IK et al (2001) Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res 3:293–298PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Campbell IK, Rich MJ, Bischof RJ, Hamilton JA (2000) The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF. J Leukoc Biol 68:144–150PubMedGoogle Scholar
  19. 19.
    Pillay J, den Braber I, Vrisekoop N et al (2010) In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 116:625–627PubMedCrossRefGoogle Scholar
  20. 20.
    Puga I, Cols M, Barra C et al (2012) B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 13:170–250CrossRefGoogle Scholar
  21. 21.
    Zhang X, Majlessi L, Deriaud E et al (2009) Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity 31:761–771PubMedCrossRefGoogle Scholar
  22. 22.
    Lindau D, Mussard J, Rabsteyn A et al (2014) TLR9 independent interferon alpha production by neutrophils on NETosis in response to circulating chromatin, a key lupus autoantigen. Ann Rheum Dis 73:2199–2207PubMedCrossRefGoogle Scholar
  23. 23.
    Decker P (2011) Neutrophils and interferon-alpha-producing cells: who produces interferon in lupus? Arthritis ResTher 13:118CrossRefGoogle Scholar
  24. 24.
    Iking-Konert C, Ostendorf B, Sander O et al (2005) Transdifferentiation of polymorphonuclear neutrophils to dendritic-like cells at the site of inflammation in rheumatoid arthritis: evidence for activation by T cells. Ann Rheum Dis 64:1436–1442PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Poubelle PE, Chakravarti A, Fernandes MJ et al (2007) Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther 9:R25PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Tanaka D, Kagari T, Doi H, Shimozato T (2006) Essential role of neutrophils in anti-type II collagen antibody and lipopolysaccharide-induced arthritis. Immunology 119:195–202PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Wang JX, Bair AM, King SL et al (2012) Ly6G ligation blocks recruitment of neutrophils via a beta2-integrin-dependent mechanism. Blood 120:1489–1498PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Lawlor KE, Campbell IK, Metcalf D et al (2004) Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. Proc Natl Acad Sci U S A 101:11398–11403PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Eyles JL, Hickey MJ, Norman MU et al (2008) A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis. Blood 112:5193–5201PubMedCrossRefGoogle Scholar
  30. 30.
    Campbell IK, Leong D, Edwards KM et al (2016) Therapeutic targeting of the G-CSF receptor reduces neutrophil trafficking and joint inflammation in antibody-mediated inflammatory arthritis. J Immunol 197:4392–4402PubMedCrossRefGoogle Scholar
  31. 31.
    Chou RC, Kim ND, Sadik CD et al (2010) Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. Immunity 33:266–278PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Niki Y, Yamada H, Seki S et al (2001) Macrophage- and neutrophil-dominant arthritis in human IL-1 alpha transgenic mice. J Clin Invest 107:1127–1135PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Martin P, Palmer G, Rodriguez E et al (2017) Deficiency in IL-1 receptor type 2 aggravates K/BxN serum transfer-induced arthritis in mice but has no impact on systemic inflammatory responses. J Immunol Baltim Md 1950. doi: 10.4049/jimmunol.1600855 Google Scholar
  34. 34.
    Brinkmann V, Reichard U, Goosmann C et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535PubMedCrossRefGoogle Scholar
  35. 35.
    Li P, Li M, Lindberg MR et al (2010) PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 207:1853–1862PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A et al (2013) NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 5:178ra40PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Pratesi F, Dioni I, Tommasi C, et al (2014) Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps. Ann Rheum Dis 73:1414–1422Google Scholar
  38. 38.
    Spengler J, Lugonja B, Ytterberg AJ et al (2015) Release of active peptidyl arginine deiminases by neutrophils can explain production of extracellular citrullinated autoantigens in rheumatoid arthritis synovial fluid. Arthritis Rheumatol 67:3135–3145PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Papadaki G, Kambas K, Choulaki C et al (2016) Neutrophil extracellular traps exacerbate Th1-mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation. Eur J Immunol 46:2542–2554PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Kawalkowska J, Quirke AM, Ghari F et al (2016) Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses. Sci Rep 6:26430PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Willis VC, Gizinski AM, Banda NK et al (2011) N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis. J Immunol 186:4396–4404PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Rohrbach AS, Hemmers S, Arandjelovic S et al (2012) PAD4 is not essential for disease in the K/BxN murine autoantibody-mediated model of arthritis. Arthritis Res Ther 14:R104PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Monach PA, Hueber W, Kessler B et al (2009) A broad screen for targets of immune complexes decorating arthritic joints highlights deposition of nucleosomes in rheumatoid arthritis. Proc Natl Acad Sci U A 106:15867–15872CrossRefGoogle Scholar
  44. 44.
    Yu D, Rumore PM, Liu Q, Steinman CR (1997) Soluble oligonucleosomal complexes in synovial fluid from inflamed joints. Arthritis Rheum 40:648–654PubMedCrossRefGoogle Scholar
  45. 45.
    Ronnefarth VM, Erbacher AI, Lamkemeyer T et al (2006) TLR2/TLR4-independent neutrophil activation and recruitment upon endocytosis of nucleosomes reveals a new pathway of innate immunity in systemic lupus erythematosus. J Immunol 177:7740–7749PubMedCrossRefGoogle Scholar
  46. 46.
