Skip to main content

Advertisement

SpringerLink
Log in

Cellular and molecular perspectives in rheumatoid arthritis

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Synovial immunopathology in rheumatoid arthritis is complex involving both resident and infiltrating cells. The synovial tissue undergoes significant neovascularization, facilitating an influx of lymphocytes and monocytes that transform a typically acellular loose areolar membrane into an invasive tumour-like pannus. The microvasculature proliferates to form straight regularly-branching vessels; however, they are highly dysfunctional resulting in reduced oxygen supply and a hypoxic microenvironment. Autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies are found at an early stage, often before arthritis has developed, and they have been implicated in the pathogenesis of RA. Abnormal cellular metabolism and mitochondrial dysfunction thus ensue and, in turn, through the increased production of reactive oxygen species actively induce inflammation. Key pro-inflammatory cytokines, chemokines and growth factors and their signalling pathways, including nuclear factor κB, Janus kinase-signal transducer, are highly activated when immune cells are exposed to hypoxia in the inflamed rheumatoid joint show adaptive survival reactions by activating. This review attempts to highlight those aberrations in the innate and adaptive immune systems including the role of genetic and environmental factors, autoantibodies, cellular alterations, signalling pathways and metabolism that are implicated in the pathogenesis of RA and may therefore provide an opportunity for therapeutic intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442

    Article  CAS  PubMed  Google Scholar 

  2. van der Heijde DM (1995) Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol 34:74–78

    Article  PubMed  Google Scholar 

  3. Orr C et al (2017) Synovial immunophenotype and anti-citrullinated protein antibodies in rheumatoid arthritis patients: relationship to treatment response and radiological prognosis. Ann Rheum Dis

  4. Gerlag DM et al (2012) EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the study group for risk factors for rheumatoid arthritis. Ann Rheum Dis 71:638–641

    Article  PubMed  PubMed Central  Google Scholar 

  5. van de Sande MG et al (2011) Different stages of rheumatoid arthritis: features of the synovium in the preclinical phase. Ann Rheum Dis 70:772–777

    Article  PubMed  Google Scholar 

  6. Nielen MMJ et al (2004) Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 50:380–386. doi:10.1002/art.20018

    Article  PubMed  Google Scholar 

  7. Rantapaa-Dahlqvist S et al (2003) Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749

    Article  PubMed  CAS  Google Scholar 

  8. de Hair MJ et al (2014) Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis. Arthritis Rheumatol 66:513–522. doi:10.1002/art.38273

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Bos WH et al (2010) Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheum Dis 69:490–494

    Article  CAS  PubMed  Google Scholar 

  10. van der Heide A et al (1996) The effectiveness of early treatment with “second-line” antirheumatic drugs. A randomized, controlled trial. Ann Intern Med 124:699–707

    Article  PubMed  Google Scholar 

  11. Lard LR et al (2001) Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med 111:446–451

    Article  CAS  PubMed  Google Scholar 

  12. Nell VPK et al (2004) Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology 43:906–914

    Article  CAS  PubMed  Google Scholar 

  13. Smolen JS et al (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheumatic Dis 69:964–975

    Article  CAS  Google Scholar 

  14. Baeten D et al (2000) Comparative study of the synovial histology in rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: influence of disease duration and activity. Ann Rheum Dis 59:945–953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tak PP et al (1995) Expression of adhesion molecules in early rheumatoid synovial tissue. Clin Immunol Immunopathol 77:236–242

    Article  CAS  PubMed  Google Scholar 

  16. Smeets TJ et al (1998) Poor expression of T cell-derived cytokines and activation and proliferation markers in early rheumatoid synovial tissue. Clin Immunol Immunopathol 88:84–90

    Article  CAS  PubMed  Google Scholar 

  17. Yeo L et al (2016) Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis. Ann Rheum Dis 75:763–771

    Article  CAS  PubMed  Google Scholar 

  18. Klarenbeek PL et al (2012) Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease. Ann Rheum Dis 71:1088–1093

    Article  CAS  PubMed  Google Scholar 

  19. Raza K et al (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:R784–R795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hurd ER (1979) Extraarticular manifestations of rheumatoid arthritis. Semin Arthritis Rheum 8:151–176

