Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting

An Author Correction to this article was published on 30 May 2022

This article has been updated

Key Points

  • Rheumatoid arthritis (RA) is a heterogeneous disease. The main subdivision of RA is according to the presence or absence of antibodies to citrullinated protein antigens (ACPAs) and of rheumatoid factor (RF), whereby the presence of either or both of these types of autoantibody defines the seropositive subset of disease.

  • This subdivision of patients with RA has greatly enhanced pathogenetic studies and has shown how linkage to MHC class II alleles and MHC class II-dependent immunity is predominantly restricted to the seropositive form of RA.

  • In many cases, seropositive RA develops gradually, starting with the emergence of autoantibodies and only subsequently including symptoms such as pain and/or fatigue and then joint inflammation.

  • Triggering of autoimmunity to citrullinated and other post-translationally modified autoantigens may occur in the lungs and other mucosal surfaces after exposure to noxious environmental agents such as smoke, which drive both the post-translational modifications of autoantigens and the local accumulation and activation of antigen-presenting cells.

  • ACPAs can target the bone and joint compartments through the specific activation of osteoclasts, leading to CXCL8 production. This process results in erosion (by osteoclasts) and pain (by CXCL8-dependent engagement of CXCR1 and CXCR2 on nociceptive nerves).

  • The recognition of a gradual development of seropositive disease, and the emerging understanding of the molecular mechanisms in the early phases of disease, provide a new time window as well as new targets for prevention and early therapy.

Abstract

Patients with rheumatoid arthritis can be divided into two major subsets characterized by the presence versus absence of antibodies to citrullinated protein antigens (ACPAs) and of rheumatoid factor (RF). The antibody-positive subset of disease, also known as seropositive rheumatoid arthritis, constitutes approximately two-thirds of all cases of rheumatoid arthritis and generally has a more severe disease course. ACPAs and RF are often present in the blood long before any signs of joint inflammation, which suggests that the triggering of autoimmunity may occur at sites other than the joints (for example, in the lung). This Review summarizes recent progress in our understanding of this gradual disease development in seropositive patients. We also emphasize the implications of this new understanding for the development of preventive and therapeutic strategies. Similar temporal and spatial separation of immune triggering and clinical manifestations, with novel opportunities for early intervention, may also occur in other immune-mediated diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genetic epidemiology of RA.
Figure 2: From triggering to targeting: a longitudinal perspective on the development of seropositive RA.
Figure 3: Local early immune activation in the lungs.
Figure 4: Involvement of adaptive immunity.
Figure 5: Development of ACPA-mediated disease as a precursor to RA.
Figure 6: The inflammatory cascade in established RA.

Similar content being viewed by others

Change history

References

  1. Arnett, F. C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

    Article  CAS  PubMed  Google Scholar 

  2. Aletaha, D. et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann. Rheum. Dis. 69, 1580–1588 (2010).

    Article  PubMed  Google Scholar 

  3. Chatzidionysiou, K. et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann. Rheum. Dis. 70, 1575–1580 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Gottenberg, J. E. et al. Rheumatoid factor and anti-citrullinated protein antibody positivity are associated with a better effectiveness of abatacept: results from the Pan-European registry analysis. Arthritis Rheumatol. 68, 1346–1352 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Klareskog, L. et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 54, 38–46 (2006). Provides the first description of a gene–environment interaction that implicates a role for the lungs in the triggering of anti-citrulline immunity.

    Article  CAS  PubMed  Google Scholar 

  6. Linn-Rasker, S. P. et al. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann. Rheum. Dis. 65, 366–371 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Waaler, E. On the occurrence of a factor in human serum activating the specific agglutination of sheep blood corpuscles. APMIS 115, 422–438 (1939).

    Google Scholar 

  8. Nemazee, D. A. Immune complexes can trigger specific, T cell-dependent, autoanti-IgG antibody production in mice. J. Exp. Med. 161, 242–256 (1985).