    Lindau D, Ronnefarth V, Erbacher A et al (2011) Nucleosome-induced neutrophil activation occurs independently of TLR9 and endosomal acidification: implications for systemic lupus erythematosus. Eur J Immunol 41:669–681PubMedCrossRefGoogle Scholar
  47. 47.
    Decker P, Singh-Jasuja H, Haager S et al (2005) Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation. J Immunol 174:3326–3334PubMedCrossRefGoogle Scholar
  48. 48.
    Gravallese EM, Harada Y, Wang JT et al (1998) Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol 152:943–951PubMedPubMedCentralGoogle Scholar
  49. 49.
    Zaiss MM, Axmann R, Zwerina J et al (2007) Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum 56:4104–4112PubMedCrossRefGoogle Scholar
  50. 50.
    Kim KW, Cho ML, Oh HJ et al (2009) TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis. Immunol Lett 124:9–17PubMedCrossRefGoogle Scholar
  51. 51.
    Yeo L, Toellner KM, Salmon M et al (2011) Cytokine mRNA profiling identifies B cells as a major source of RANKL in rheumatoid arthritis. Ann Rheum Dis 70:2022–2028PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Krishnamurthy A, Joshua V, Haj HA et al (2016) Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis 75:721–729PubMedCrossRefGoogle Scholar
  53. 53.
    Danks L, Komatsu N, Guerrini MM et al (2016) RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann Rheum Dis 75:1187–1195PubMedCrossRefGoogle Scholar
  54. 54.
    Feng X, Shi Y, Xu L et al (2016) Modulation of IL-6 induced RANKL expression in arthritic synovium by a transcription factor SOX5. SciRep 6:32001Google Scholar
  55. 55.
    LaBranche TP, Jesson MI, Radi ZA et al (2012) JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum 64:3531–3542PubMedCrossRefGoogle Scholar
  56. 56.
    Charles JF, Hsu LY, Niemi EC et al (2012) Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function. J Clin Invest 122:4592–4605PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Zhang AL, Colmenero P, Purath U et al (2007) Natural killer cells trigger differentiation of monocytes into dendritic cells. Blood 110:2484–2493PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Soderstrom K, Stein E, Colmenero P et al (2010) Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci U S A 107:13028–13033PubMedCrossRefGoogle Scholar
  59. 59.
    Andersson AK, Sumariwalla PF, McCann FE et al (2011) Blockade of NKG2D ameliorates disease in mice with collagen-induced arthritis: a potential pathogenic role in chronic inflammatory arthritis. Arthritis Rheum 63:2617–2629PubMedCrossRefGoogle Scholar
  60. 60.
    Groh V, Bruhl A, El Gabalawy H et al (2003) Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci U S A 100:9452–9457PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Bradfield PF, Amft N, Vernon-Wilson E et al (2003) Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum 48:2472–2482PubMedCrossRefGoogle Scholar
  62. 62.
    Lefevre S, Knedla A, Tennie C et al (2009) Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 15:1414–1420PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hu F, Li Y, Zheng L et al (2014) Toll-like receptors expressed by synovial fibroblasts perpetuate Th1 and th17 cell responses in rheumatoid arthritis. PLoS One 9:e100266PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Zhu W, Meng L, Jiang C et al (2011) Arthritis is associated with T-cell-induced upregulation of toll-like receptor 3 on synovial fibroblasts. Arthritis Res Ther 13:R103PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Huang Q, Ma Y, Adebayo A, Pope RM (2007) Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis. Arthritis Rheum 56:2192–2201PubMedCrossRefGoogle Scholar
  66. 66.
    Abdollahi-Roodsaz S, Joosten LA, Roelofs MF et al (2007) Inhibition of toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum 56:2957–2967PubMedCrossRefGoogle Scholar
  67. 67.
    Pierer M, Wagner U, Rossol M, Ibrahim S (2011) Toll-like receptor 4 is involved in inflammatory and joint destructive pathways in collagen-induced arthritis in DBA1J mice. PLoS One 6:e23539PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kim HS, Chung DH (2012) TLR4-mediated IL-12 production enhances IFN-gamma and IL-1beta production, which inhibits TGF-beta production and promotes antibody-induced joint inflammation. Arthritis Res Ther 14:R210PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Taniguchi N, Kawahara K, Yone K et al (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum 48:971–981PubMedCrossRefGoogle Scholar
  70. 70.
    Abdollahi-Roodsaz S, Joosten LA, Koenders MI et al (2008) Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest 118:205–216PubMedCrossRefGoogle Scholar
  71. 71.
    Hayashi T, Gray CS, Chan M et al (2009) Prevention of autoimmune disease by induction of tolerance to toll-like receptor 7. Proc Natl Acad Sci U S A 106:2764–2769PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Alzabin S, Kong P, Medghalchi M et al (2012) Investigation of the role of endosomal toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance. Arthritis Res Ther 14:R142PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Kim SJ, Chen Z, Essani AB et al (2016) Identification of a novel toll-like receptor 7 endogenous ligand in rheumatoid arthritis synovial fluid that can provoke arthritic joint inflammation. Arthritis Rheumatol 68:1099–1110PubMedPubMedCentralGoogle Scholar
  74. 74.