    Article  CAS  PubMed  Google Scholar 

  21. Cimmino MA et al (2000) Extra-articular manifestations in 587 Italian patients with rheumatoid arthritis. Rheumatol Int 19:213–217

    Article  CAS  PubMed  Google Scholar 

  22. Sugiyama D 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

    Article  CAS  PubMed  Google Scholar 

  23. Stolt P et al (2003) Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis 62:835–841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Di Giuseppe D et al (2014) Cigarette smoking and risk of rheumatoid arthritis: a dose-response meta-analysis. Arthritis Res Ther 16:R61

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Padyukov L et al (2004) A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum 50:3085–3092

    Article  CAS  PubMed  Google Scholar 

  26. Klareskog L et al (2006) Mechanisms of disease: genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat Clin Pract Rheumatol 2:425–433

    Article  CAS  PubMed  Google Scholar 

  27. Lu B et al (2014) Associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis. J Rheumatol 41:24–30

    Article  CAS  PubMed  Google Scholar 

  28. Saag KG et al (1997) Cigarette smoking and rheumatoid arthritis severity. Ann Rheum Dis 56:463–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Masdottir B et al (2000) Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis. Rheumatology (Oxford) 39:1202–1205

    Article  CAS  Google Scholar 

  30. Tedeschi SK, Costenbader KH (2016) Is there a role for diet in the therapy of rheumatoid arthritis? Curr Rheumatol Rep 18:23

    Article  PubMed  CAS  Google Scholar 

  31. Naranjo A et al (2008) Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study. Arthritis Res Ther 10:R30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Armstrong DJ et al (2006) Obesity and cardiovascular risk factors in rheumatoid arthritis. Rheumatology (Oxford) 45:782

    Article  CAS  Google Scholar 

  33. Maxwell JR et al (2010) Alcohol consumption is inversely associated with risk and severity of rheumatoid arthritis. Rheumatology (Oxford) 49:2140–2146

    Article  CAS  Google Scholar 

  34. Källberg H et al (2009) Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case-control studies. Ann Rheumatic Dis 68:222–227

    Article  Google Scholar 

  35. Scott IC et al (2013) The protective effect of alcohol on developing rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology (Oxford) 52:856–867

    Article  CAS  Google Scholar 

  36. Jonsson IM et al (2007) Ethanol prevents development of destructive arthritis. Proc Natl Acad Sci U S A 104:258–263

    Article  CAS  PubMed  Google Scholar 

  37. Krco CJ et al (1996) Characterization of the antigenic structure of human type II collagen. J Immunol 156:2761–2768

    CAS  PubMed  Google Scholar 

  38. Auger I, Roudier J (1997) A function for the QKRAA amino acid motif: mediating binding of DnaJ to DnaK. Implications for the association of rheumatoid arthritis with HLA-DR4. J Clin Invest 99:1818–1822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wegner N et al (2010) Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum 62:2662–2672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kouri T et al (1990) Antibodies to synthetic peptides from Epstein-Barr nuclear antigen-1 in sera of patients with early rheumatoid arthritis and in preillness sera. J Rheumatol 17:1442–1449

    CAS  PubMed  Google Scholar 

  41. Blaschke S et al (2000) Epstein-Barr virus infection in peripheral blood mononuclear cells, synovial fluid cells, and synovial membranes of patients with rheumatoid arthritis. J Rheumatol 27:866–873

    CAS  PubMed  Google Scholar 

  42. Ebringer A et al (1985) Antibodies to proteus in rheumatoid arthritis. Lancet 2:305–307

    Article  CAS  PubMed  Google Scholar 

  43. Ray NB et al (2001) Induction of an invasive phenotype by human parvovirus B19 in normal human synovial fibroblasts. Arthritis Rheum 44:1582–1586

    Article  CAS  PubMed  Google Scholar 

  44. Kanagawa H et al (2015) Mycobacterium tuberculosis promotes arthritis development through Toll-like receptor 2. J Bone Miner Metab 33:135–141