    Article  CAS  PubMed  Google Scholar 

  9. Roosnek, E. & Lanzavecchia, A. Efficient and selective presentation of antigen–antibody complexes by rheumatoid factor B cells. J. Exp. Med. 173, 487–489 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Nienhuis, R. L. & Mandema, E. A. New serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Ann. Rheum. Dis. 23, 302–305 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Young, B. J., Mallya, R. K., Leslie, R. D., Clark, C. J. & Hamblin, T. J. Anti-keratin antibodies in rheumatoid arthritis. BMJ 2, 97–99 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sebbag, M. et al. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 95, 2672–2679 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schellekens, G. A., de Jong, B. A., van den Hoogen, F. H., van de Putte, L. B. & van Venrooij, W. J. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101, 273–281 (1998). The first article to describe citrullinated peptides and proteins as targets of RA-associated autoantibodies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Girbal-Neuhauser, E. et al. 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, 585–594 (1999).

    CAS  PubMed  Google Scholar 

  15. Schellekens, G. A. et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43, 155–163 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Juarez, M. et al. Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis. Ann. Rheum. Dis. 75, 1099–1107 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Jiang, X. et al. Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies. Ann. Rheum. Dis. 73, 1761–1768 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Reed, E. et al. Antibodies to carbamylated α-enolase epitopes in rheumatoid arthritis also bind citrullinated epitopes and are largely indistinct from anti-citrullinated protein antibodies. Arthritis Res. Ther. 18, 96 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Auger, I. et al. Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum. 52, 3424–3432 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Burkhardt, H. et al. Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis. Eur. J. Immunol. 35, 1643–1652 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Kinloch, A. et al. Identification of citrullinated α-enolase as a candidate autoantigen in rheumatoid arthritis. Arthritis Res. Ther. 7, R1421–R1429 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pratesi, F. et al. Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps. Ann. Rheum. Dis. 73, 1414–1422 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Schwenzer, A. et al. Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis. Ann. Rheum. Dis. 75, 1876–1883 (2015).

    Article  PubMed  CAS  Google Scholar 

  25. Aho, K., Heliovaara, M., Maatela, J., Tuomi, T. & Palosuo, T. Rheumatoid factors antedating clinical rheumatoid arthritis. J. Rheumatol. 18, 1282–1284 (1991).

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004). References 26 and 27 demonstrate that ACPAs are present in blood long before the development of RA.

    Article  PubMed  Google Scholar 

  28. van der Woude, D. et al. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann. Rheum. Dis. 69, 1554–1561 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Sokolove, J. et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 7, e35296 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brink, M. et al. Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum. 65, 899–910 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Shi, J. et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann. Rheum. Dis. 73, 780–783 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Ronnelid, J. et al. Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann. Rheum. Dis. 64, 1744–1749 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Willis, V. C. et al. Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. Arthritis Rheum. 65, 2545–2554 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Reynisdottir, G. et al. Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol. 66, 31–39 (2014). Demonstrates that both structural changes and immune activation occur in the lungs of patients with early untreated ACPA-positive RA.

    Article  CAS  PubMed  Google Scholar 

  35. Reynisdottir, G. et al. Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis. Ann. Rheum. Dis. 75, 1722–1727 (2015).

    Article  PubMed  CAS  Google Scholar 

  36. Demoruelle, M. K. et al. Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? Arthritis Rheum. 64, 1756–1761 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Rangel-Moreno, J. et al. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J. Clin. Invest. 116, 3183–3194 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kokkonen, H. et al. Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. Arthritis Res. Ther. 13, R13 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kinslow, J. D. et al. IgA plasmablasts are elevated in subjects at risk for future rheumatoid arthritis. Arthritis Rheumatol. 68, 2372–2383 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bas, S., Genevay, S., Meyer, O. & Gabay, C. Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology 42, 677–680 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Svard, A. et al. Associations with smoking and shared epitope differ between IgA- and IgG-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis. Arthritis Rheumatol. 67, 2032–2037 (2015).

    Article  PubMed  CAS  Google Scholar 

  42. Padyukov, L., Silva, C., Stolt, P., Alfredsson, L. & Klareskog, L. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Stolt, P. et al. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann. Rheum. Dis. 69, 1072–1076 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Too, C. L. et al. Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case–control study. Ann. Rheum. Dis. 75, 997–1002 (2015).