    Lacerte P, Brunet A, Egarnes B et al (2016) Overexpression of TLR2 and TLR9 on monocyte subsets of active rheumatoid arthritis patients contributes to enhance responsiveness to TLR agonists. Arthritis Res Ther 18:10PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Hemmi H, Takeuchi O, Kawai T et al (2000) A toll-like receptor recognizes bacterial DNA. Nature 408:740–745PubMedCrossRefGoogle Scholar
  76. 76.
    Deng GM, Nilsson IM, Verdrengh M et al (1999) Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med 5:702–705PubMedCrossRefGoogle Scholar
  77. 77.
    Lindau D, Mussard J, Wagner BJ et al (2013) Primary blood neutrophils express a functional cell surface toll-like receptor 9. Eur J Immunol 43:2101–2113PubMedCrossRefGoogle Scholar
  78. 78.
    Asagiri M, Hirai T, Kunigami T et al (2008) Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science 319:624–627PubMedCrossRefGoogle Scholar
  79. 79.
    Carrion M, Juarranz Y, Perez-Garcia S et al (2011) RNA sensors in human osteoarthritis and rheumatoid arthritis synovial fibroblasts: immune regulation by vasoactive intestinal peptide. Arthritis Rheum 63:1626–1636PubMedCrossRefGoogle Scholar
  80. 80.
    Magnusson M, Zare F, Tarkowski A (2006) Requirement of type I interferon signaling for arthritis triggered by double-stranded RNA. Arthritis Rheum 54:148–157PubMedCrossRefGoogle Scholar
  81. 81.
    Yarilina A, DiCarlo E, Ivashkiv LB (2007) Suppression of the effector phase of inflammatory arthritis by double-stranded RNA is mediated by type I IFNs. J Immunol 178:2204–2211PubMedCrossRefGoogle Scholar
  82. 82.
    Kawane K, Ohtani M, Miwa K et al (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443:998–1002PubMedCrossRefGoogle Scholar
  83. 83.
    Neidhart M, Karouzakis E, Schumann GG et al (2010) Trex-1 deficiency in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 62:2673–2679PubMedCrossRefGoogle Scholar
  84. 84.
    Clavel C, Nogueira L, Laurent L et al (2008) Induction of macrophage secretion of tumor necrosis factor alpha through Fcgamma receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum 58:678–688PubMedCrossRefGoogle Scholar
  85. 85.
    Sokolove J, Zhao X, Chandra PE, Robinson WH (2011) Immune complexes containing citrullinated fibrinogen costimulate macrophages via toll-like receptor 4 and Fcgamma receptor. Arthritis Rheum 63:53–62PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Ben Mkaddem S, Hayem G, Jonsson F et al (2014) Shifting FcgammaRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis. J Clin Invest 124:3945–3959PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Boross P, van Lent PL, Martin-Ramirez J et al (2008) Destructive arthritis in the absence of both FcgammaRI and FcgammaRIII. J Immunol 180:5083–5091PubMedCrossRefGoogle Scholar
  88. 88.
    Seeling M, Hillenhoff U, David JP et al (2013) Inflammatory monocytes and Fcgamma receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. Proc Natl Acad Sci U S A 110:10729–10734PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Espeli M, Clatworthy MR, Bokers S et al (2012) Analysis of a wild mouse promoter variant reveals a novel role for FcgammaRIIb in the control of the germinal center and autoimmunity. J Exp Med 209:2307–2319PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Trouw LA, Daha N, Kurreeman FA et al (2013) Genetic variants in the region of the C1q genes are associated with rheumatoid arthritis. Clin Exp Immunol 173:76–83PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Trouw LA, Haisma EM, Levarht EW et al (2009) Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways. Arthritis Rheum 60:1923–1931PubMedCrossRefGoogle Scholar
  92. 92.
    Ji H, Ohmura K, Mahmood U et al (2002) Arthritis critically dependent on innate immune system players. Immunity 16:157–168PubMedCrossRefGoogle Scholar
  93. 93.
    Banda NK, Takahashi K, Wood AK et al (2007) Pathogenic complement activation in collagen antibody-induced arthritis in mice requires amplification by the alternative pathway. JImmunol 179:4101–4109CrossRefGoogle Scholar
  94. 94.
    Strainic MG, Liu J, Huang D et al (2008) Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 28:425–435PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Jose PJ, Moss IK, Maini RN, Williams TJ (1990) Measurement of the chemotactic complement fragment C5a in rheumatoid synovial fluids by radioimmunoassay: role of C5a in the acute inflammatory phase. Ann Rheum Dis 49:747–752PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Sadik CD, Kim ND, Iwakura Y, Luster AD (2012) Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcgammaR signaling. Proc Natl Acad Sci U S A 109:E3177–E3185PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Tsuboi N, Ernandez T, Li X et al (2011) Regulation of human neutrophil Fcgamma receptor IIa by C5a receptor promotes inflammatory arthritis in mice. Arthritis Rheum 63:467–478PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Kessel C, Nandakumar KS, Peters FB et al (2014) A single functional group substitution in c5a breaks B cell and T cell tolerance and protects against experimental arthritis. Arthritis Rheumatol 66:610–621PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Andersson C, Wenander CS, Usher PA et al (2014) Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model. Clin Exp Immunol 177:219–233PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Dimitrova P, Ivanovska N, Belenska L et al (2012) Abrogated RANKL expression in properdin-deficient mice is associated with better outcome from collagen-antibody-induced arthritis. Arthritis Res Ther 14:R173PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Svensson L, Jirholt J, Holmdahl R, Jansson L (1998) B cell-deficient mice do not develop type II collagen-induced arthritis (CIA). Clin Exp Immunol 111:521–526PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Schellekens GA, de Jong BA, van den Hoogen FH et al (1998) Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. JClinInvest 101:273–281Google Scholar
  103. 103.