    Article  CAS  PubMed  Google Scholar 

  45. Forslind K et al (2007) Sex: a major predictor of remission in early rheumatoid arthritis? Ann Rheum Dis 66:46–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cutolo M et al (2000) The hypothalamic-pituitary-adrenocortical and gonadal axis function in rheumatoid arthritis. Z Rheumatol 59:II/65–II/69

    Article  CAS  Google Scholar 

  47. Cutolo M et al (2006) Estrogens and autoimmune diseases. Ann N Y Acad Sci 1089:538–547

    Article  CAS  PubMed  Google Scholar 

  48. Gordon D et al (1988) Prolonged hypogonadism in male patients with rheumatoid arthritis during flares in disease activity. Br J Rheumatol 27:440–444

    Article  CAS  PubMed  Google Scholar 

  49. Auci D et al (2007) A new orally bioavailable syntheic androstene inhibits collagen-induced arthritis in the mouse. Ann N Y Acad Sci 1110:630–640

    Article  CAS  PubMed  Google Scholar 

  50. Röntzsch A et al (2004) Amelioration of murine antigen-induced arthritis by dehydroepiandrosterone (DHEA). Inflamm Research 53:189–198

    Article  CAS  Google Scholar 

  51. Hassfeld W et al (1989) Demonstration of a new antinuclear antibody (anti-RA33) that is highly specific for rheumatoid arthritis. Arthritis Rheum 32:1515–1520

    Article  CAS  PubMed  Google Scholar 

  52. Skriner K et al (1997) Anti-A2 / RA33 autoantibodies are directed to the RNA binding region of the A2 protein of the heterogeneous nuclear ribonucleoprotein complex. J Clin Invest 100:127–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shi J et al (2011) Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Nat Acad Sci USA 108:17372–17377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schellekens GA et al (2000) The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43:155–163

    Article  CAS  PubMed  Google Scholar 

  55. Rantapää-Dahlqvist S et al (2003) Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749

    Article  PubMed  CAS  Google Scholar 

  56. Mjaavatten MD et al (2009) Positive anti-citrullinated protein antibody status and small joint arthritis are consistent predictors of chronic disease in patients with very early arthritis: results from the NOR-VEAC cohort. Arthritis Res Ther 11:R146. doi:10.1186/ar2820. 63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Machold KP et al (2007) Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology (Oxford) 46:342–349

    Article  CAS  Google Scholar 

  58. van der Helm-van Mil AH et al (2005) Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther 7:R949–R958

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Jansen LM et al (2003) The predictive value of anti-cyclic citrullinated peptide antibodies in early arthritis. J Rheumatol 30:1691–1695

    CAS  PubMed  Google Scholar 

  60. Kroot EJ et al (2000) The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 43:1831–1835

    Article  CAS  PubMed  Google Scholar 

  61. Syversen SW et al (2008) High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann Rheum Dis 67:212–217

    Article  CAS  PubMed  Google Scholar 

  62. Aubart F et al (2011) High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J Rheumatol 38:979–982

    Article  CAS  PubMed  Google Scholar 

  63. Nordberg LB et al (2017) Patients with seronegative RA have more inflammatory activity compared with patients with seropositive RA in an inception cohort of DMARD-naive patients classified according to the 2010 ACR/EULAR criteria. Ann Rheum Dis 76:341–345

    Article  PubMed  Google Scholar 

  64. Waaler E (2007) On the occurrence of a factor in human serum activating the specific agglutintion of sheep blood corpuscles. 1939. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 115:422–438

    Article  PubMed  Google Scholar 

  65. Masi AT (1976) Prospective study of the early course of rheumatoid arthritis in young adults:comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome. Semin Arthritis Rheum 4:299–326

    Article  CAS  PubMed  Google Scholar 

  66. Shiel WC Jr, Jason M (1989) The diagnostic associations of patients with antinuclear antibodies referred to a community rheumatologist. J Rheumatol 16:782–785