    Article  PubMed  CAS  Google Scholar 

  45. Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Watkin, L. B. et al. COPA mutations impair ER–Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat. Genet. 47, 654–660 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lundberg, K. et al. Antibodies to citrullinated α-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 58, 3009–3019 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Mikuls, T. R. et al. Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int. Immunopharmacol. 9, 38–42 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. McGraw, W. T., Potempa, J., Farley, D. & Travis, J. Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect. Immun. 67, 3248–3256 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wegner, N. et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol. Rev. 233, 34–54 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Eriksson, K. et al. Prevalence of periodontitis in patients with established rheumatoid arthritis: a Swedish population based case–control study. PLoS ONE 11, e0155956 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Kharlamova, N. et al. Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis etiology. Arthritis Rheumatol. 68, 604–613 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Olhagen, B. The intestine and rheumatism. Acta Rheumatol. Scand. 16, 177–183 (1970).

    Article  CAS  PubMed  Google Scholar 

  54. Svartz, N. The origin of rheumatoid arthritis. Rheumatology 6, 322–328 (1975).

    CAS  PubMed  Google Scholar 

  55. Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Gomez, A. et al. Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice. PLoS ONE 7, e36095 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Abdollahi-Roodsaz, S. et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J. Clin. Invest. 118, 205–216 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Abdollahi-Roodsaz, S., Abramson, S. B. & Scher, J. U. The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions. Nat. Rev. Rheumatol. 12, 446–455 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Terao, C. et al. Effects of smoking and shared epitope on the production of anti-citrullinated peptide antibody in a Japanese adult population. Arthritis Care Res. 66, 1818–1827 (2014).

    Article  CAS  Google Scholar 

  61. Hensvold, A. H. et al. Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins. Ann. Rheum. Dis. 74, 375–380 (2015).

    Article  PubMed  Google Scholar 

  62. Kokkonen, H. et al. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 62, 383–391 (2010).

    CAS  PubMed  Google Scholar 

  63. Rombouts, Y. et al. Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann. Rheum. Dis. 74, 234–241 (2015). Demonstrates that ACPAs from patients with RA have unusual glycosylation of the antigen-binding portion.

    Article  CAS  PubMed  Google Scholar 

  64. Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).

    Article  CAS  PubMed  Google Scholar 

  65. Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012). Provides a genetic dissection of the amino acid requirements of the association between HLA alleles and ACPA-positive RA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Scally, S. W. et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210, 2569–2582 (2013). Presents the first crystal structure of citrullinated peptides presented by HLA-DR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Stamnaes, J. & Sollid, L. M. Celiac disease: autoimmunity in response to food antigen. Semin. Immunol. 27, 343–352 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Snir, O. et al. Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients. Arthritis Rheum. 63, 2873–2883 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. James, E. A. et al. Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol. 66, 1712–1722 (2014). Uses ex vivo phenotyping of several different citrulline-specific CD4+ T cells in patients with RA and in HLA-matched healthy controls to demonstrate both increased numbers and higher frequencies of effector/memory CD4+ T cells in patients with RA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Salmond, R. J., Brownlie, R. J., Morrison, V. L. & Zamoyska, R. The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals. Nat. Immunol. 15, 875–883 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Menard, L. et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Invest. 121, 3635–3644 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kallberg, H. et al. Gene–gene and gene–environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am. J. Hum. Genet. 80, 867–875 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl. Med. 8, 331ra38 (2016).

    PubMed  PubMed Central  Google Scholar 

  74. Zvaifler, N. J. The immunopathology of joint inflammation in rheumatoid arthritis. Adv. Immunol. 16, 265–336 (1973).

    Article  CAS  PubMed  Google Scholar 

  75. Tan, Y. C. et al. Barcode-enabled sequencing of plasmablast antibody repertoires in rheumatoid arthritis. Arthritis Rheumatol. 66, 2706–2715 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li, S. et al. Autoantibodies from single circulating plasmablasts react with citrullinated antigens and Porphyromonas gingivalis in rheumatoid arthritis. Arthritis Rheumatol. 68, 614–626 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Amara, K. et al. 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 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Corsiero, E. et al. Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs. Ann. Rheum. Dis. 75, 1866–1875 (2015).