    Girbal-Neuhauser E, Durieux JJ, Arnaud M et al (1999) The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro) filaggrin by deimination of arginine residues. J Immunol 162:585–594PubMedGoogle Scholar
  104. 104.
    Clavel C, Ceccato L, Anquetil F, et al (2016) Among human macrophages polarised to different phenotypes, the M-CSF-oriented cells present the highest pro-inflammatory response to the rheumatoid arthritis-specific immune complexes containing ACPA. Ann Rheum Dis 75:2184–2191Google Scholar
  105. 105.
    Harre U, Georgess D, Bang H, et al (2012) Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 122:1791–1802Google Scholar
  106. 106.
    Kidd BA, Ho PP, Sharpe O et al (2008) Epitope spreading to citrullinated antigens in mouse models of autoimmune arthritis and demyelination. Arthritis Res Ther 10:R119PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Kuhn KA, Kulik L, Tomooka B et al (2006) Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 116:961–973PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Uysal H, Bockermann R, Nandakumar KS et al (2009) Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. J Exp Med 206:449–462PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Vossenaar ER, Nijenhuis S, Helsen MM et al (2003) Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 48:2489–2500PubMedCrossRefGoogle Scholar
  110. 110.
    Cantaert T, Teitsma C, Tak PP, Baeten D (2013) Presence and role of anti-citrullinated protein antibodies in experimental arthritis models. Arthritis Rheum 65:939–948PubMedCrossRefGoogle Scholar
  111. 111.
    Duplan V, Foulquier C, Clavel C et al (2006) In the rat, citrullinated autologous fibrinogen is immunogenic but the induced autoimmune response is not arthritogenic. Clin Exp Immunol 145:502–512PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Benham H, Nel HJ, Law SC et al (2015) Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci Transl Med 7:290ra87PubMedCrossRefGoogle Scholar
  113. 113.
    Darrah E, Giles JT, Ols ML et al (2013) Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity. Sci Transl Med 5:186ra65PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Khalifeh MS, Al Rukibat R, Hananeh W et al (2010) Investigation of the role of tumour necrosis factor-{alpha}, interleukin-1{beta}, interleukin-10, nitric oxide and rheumatoid factor-immunoglobulin M in a rat model of arthritis. Lab Anim 44:143–149PubMedCrossRefGoogle Scholar
  115. 115.
    Laurent L, Anquetil F, Clavel C et al (2015) IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies. Ann Rheum Dis 74:1425–1431PubMedCrossRefGoogle Scholar
  116. 116.
    Anquetil F, Clavel C, Offer G et al (2015) IgM and IgA rheumatoid factors purified from rheumatoid arthritis sera boost the Fc receptor- and complement-dependent effector functions of the disease-specific anti-citrullinated protein autoantibodies. J Immunol 194:3664–3674PubMedCrossRefGoogle Scholar
  117. 117.
    Shi J, Knevel R, Suwannalai P et al (2011) Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci U S A 108:17372–17377PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Brink M, Verheul MK, Ronnelid J et al (2015) Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther 17:25PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Stoop JN, Fischer A, Hayer S et al (2015) Anticarbamylated protein antibodies can be detected in animal models of arthritis that require active involvement of the adaptive immune system. Ann Rheum Dis 74:949–950PubMedCrossRefGoogle Scholar
  120. 120.
    Stoop JN, Liu BS, Shi J et al (2014) Antibodies specific for carbamylated proteins precede the onset of clinical symptoms in mice with collagen induced arthritis. PLoS One 9:e102163PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Carter NA, Vasconcellos R, Rosser EC et al (2011) Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol 186:5569–5579PubMedCrossRefGoogle Scholar
  122. 122.
    Daien CI, Gailhac S, Mura T et al (2014) Regulatory B10 cells are decreased in patients with rheumatoid arthritis and are inversely correlated with disease activity. Arthritis Rheumatol 66:2037–2046PubMedCrossRefGoogle Scholar
  123. 123.
    Chu CQ, Londei M (1996) Induction of Th2 cytokines and control of collagen-induced arthritis by nondepleting anti-CD4 Abs. J Immunol Baltim Md 1950 157:2685–2689Google Scholar
  124. 124.
    Goldschmidt TJ, Andersson M, Malmström V, Holmdahl R (1992) Activated type II collagen reactive T cells are not eliminated by in vivo anti-CD4 treatment. Implications for therapeutic approaches on autoimmune arthritis. Immunobiology 184:359–371. doi: 10.1016/S0171-2985(11)80593-0 PubMedCrossRefGoogle Scholar
  125. 125.