    PubMed  Google Scholar 

  67. Slater CA et al (1996) Antinuclear antibody testing. A study of clinical utility. Arch Intern Med 156:1421–1425

    Article  CAS  PubMed  Google Scholar 

  68. Smith MD et al (2003) Microarchitecture and protective mechanisms in synovial tissue from clinically and arthroscopically normal knee joints. Ann Rheum Dis 62:303–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Firestein GS, Veale DJ (2016) Synovium. In: Kelley and Firestein’s (ed) Textbook of rheumatology, 10th edn. Elsevier Health Sciences

  70. Rhee DK et al (2005) The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth. J Clin Invest 115:622–631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hyc A et al (2009) Pro-and anti-inflammatory cytokines increase hyaluronan production by rat synovial membrane in vitro. Int J Mol Med 24(4):579

    CAS  PubMed  Google Scholar 

  72. Blewis ME et al (2009) Interactive cytokine regulation of synoviocyte lubricant secretion. Tissue Eng Part A 16:1329–1337

    Article  PubMed Central  Google Scholar 

  73. Cretu D et al (2013) Delineating the synovial fluid proteome: recent advancements and ongoing challenges in biomarker research. Crit Rev Clin Lab Sci 50:51–63

    Article  CAS  PubMed  Google Scholar 

  74. Oliver KM et al (2009) Hypoxia activates NF-kappaB-dependent gene expression through the canonical signaling pathway. Antioxid Redox Signal 11:2057–2064

    Article  CAS  PubMed  Google Scholar 

  75. Gao W et al (2015) Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis. Ann Rheum Dis 74:1275–1283

    Article  CAS  PubMed  Google Scholar 

  76. Tchetverikov I et al (2005) MMP protein and activity levels in synovial fluid from patients with joint injury, inflammatory arthritis, and osteoarthritis. Ann Rheum Dis 64:694–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Fearon U et al (1999) Synovial cytokine and growth factor regulation of MMPs/TIMPs: implications for erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients. Ann N Y Acad Sci 30:619–621

    Article  Google Scholar 

  78. Tak PP et al (1997) Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 40:217–225

    Article  CAS  PubMed  Google Scholar 

  79. Smith MD et al (2006) Standardisation of synovial tissue infiltrate analysis: how far have we come? How much further do we need to go? Ann Rheum Dis 65:93–100

    Article  CAS  PubMed  Google Scholar 

  80. Kennedy A et al (2010) Angiogenesis and blood vessel stability in inflammatory arthritis. Arthritis Rheum 62:711–721

    Article  CAS  PubMed  Google Scholar 

  81. Epstein FH, Harris ED Jr (1990) Rheumatoid arthritis: pathophysiology and implications for therapy. New Eng J Med 322:1277–1289

    Article  Google Scholar 

  82. Månsson B et al (1995) Cartilage and bone metabolism in rheumatoid arthritis. Differences between rapid and slow progression of disease identified by serum markers of cartilage metabolism. J Clin Invest 95:1071–1077

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ng CT et al (2010) Synovial tissue hypoxia and inflammation in vivo. Ann Rheum Dis 69:1389–1395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fearon U et al (2003) Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol 30:260–268

    CAS  PubMed  Google Scholar 

  85. Fraser A et al (2001) Matrix metalloproteinase 9, apoptosis, and vascular morphology in early arthritis. Arthritis Rheum 44:2024–2028

    Article  CAS  PubMed  Google Scholar 

  86. García S et al (2014) Tie2 signaling cooperates with TNF to promote the pro-inflammatory activation of human macrophages independently of macrophage functional phenotype. PLoS One 9(1):e82088. doi:10.1371/journal.pone.0082088

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Krausz S et al (2012) Angiopoietin-2 promotes inflammatory activation of human macrophages. Ann Rheum Dis 71:1402–1410

    Article  CAS  PubMed  Google Scholar 

  88. Fearon U et al (2016) Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat Rev Rheumatol 12:385–397

    Article  CAS  PubMed  Google Scholar 

  89. Levick JR (1981) Permeability of rheumatoid and normal human synovium to specific plasma proteins. Arthritis Rheum 24:1550–1560