    Article  PubMed  CAS  Google Scholar 

  79. Titcombe, P. J. et al. Citrullinated self antigen-specific blood B cells carry cross reactive immunoglobulins with effector potential. Ann. Rheum. Dis. 75, A2.33 (2016).

    Article  Google Scholar 

  80. Ambrosi, A., Sonesson, S. E. & Wahren-Herlenius, M. Molecular mechanisms of congenital heart block. Exp. Cell Res. 325, 2–9 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Harre, U. et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 122, 1791–1802 (2012). Provides the first demonstration that ACPAs can promote osteoclast differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Krishnamurthy, A. et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann. Rheum. Dis. 75, 721–729 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Harre, U. et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat. Commun. 6, 6651 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Wigerblad, G. et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann. Rheum. Dis. 75, 730–738 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Rothe, L. et al. Human osteoclasts and osteoclast- like cells synthesize and release high basal and inflammatory stimulated levels of the potent chemokine interleukin-8. Endocrinology 139, 4353–4363 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. van de Stadt, L. A., Witte, B. I., Bos, W. H. & van Schaardenburg, D. A prediction rule for the development of arthritis in seropositive arthralgia patients. Ann. Rheum. Dis. 72, 1920–1926 (2013).

    Article  PubMed  Google Scholar 

  87. Zhang, Z. J., Cao, D. L., Zhang, X., Ji, R. R. & Gao, Y. J. Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 154, 2185–2197 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kuhn, K. A. et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J. Clin. Invest. 116, 961–973 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Keshari, R. S. et al. Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition. PLoS ONE 7, e48111 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sanchez-Pernaute, O. et al. Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 72, 1400–1406 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Sokolove, J., Zhao, X., Chandra, P. E. & Robinson, W. H. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum. 63, 53–62 (2011). Provides the first demonstration that immune complexes with citrullinated antigens have proinflammatory potential.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lefevre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ai, R. et al. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat. Commun. 7, 11849 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Filer, A. et al. Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways. PLoS ONE 10, e0120917 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Ospelt, C. et al. Smoking induces transcription of the heat shock protein system in the joints. Ann. Rheum. Dis. 73, 1423–1426 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Mullazehi, M., Mathsson, L., Lampa, J. & Ronnelid, J. High anti-collagen type-II antibody levels and induction of proinflammatory cytokines by anti-collagen antibody-containing immune complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with acute inflammation at the time of disease onset. Ann. Rheum. Dis. 66, 537–541 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Haag, S. et al. Identification of new citrulline-specific autoantibodies, which bind to human arthritic cartilage, by mass spectrometric analysis of citrullinated type II collagen. Arthritis Rheumatol. 66, 1440–1449 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Matsumoto, I. et al. How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat. Immunol. 3, 360–365 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Matsumoto, I. et al. Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders. Arthritis Rheum. 48, 944–954 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Feldmann, M. & Maini, S. R. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol. Rev. 223, 7–19 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Schett, G., Elewaut, D., McInnes, I. B., Dayer, J. M. & Neurath, M. F. How cytokine networks fuel inflammation: toward a cytokine-based disease taxonomy. Nat. Med. 19, 822–824 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Smolen, J. S. & Aletaha, D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat. Rev. Rheumatol. 11, 276–289 (2015).

    Article  PubMed  Google Scholar 

  104. Gerlag, D. M. et al. OP0182. Prevention of rheumatoid arthritis by B cell directed therapy in the earliest phase of the disease: the PRAIRI study. Ann. Rheum. Dis. 75 (Suppl. 2), 125–126 (2016).