    Banerjee S, Webber C, Poole AR (1992) The induction of arthritis in mice by the cartilage proteoglycan aggrecan: roles of CD4+ and CD8+ T cells. Cell Immunol 144:347–357PubMedCrossRefGoogle Scholar
  126. 126.
    Duarte J, Agua-Doce A, Oliveira VG et al (2010) Modulation of IL-17 and Foxp3 expression in the prevention of autoimmune arthritis in mice. PLoS One 5:e10558PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Schubert D, Maier B, Morawietz L et al (2004) Immunization with glucose-6-phosphate isomerase induces T cell-dependent peripheral polyarthritis in genetically unaltered mice. J Immunol Baltim Md 1950 172:4503–4509Google Scholar
  128. 128.
    Van den Broek MF, Van de Langerijt LG, Van Bruggen MC et al (1992) Treatment of rats with monoclonal anti-CD4 induces long-term resistance to streptococcal cell wall-induced arthritis. Eur J Immunol 22:57–61. doi: 10.1002/eji.1830220110 PubMedCrossRefGoogle Scholar
  129. 129.
    Sakaguchi N, Takahashi T, Hata H et al (2003) Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426:454–460PubMedCrossRefGoogle Scholar
  130. 130.
    Kis-Toth K, Radacs M, Olasz K et al (2012) Arthritogenic T cells drive the recovery of autoantibody-producing B cell homeostasis and the adoptive transfer of arthritis in SCID mice. Int Immunol 24:507–517. doi: 10.1093/intimm/dxs057 PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Raphael I, Nalawade S, Eagar TN, Forsthuber TG (2015) T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 74:5–17. doi: 10.1016/j.cyto.2014.09.011 PubMedCrossRefGoogle Scholar
  132. 132.
    Geginat J, Paroni M, Maglie S et al (2014) Plasticity of human CD4 T cell subsets. Front Immunol 5:630. doi: 10.3389/fimmu.2014.00630 PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Boissier MC, Chiocchia G, Bessis N et al (1995) Biphasic effect of interferon-gamma in murine collagen-induced arthritis. Eur J Immunol 25:1184–1190PubMedCrossRefGoogle Scholar
  134. 134.
    Alzabin S, Williams RO (2011) Effector T cells in rheumatoid arthritis: lessons from animal models. FEBS Lett 585:3649–3659. doi: 10.1016/j.febslet.2011.04.034 PubMedCrossRefGoogle Scholar
  135. 135.
    van Hamburg JP, Asmawidjaja PS, Davelaar N et al (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 63:73–83. doi: 10.1002/art.30093 PubMedCrossRefGoogle Scholar
  136. 136.
    Evans HG, Gullick NJ, Kelly S et al (2009) In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses. Proc Natl Acad Sci U S A 106:6232–6237. doi: 10.1073/pnas.0808144106 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Lubberts E, Joosten LA, Oppers B et al (1950) (2001) IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol Baltim Md 167:1004–1013Google Scholar
  138. 138.
    Lubberts E, Koenders MI, Oppers-Walgreen B et al (2004) Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum 50:650–659. doi: 10.1002/art.20001 PubMedCrossRefGoogle Scholar
  139. 139.
    Nakae S, Nambu A, Sudo K, Iwakura Y (2003) Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171:6173–6177PubMedCrossRefGoogle Scholar
  140. 140.
    Nakae S, Saijo S, Horai R et al (2003) IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci U S A 100:5986–5990. doi: 10.1073/pnas.1035999100 PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Koenders MI, Kolls JK, Oppers-Walgreen B et al (2005) Interleukin-17 receptor deficiency results in impaired synovial expression of interleukin-1 and matrix metalloproteinases 3, 9, and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall-induced arthritis. Arthritis Rheum 52:3239–3247. doi: 10.1002/art.21342 PubMedCrossRefGoogle Scholar
  142. 142.
    Jacobs JP, Wu H-J, Benoist C, Mathis D (2009) IL-17-producing T cells can augment autoantibody-induced arthritis. Proc Natl Acad Sci U S A 106:21789–21794. doi: 10.1073/pnas.0912152106 PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Auger JL, Cowan HM, Engelson BJ et al (2016) Brief report: arthritis in KRN T cell receptor-transgenic mice does not require interleukin-17 or Th17 cells. Arthritis Rheumatol Hoboken NJ 68:1849–1855. doi: 10.1002/art.39646 CrossRefGoogle Scholar
  144. 144.
    Doodes PD, Cao Y, Hamel KM et al (2008) Development of proteoglycan-induced arthritis is independent of IL-17. J Immunol Baltim Md 1950 181:329–337Google Scholar
  145. 145.
    Pandya JM, Lundell A-C, Hallström M et al (2016) Circulating T helper and T regulatory subsets in untreated early rheumatoid arthritis and healthy control subjects. J Leukoc Biol 100:823–833. doi: 10.1189/jlb.5A0116-025R PubMedCrossRefGoogle Scholar
  146. 146.
    Lavocat F, Maggi L, Annunziato F, Miossec P (2016) T-cell clones from Th1, Th17 or Th1/17 lineages and their signature cytokines have different capacity to activate endothelial cells or synoviocytes. Cytokine 88:241–250. doi: 10.1016/j.cyto.2016.09.019 PubMedCrossRefGoogle Scholar
  147. 147.