    Article  CAS  PubMed  Google Scholar 

  90. Dahl LB et al (1985) Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies. Ann Rheum Dis 44:817–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hui AY et al (2012) A systems biology approach to synovial joint lubrication in health, injury, and disease. Wiley Interdiscip Rev Syst Biol Med 4:15–37

    Article  CAS  PubMed  Google Scholar 

  92. Reece RJ et al (1999) Distinct vascular patterns of early synovitis in psoriatic, reactive, and rheumatoid arthritis. Arthritis & Rheumatism 42(7):1481–1484

    Article  CAS  Google Scholar 

  93. Izquierdo E et al (2009) Immature blood vessels in rheumatoid synovium are selectively depleted in response to anti-TNF therapy. PLoS One 4(12):e8131. doi:10.1371/journal.pone.0008131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Dennis G Jr et al (2014) Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Arthritis Res Ther 16(2):R90

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Mulherin D et al (1996) Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 39:115–124

    Article  CAS  PubMed  Google Scholar 

  96. Smolen JS, Steiner G (2003) Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Dis 2:473–488

    Article  CAS  Google Scholar 

  97. Haringman JJ et al (2005) Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 64:834–838

    Article  CAS  PubMed  Google Scholar 

  98. Bresnihan B et al (2009) Synovial tissue sublining CD68 expression is a biomarker of therapeutic response in rheumatoid arthritis clinical trials: consistency across centers. J Rheumatol 36:1800–1802

    Article  PubMed  Google Scholar 

  99. Szekanecz Z, Koch AE (2007) Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol 19:289–295

    Article  PubMed  Google Scholar 

  100. McInnes IB et al (2000) Cell-cell interactions in synovitis. Interactions between T lymphocytes and synovial cells. Arthritis Res 2:374–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Burger D, Dayer J-M (2002) The role of human T-lymphocyte-monocyte contact in inflammation and tissue destruction. Arthritis Res 4(Suppl 3):S169–S176

    Article  PubMed  PubMed Central  Google Scholar 

  102. Soler Palacios B et al (2015) Macrophages from the synovium of active rheumatoid arthritis exhibit an activin A-dependent pro-inflammatory profile. J Pathol 235:515–526

    Article  CAS  PubMed  Google Scholar 

  103. Strehl C et al (2014) Hypoxia: how does the monocyte-macrophage system respond to changes in oxygen availability? J Leukoc Biol 95:233–241. doi:10.1189/jlb.1212627

    Article  PubMed  CAS  Google Scholar 

  104. Iguchi T, Ziff M (1986) Electron microscopic study of rheumatoid synovial vasculature. Intimate relationship between tall endothelium and lymphoid aggregation. J Clin Invest 77:355–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cañete JD et al (2009) Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis 68:751–756

    Article  PubMed  CAS  Google Scholar 

  106. Klimiuk PA et al (2003) Circulating tumour necrosis factor alpha and soluble tumour necrosis factor receptors in patients with different patterns of rheumatoid synovitis. Ann Rheum Dis 62:472–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Miossec P et al (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361:888–898

    Article  CAS  PubMed  Google Scholar 

  108. Lubberts E et al (2005) The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther 7:29–37

    Article  CAS  PubMed  Google Scholar 

  109. Basdeo SA et al (2015) Polyfunctional, pathogenic CD161+ Th17 lineage cells are resistant to regulatory T cell-mediated suppression in the context of autoimmunity. J Immunol 195:528–540

    Article  CAS  PubMed  Google Scholar 

  110. Choy EH et al (1996) Percentage of anti-CD4 monoclonal antibody-coated lymphocytes in the rheumatoid joint is associated with clinical improvement. Implications for the development of immunotherapeutic dosing regimens. Arthritis Rheum 39:52–56

    Article  CAS  PubMed  Google Scholar 

  111. Veale DJ et al (1999) Intra-articular primatised anti-CD4: efficacy in resistant rheumatoid knees. A study of combined arthroscopy, magnetic resonance imaging, and histology. Ann Rheum Dis 58:342–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mason U et al (2002) CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis. J Rheumatol 29:220–229