    Google Scholar 

  105. Benham, H. et al. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci. Transl. Med. 7, 290ra87 (2015).

    Article  PubMed  CAS  Google Scholar 

  106. Bell, G. M. et al. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2015-208456 (2016).

  107. Clemente-Casares, X. et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530, 434–440 (2016).

    Article  CAS  PubMed  Google Scholar 

  108. Dzhambazov, B. et al. Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide in complex with MHC class II molecules. J. Immunol. 176, 1525–1533 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Streeter, H. B., Rigden, R., Martin, K. F., Scolding, N. J. & Wraith, D. C. Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS. Neurol. Neuroimmunol. Neuroinflamm. 2, e93 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Huizinga, T. W. et al. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 52, 3433–3438 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Viatte, S. et al. Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Ann. Rheum. Dis. 71, 1984–1990 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Wagner, C. A. et al. Identification of anticitrullinated protein antibody reactivities in a subset of anti-CCP-negative rheumatoid arthritis: association with cigarette smoking and HLA-DRB1 'shared epitope' alleles. Ann. Rheum. Dis. 74, 579–586 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Han, B. et al. Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity. Am. J. Hum. Genet. 94, 522–532 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Martin-Mola, E. et al. Anti-citrullinated peptide antibodies and their value for predicting responses to biologic agents: a review. Rheumatol. Int. 36, 1043–1063 (2016).

    Article  CAS  PubMed  Google Scholar 

  115. Sokolove, J. et al. Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial. Ann. Rheum. Dis. 75, 709–714 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).

    Article  CAS  PubMed  Google Scholar 

  117. Willemze, A., Trouw, L. A., Toes, R. E. & Huizinga, T. W. The influence of ACPA status and characteristics on the course of RA. Nat. Rev. Rheumatol. 8, 144–152 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Turesson, C. et al. Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann. Rheum. Dis. 66, 59–64 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Korkmaz, C., Us, T., Kasifoglu, T. & Akgun, Y. Anti-cyclic citrullinated peptide (CCP) antibodies in patients with long-standing rheumatoid arthritis and their relationship with extra-articular manifestations. Clin. Biochem. 39, 961–965 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Padyukov, L. et al. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann. Rheum. Dis. 70, 259–265 (2011).

    Article  PubMed  Google Scholar 

  121. Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014). A comprehensive analysis of the genetics of RA and its implications for therapeutic approaches.

    Article  CAS  PubMed  Google Scholar 

  122. Frisell, T. et al. Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case–control study in Sweden. Ann. Rheum. Dis. 75, 183–189 (2016).

    Article  PubMed  Google Scholar 

  123. Neovius, M., Simard, J. F., Askling, J. & ARTIS Study Group. Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs in Sweden. Ann. Rheum. Dis. 70, 624–629 (2011).

    Article  PubMed  Google Scholar 

  124. Kallberg, H. et al. Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case–control studies. Ann. Rheum. Dis. 68, 222–227 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Hu, X. et al. Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89, 496–506 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Trynka, G. et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat. Genet. 45, 124–130 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Gutierrez-Arcelus, M., Rich, S. S. & Raychaudhuri, S. Autoimmune diseases — connecting risk alleles with molecular traits of the immune system. Nat. Rev. Genet. 17, 160–174 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Hecht, C. et al. Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Ann. Rheum. Dis. 74, 2151–2156 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Stack, R. J. et al. Symptom complexes in patients with seropositive arthralgia and in patients newly diagnosed with rheumatoid arthritis: a qualitative exploration of symptom development. Rheumatology 53, 1646–1653 (2014).

    Article  CAS  PubMed  Google Scholar 

  130. Chemin, K. et al. A novel HLA-DRB1*10:01 restricted T cell epitope from citrullinated type II collagen relevant for rheumatoid arthritis. Arthritis Rheumatol. 68, 1124–1135 (2016).

    Article  CAS  PubMed  Google Scholar 

  131. Negishi-Koga, T. et al. Immune complexes regulate bone metabolism through FcRγ signalling. Nat. Commun. 6, 6637 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Cunha, T. M. et al. A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc. Natl Acad. Sci. USA 102, 1755–1760 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Guerrero, A. T. et al. Toll-like receptor 2/MyD88 signaling mediates zymosan-induced joint hypernociception in mice: participation of TNF-α, IL-1β and CXCL1/KC. Eur. J. Pharmacol. 674, 51–57 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Qin, X., Wan, Y. & Wang, X. CCL2 and CXCL1 trigger calcitonin gene-related peptide release by exciting primary nociceptive neurons. J. Neurosci. Res. 82, 51–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Wang, J. G. et al. The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons. Mol. Pain 4, 38 (2008).