    Murphy CA, Langrish CL, Chen Y et al (2003) Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951–1957PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Yago T, Nanke Y, Kawamoto M et al (2007) IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats. Arthritis Res Ther 9:R96. doi: 10.1186/ar2297 PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Ratsimandresy R, Duvallet E, Assier E et al (2011) Active immunization against IL-23p19 improves experimental arthritis. Vaccine 29:9329–9365PubMedCrossRefGoogle Scholar
  150. 150.
    Cornelissen F, Asmawidjaja PS, Mus AMC et al (2013) IL-23 dependent and independent stages of experimental arthritis: no clinical effect of therapeutic IL-23p19 inhibition in collagen-induced arthritis. PLoS One 8:e57553. doi: 10.1371/journal.pone.0057553 PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Cornelissen F, Mus AM, Asmawidjaja PS et al (2009) Interleukin-23 is critical for full-blown expression of a non-autoimmune destructive arthritis and regulates interleukin-17A and RORgammat in gammadelta T cells. Arthritis Res Ther 11:R194. doi: 10.1186/ar2893 PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Lemos HP, Grespan R, Vieira SM et al (2009) Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNgamma production. Proc Natl Acad Sci U S A 106:5954–5959. doi: 10.1073/pnas.0812782106 PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Fragoulis GE, Siebert S, McInnes IB (2016) Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases. Annu Rev Med 67:337–353. doi: 10.1146/annurev-med-051914-021944 PubMedCrossRefGoogle Scholar
  154. 154.
    Bessis N, Cottard V, Saidenberg-Kermanach’ N et al (2002) Syngeneic fibroblasts transfected with a plasmid encoding interleukin-4 as non-viral vectors for anti-inflammatory gene therapy in collagen-induced arthritis. J Gene Med 4:300–307PubMedCrossRefGoogle Scholar
  155. 155.
    Cottard V, Mulleman D, Bouille P et al (2000) Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis. Gene Ther 7:1930–1939PubMedCrossRefGoogle Scholar
  156. 156.
    Horsfall AC, Butler DM, Marinova L et al (1997) Suppression of collagen-induced arthritis by continuous administration of IL-4. J Immunol 159:5687–5696PubMedGoogle Scholar
  157. 157.
    Joosten LA, Lubberts E, Helsen MM et al (1999) Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis. Arthritis Res 1:81–91. doi: 10.1186/ar14 PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Cao Y, Brombacher F, Tunyogi-Csapo M et al (2007) Interleukin-4 regulates proteoglycan-induced arthritis by specifically suppressing the innate immune response. Arthritis Rheum 56:861–870. doi: 10.1002/art.22422 PubMedCrossRefGoogle Scholar
  159. 159.
    Yoshino S (1998) Effect of a monoclonal antibody against interleukin-4 on collagen-induced arthritis in mice. Br J Pharmacol 123:237–242. doi: 10.1038/sj.bjp.0701607 PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Ohmura K, Nguyen LT, Locksley RM et al (2005) Interleukin-4 can be a key positive regulator of inflammatory arthritis. Arthritis Rheum 52:1866–1875. doi: 10.1002/art.21104 PubMedCrossRefGoogle Scholar
  161. 161.
    van Roon JAG, Bijlsma JWJ (2002) Th2 mediated regulation in RA and the spondyloarthropathies. Ann Rheum Dis 61:951–954PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Rasmussen TK (2016) Follicular T helper cells and IL-21 in rheumatic diseases. Dan Med J 63Google Scholar
  163. 163.
    Sakuraba K, Oyamada A, Fujimura K et al (2016) Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice. Arthritis Res Ther 18:188. doi: 10.1186/s13075-016-1086-y PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Sakaguchi S, Sakaguchi N, Asano M et al (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMedGoogle Scholar
  165. 165.
    Buckner JH (2010) Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol 10:849–859. doi: 10.1038/nri2889 PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Mottonen M, Heikkinen J, Mustonen L et al (2005) CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 140:360–367PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Sarkar S, Fox DA (2007) Regulatory T cell defects in rheumatoid arthritis. Arthritis Rheum 56:710–713. doi: 10.1002/art.22415 PubMedCrossRefGoogle Scholar
  168. 168.
    Ehrenstein MR, Evans JG, Singh A et al (2004) Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 200:277–285PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Rapetti L, Chavele K-M, Evans CM, Ehrenstein MR (2015) B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis. Ann Rheum Dis 74:294–302. doi: 10.1136/annrheumdis-2013-204049 PubMedCrossRefGoogle Scholar
  170. 170.
    Morgan ME, Flierman R, van Duivenvoorde LM et al (2005) Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 52:2212–2221PubMedCrossRefGoogle Scholar
  171. 171.
    Frey O, Reichel A, Bonhagen K et al (2010) Regulatory T cells control the transition from acute into chronic inflammation in glucose-6-phosphate isomerase-induced arthritis. Ann Rheum Dis 69:1511–1518. doi: 10.1136/ard.2009.123422 PubMedCrossRefGoogle Scholar
  172. 172.