    CAS  PubMed  Google Scholar 

  113. Rao DA et al (2017) Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542:110–114

    Article  CAS  PubMed  Google Scholar 

  114. Porter D et al (2016) Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial. Lancet 388:239–247

    Article  CAS  PubMed  Google Scholar 

  115. Teng YK et al (2007) Immunohistochemical analysis as a means to predict responsiveness to rituximab treatment. Arthritis Rheum 56:3909–3918

    Article  CAS  PubMed  Google Scholar 

  116. Humby F et al (2009) Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med 6(1):e1. doi:10.1371/journal.pmed.0060001

    Article  PubMed  PubMed Central  Google Scholar 

  117. Amara K et al (2013) Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J Exp Med 210:445–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bugatti S et al (2014) High expression levels of the B cell chemoattractant CXCL13 in rheumatoid synovium are a marker of severe disease. Rheumatology (Oxford) 53:1886–1895

    Article  CAS  Google Scholar 

  119. Rombouts Y et al (2016) Extensive glycosylation of ACPA-IgG variable domains modulates binding to citrullinated antigens in rheumatoid arthritis. Ann Rheum Dis 75:578–585

    Article  CAS  PubMed  Google Scholar 

  120. Fassbender HG, Simmling-Annefeld M (1983) The potential aggressiveness of synovial tissue in rheumatoid arthritis. J Pathol 139:399–406

    Article  CAS  PubMed  Google Scholar 

  121. Mor A et al (2005) The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol 115:118–128

    Article  CAS  PubMed  Google Scholar 

  122. Korb A et al (2009) Cell death in rheumatoid arthritis. Apoptosis 14:447–454. doi:10.1007/s10495-009-0317-y

    Article  PubMed  Google Scholar 

  123. Seemayer CA et al (2003) Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in rheumatoid arthritis. Am J Pathol 162:1549–1557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Vallejo AN et al (2003) Synoviocyte-mediated expansion of inflammatory T cells in rheumatoid synovitis is dependent on CD47-thrombospondin 1 interaction. J Immunol 171:1732–1740

    Article  CAS  PubMed  Google Scholar 

  125. Abeles AM, Pillinger MH (2006) The role of the synovial fibroblast in rheumatoid arthritis: cartilage destruction and the regulation of matrix metalloproteinases. Bull NYU Hosp Jt Dis 64:20–24

    PubMed  Google Scholar 

  126. Burmester GR et al (1997) Mononuclear phagocytes and rheumatoid synovitis. Mastermind or workhorse in arthritis? Arthritis Rheum 40:5–18

    Article  CAS  PubMed  Google Scholar 

  127. Tolboom TCA et al (2005) Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis. Arthritis Rheum 52:1999–2002

    Article  PubMed  Google Scholar 

  128. Darnell JE et al (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421

    Article  CAS  PubMed  Google Scholar 

  129. Leonard WJ, O'Shea JJ (1998) Jaks and STATs: biological implications. Annu Rev Immunol 16:293–322

    Article  CAS  PubMed  Google Scholar 

  130. Ghoreschi K et al (2011) Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol 186:4234–4243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Burmester GR (2013) Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 381:451–460

    Article  CAS  PubMed  Google Scholar 

  132. van der Heijde D et al (2013) Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum 65:559–570

    Article  PubMed  CAS  Google Scholar 

  133. Lee YH et al (2015) Comparative efficacy and safety of tofacitinib, with or without methotrexate, in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Rheumatol Int 35:1965–1974

    Article  CAS  PubMed  Google Scholar 

  134. Boyle DL et al (2015) The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis 74:1311–1316

    Article  CAS  PubMed  Google Scholar 

  135. Distler JHW et al (2004) Physiologic responses to hypoxia and implications for hypoxia-inducible factors in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 50:10–23

    Article  CAS  PubMed  Google Scholar 

  136. Harty LC et al (2012) Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis. Ann Rheum Dis 71(4):582–588

    Article  CAS  PubMed  Google Scholar 

  137. Chang X, Wei C (2011) Glycolysis and rheumatoid arthritis. Int J Rheum Dis 14:217–222. doi:10.1111/j.1756-185X.2011.01598.x