    Frey O, Petrow PK, Gajda M et al (2005) The role of regulatory T cells in antigen-induced arthritis: aggravation of arthritis after depletion and amelioration after transfer of CD4+CD25+ T cells. Arthritis Res Ther 7:R291–R301. doi: 10.1186/ar1484 PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Biton J, Semerano L, Delavallee L et al (2011) Interplay between TNF and regulatory T cells in a TNF-driven murine model of arthritis. J Immunol 186:3899–3910PubMedCrossRefGoogle Scholar
  174. 174.
    Nadkarni S, Mauri C, Ehrenstein MR (2007) Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 204:33–39PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Nguyen DX, Ehrenstein MR (2016) Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis. J Exp Med 213:1241–1253. doi: 10.1084/jem.20151255 PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Thiolat A, Semerano L, Pers YM et al (2014) Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheumatol Hoboken NJ 66:273–283. doi: 10.1002/art.38246 CrossRefGoogle Scholar
  177. 177.
    Barbi J, Pardoll D, Pan F (2014) Treg functional stability and its responsiveness to the microenvironment. Immunol Rev 259:115–139. doi: 10.1111/imr.12172 PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Zheng SG, Wang J, Horwitz DA (2008) Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol Baltim Md 1950 180:7112–7116Google Scholar
  179. 179.
    Lal G, Zhang N, van der Touw W et al (2009) Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol Baltim Md 1950 182:259–273Google Scholar
  180. 180.
    Semerano L, Clavel G, Assier E et al (2011) Blood vessels, a potential therapeutic target in rheumatoid arthritis? Jt Bone Spine Rev Rhum 78:118–123. doi: 10.1016/j.jbspin.2010.06.004 CrossRefGoogle Scholar
  181. 181.
    Clavel G, Valvason C, Yamaoka K et al (2006) Relationship between angiogenesis and inflammation in experimental arthritis. Eur Cytokine Netw 17:202–210PubMedGoogle Scholar
  182. 182.
    Jain A, Nanchahal J, Troeberg L et al (2001) Production of cytokines, vascular endothelial growth factor, matrix metalloproteinases, and tissue inhibitor of metalloproteinases 1 by tenosynovium demonstrates its potential for tendon destruction in rheumatoid arthritis. Arthritis Rheum 44:1754–1760. doi: 10.1002/1529-0131(200108)44:8<1754::AID-ART310>3.0.CO;2-8 PubMedCrossRefGoogle Scholar
  183. 183.
    Ballara S, Taylor PC, Reusch P et al (2001) Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum 44:2055–2064. doi: 10.1002/1529-0131(200109)44:9<2055::AID-ART355>3.0.CO;2-2 PubMedCrossRefGoogle Scholar
  184. 184.
    Lu J, Kasama T, Kobayashi K et al (2000) Vascular endothelial growth factor expression and regulation of murine collagen-induced arthritis. J Immunol Baltim Md 1950 164:5922–5927Google Scholar
  185. 185.
    Semerano L, Duvallet E, Belmellat N et al (2016) Targeting VEGF-A with a vaccine decreases inflammation and joint destruction in experimental arthritis. Angiogenesis 19:39–52. doi: 10.1007/s10456-015-9487-0 PubMedCrossRefGoogle Scholar
  186. 186.
    Hu F, Mu R, Zhu J et al (2014) Hypoxia and hypoxia-inducible factor-1α provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis. Ann Rheum Dis 73:928–936. doi: 10.1136/annrheumdis-2012-202444 PubMedCrossRefGoogle Scholar
  187. 187.
    Cramer T, Yamanishi Y, Clausen BE et al (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Lee DM, Phillips R, Hagan EM et al (2009) Quantifying anti-cyclic citrullinated peptide titres: clinical utility and association with tobacco exposure in patients with rheumatoid arthritis. Ann Rheum Dis 68:201–208. doi: 10.1136/ard.2007.084509 PubMedCrossRefGoogle Scholar
  189. 189.
    Sugiyama D, Nishimura K, Tamaki K et al (2010) Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 69:70–81. doi: 10.1136/ard.2008.096487 PubMedCrossRefGoogle Scholar
  190. 190.
    Karlson EW, Chang S-C, Cui J et al (2010) Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Ann Rheum Dis 69:54–60. doi: 10.1136/ard.2008.102962 PubMedCrossRefGoogle Scholar
  191. 191.
    Vessey MP, Villard-Mackintosh L, Yeates D (1987) Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception 35:457–464PubMedCrossRefGoogle Scholar
  192. 192.
    Vassallo R, Luckey D, Behrens M et al (2014) Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes. Clin Immunol Orlando Fla 152:25–35. doi: 10.1016/j.clim.2014.02.002 CrossRefGoogle Scholar
  193. 193.
    Okamoto S, Adachi M, Chujo S et al (2011) Etiological role of cigarette smoking in rheumatoid arthritis: nasal exposure to cigarette smoke condensate extracts augments the development of collagen-induced arthritis in mice. Biochem Biophys Res Commun 404:1088–1092. doi: 10.1016/j.bbrc.2010.12.118 PubMedCrossRefGoogle Scholar
  194. 194.
    Allais L, Kumar S, Debusschere K et al (2015) The effect of cigarette smoke exposure on the development of inflammation in lungs, gut and joints of TNFΔARE mice. PLoS One 10:e0141570. doi: 10.1371/journal.pone.0141570 PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Vaahtovuo J, Munukka E, Korkeamäki M et al (2008) Fecal microbiota in early rheumatoid arthritis. J Rheumatol 35:1500–1505PubMedGoogle Scholar
  196. 196.
    Liu X, Zou Q, Zeng B et al (2013) Analysis of fecal Lactobacillus community structure in patients with early rheumatoid arthritis. Curr Microbiol 67:170–176. doi: 10.1007/s00284-013-0338-1 PubMedCrossRefGoogle Scholar
  197. 197.
    Chen J, Wright K, Davis JM et al (2016) An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med 8:43. doi: 10.1186/s13073-016-0299-7 PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Zhang X, Zhang D, Jia H et al (2015) The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 21:895–905. doi: 10.1038/nm.3914 PubMedCrossRefGoogle Scholar
  199. 199.
    Maeda Y, Kurakawa T, Umemoto E et al (2016) Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol Hoboken NJ 68:2646–2661. doi: 10.1002/art.39783 CrossRefGoogle Scholar
  200. 200.
    Teng F, Klinger CN, Felix KM et al (2016) Gut microbiota drive autoimmune arthritis by promoting differentiation and migration of Peyer’s patch T follicular helper cells. Immunity 44:875–888. doi: 10.1016/j.immuni.2016.03.013 PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Wu H-J, Ivanov II, Darce J et al (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32:815–827. doi: 10.1016/j.immuni.2010.06.001 PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Williams RO, Feldmann M, Maini RN (1992) Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U A 89:9784–9788CrossRefGoogle Scholar
  203. 203.
    Keffer J, Probert L, Cazlaris H et al (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 10:4025–4031PubMedPubMedCentralGoogle Scholar
  204. 204.
    Feldmann M, Maini RN (2010) Anti-TNF therapy, from rationale to standard of care: what lessons has it taught us? J Immunol Baltim Md 1950 185:791–794. doi: 10.4049/jimmunol.1090051 Google Scholar
  205. 205.
    Biton J, Boissier MC, Bessis N (2011) TNFalpha: activator or inhibitor of regulatory T cells? Joint Bone Spine 79:119–123PubMedCrossRefGoogle Scholar
  206. 206.
    Le Buanec H, Delavallee L, Bessis N et al (2006) TNFalpha kinoid vaccination-induced neutralizing antibodies to TNFalpha protect mice from autologous TNFalpha-driven chronic and acute inflammation. Proc Natl Acad Sci U A 103:19442–19447CrossRefGoogle Scholar
  207. 207.
    Peres RS, Liew FY, Talbot J et al (2015) Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis. Proc Natl Acad Sci U S A 112:2509–2514. doi: 10.1073/pnas.1424792112 PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Hammaker D, Firestein GS (2010) “Go upstream, young man”: lessons learned from the p38 saga. Ann Rheum Dis 69(Suppl 1):i77–i82. doi: 10.1136/ard.2009.119479 PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Semerano L, Decker P, Clavel G, Boissier M-C (2016) Developments with investigational Janus kinase inhibitors for rheumatoid arthritis. Expert Opin Investig Drugs 25:1355–1359. doi: 10.1080/13543784.2016.1249565 PubMedCrossRefGoogle Scholar
  210. 210.
    Brühl H, Cihak J, Talke Y et al (2015) B-cell inhibition by cross-linking CD79b is superior to B-cell depletion with anti-CD20 antibodies in treating murine collagen-induced arthritis. Eur J Immunol 45:705–715. doi: 10.1002/eji.201444971 PubMedCrossRefGoogle Scholar
  211. 211.
    Courtenay JS, Dallman MJ, Dayan AD et al (1980) Immunisation against heterologous type II collagen induces arthrtis in mice. Nature 283:666–668PubMedCrossRefGoogle Scholar
  212. 212.
    Campbell IK, Hamilton JA, Wicks IP (2000) Collagen-induced arthritis in C57BL/6 (H-2b) mice: new insights into an important disease model of rheumatoid arthritis. Eur J Immunol 30:1568–1575PubMedCrossRefGoogle Scholar
  213. 213.
    Wieschowski S, Silva DS, Strech D (2016) Animal study registries: results from a stakeholder analysis on potential strengths, weaknesses, facilitators, and barriers. PLoS Biol 14:e2000391. doi: 10.1371/journal.pbio.2000391 PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Hawkins P, Armstrong R, Boden T et al (2015) Applying refinement to the use of mice and rats in rheumatoid arthritis research. Inflammopharmacology 23:131–150. doi: 10.1007/s10787-015-0241-4 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Natacha Bessis
    • 1
  • Patrice Decker
    • 1
  • Eric Assier
    • 1
  • Luca Semerano
    • 1
    • 2
  • Marie-Christophe Boissier
    • 1
    • 2
  1. 1.INSERM UMR 1125 Sorbonne Paris Cité, Université Paris 13BobignyFrance
  2. 2.Service de Rhumatologie, Hôpital AvicenneAssistance Publique-Hôpitaux de Paris (APHP)BobignyFrance

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