    Article  PubMed  Google Scholar 

  138. Henderson B et al (1979) Glycolytic activity in human synovial lining cells in rheumatoid arthritis. Ann Rheum Dis 38:63–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Biniecka M et al (2016) Dysregulated bioenergetics: a key regulator of joint inflammation. Ann Rheum Dis 75:2192–2200. doi:10.1136/annrheumdis-2015-208476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Frantz MC, Wipf P (2010) Mitochondria as a target in treatment. Environ Mol Mutagen 51:462–475

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Zapico SC, Ubelaker DH (2013) mtDNA mutations and their role in aging, diseases and forensic sciences. Aging Dis 4:364–380

    Article  PubMed  PubMed Central  Google Scholar 

  142. Poli G et al (2008) 4-hydroxynonenal: a membrane lipid oxidation product of medicinal interest. Med Res Rev 28:569–631

    Article  CAS  PubMed  Google Scholar 

  143. Taylor RW, Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6:389–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ospelt C, Gay S (2005) Somatic mutations in mitochondria: the chicken or the egg? Arthritis Res Ther 7:179–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Biniecka M et al (2011) Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis. Arthritis Rheum 63:2172–2182

    Article  CAS  PubMed  Google Scholar 

  146. Biniecka M et al (2010) Oxidative damage in synovial tissue is associated with in vivo hypoxic status in the arthritic joint. Ann Rheum Dis 69:1172–1178

    Article  PubMed  Google Scholar 

  147. Tannahill GM et al (2013) Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496:238–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Biniecka M et al (2014) Redox-mediated angiogenesis in the hypoxic joint of inflammatory arthritis. Arthritis Rheumatol 66:3300–3310

    Article  CAS  PubMed  Google Scholar 

  149. Szalay B et al (2014) The impact of conventional DMARD and biological therapies on CD4+ cell subsets in rheumatoid arthritis: a follow-up study. Clin Rheumatol 33:175–185

    Article  PubMed  Google Scholar 

  150. Masson-Bessiere C et al (2000) In the rheumatoid pannus, anti-filaggrin autoantibodies are produced by local plasma cells and constitute a higher proportion of IgG than in synovial fluid and serum. Clin Exp Immunol 119:544–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Masson-Bessiere C et al (2001) The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol 166:4177–4184

    Article  CAS  PubMed  Google Scholar 

  152. Reparon-Schuijt CC et al (2001) Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum 44:41–47

    Article  CAS  PubMed  Google Scholar 

  153. Sebbag M et al (2006) Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins. Eur J Immunol 36:2250–2263

    Article  CAS  PubMed  Google Scholar 

  154. Chang X et al (2005) Citrullination of fibronectin in rheumatoid arthritis synovial tissue. Rheumatology (Oxford) 44:1374–1382

    Article  CAS  Google Scholar 

  155. Vossenaar ER, van Venrooij WJ (2004) Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res Ther 6:107–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. van Venrooij WJ et al (2008) Anti-CCP antibody, a marker for the early detection of rheumatoid arthritis. Ann N Y Acad Sci 1143:268–285

    Article  PubMed  CAS  Google Scholar 

  157. van Gaalen F et al (2005) The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis. J Immunol 175:5575–5580

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Centre for Arthritis and Rheumatic Diseases, University College Dublin, Dublin 4, Ireland

    Douglas J. Veale & Carl Orr

  2. The Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Dublin 4, Ireland

    Douglas J. Veale

  3. The Department of Molecular Rheumatology, Trinity College Dublin, Dublin 2, Ireland

    Ursula Fearon

Authors
  1. Douglas J. Veale
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carl Orr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ursula Fearon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas J. Veale.

Additional information

This article is a contribution to the special issue on Immunopathology of Rheumatoid Arthritis - Guest Editors: Cem Gabay and Paul Hasler

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Veale, D.J., Orr, C. & Fearon, U. Cellular and molecular perspectives in rheumatoid arthritis. Semin Immunopathol 39, 343–354 (2017). https://doi.org/10.1007/s00281-017-0633-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-017-0633-1

Keywords

Search

Navigation