    PubMed  PubMed Central  Google Scholar 

  136. Ossipova, E. et al. Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint. Arthritis Res. Ther. 16, R167 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Klareskog, L., Forsum, U., Scheynius, A., Kabelitz, D. & Wigzell, H. Evidence in support of a self-perpetuating HLA-DR-dependent delayed-type cell reaction in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 79, 3632–3636 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  139. Stolt, P. et al. 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 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. de Hair, M. J. et al. Smoking and overweight determine the likelihood of developing rheumatoid arthritis. Ann. Rheum. Dis. 72, 1654–1658 (2013).

    Article  PubMed  Google Scholar 

  141. Gerstner, C. et al. Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis. Front. Immunol. http://dx.doi.org/10.3389/fimmu.2016.00494 (2016).

Download references

Acknowledgements

The authors thank numerous colleagues in their own and many collaborating laboratories for providing insights into the story of RA development told here. The authors give special thanks to the following individuals: L. Alfredsson and L. Padyukov, who made the initial gene–environment interaction studies possible; C. Svensson, who provided data and insights into pain mechanisms; and V. Joshua, who helped with illustrations. Studies from the authors' own laboratory described in this Review were funded by the Swedish Medical Research Council, the European Union (European Research Council senior investigator grant to L.K., and several Innovative Medicines Initiative and 7th Framework Programme (FP7) grants, including BTCure, TEAM and Osteoimmune), grants from the Swedish Strategic Foundation and Margaretha af Ugglas Foundation, and the Swedish Organization for Patients with Rheumatic Diseases.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lars Klareskog.

Ethics declarations

Competing interests

The authors have received financial support (to their host institution, the Karolinska Institute) from the following companies: Janssen, Pfizer, Bristol-Myers Squibb (BMS), AbbVie, UCB, Sobi and Roche. Support has also been given to the Rheumatology Unit of the Karolinska Institute within the projects BTCure and ULTRA-DD, which are supported by the Innovative Medicines Initiative of the European Union (EU) and by several companies (Janssen, UCB, GlaxoSmithKline, Pfizer and Thermo Fisher) according to EU rules. V.M., A.I.C. and L.K. have all given lectures supported by pharmacological companies (BMS, Pfizer, Janssen, Sobi and Novartis) within their duties of the Karolinska Institute (and with financial compensation to the Karolinska Institute). V.M., A.I.C. and L.K. have filed patent applications related to the therapeutic use of CXCL8 and peptidyl-arginine deiminase blockade. V.M. and L.K. have also filed patent applications related to tolerization with citrullinated peptides (supported by a European Research Council Proof of Concept (ERC PoC) grant). All patent applications are handled within a research and innovation foundation named Vectis.

PowerPoint slides

Glossary

Rheumatoid factor

(RF). Antibody reactive with the Fc part of self or non-self IgG. Different isotypes of RF exist, but most clinical assays that are used to determine whether an individual is RF positive measure IgM RF.

CTLA4–Ig

Also known as abatacept. This fusion protein of the cytotoxic T lymphocyte associated protein 4 (CTLA4) extracellular domain and the Fc region of IgG1 binds to the co-stimulatory receptors CD80 and CD86 on effector T cells to prevent their activation. Abatacept is an approved treatment for rheumatoid arthritis.

Citrullinated autoantigens

Proteins and/or peptides in which the amino acid arginine is changed to the amino acid citrulline. The change is mediated by one of the four enzyme variants of peptidyl-arginine deiminases (PADs).

Cyclic citrullinated peptide (CCP) assay

An assay that captures the majority of antibodies reactive to various citrullinated autoantigens (these antibodies are referred to generically as ACPAs). The assay is built on CCPs, and the most commonly used commercial variant is named CCP2.

Expression quantitative trait loci

Genomic loci where variations in nucleotide sequence (usually in a single nucleotide) determine the expression level of a particular mRNA.

High-resolution computed tomography

A sensitive imaging technique that, in the context of this Review, is used to visualize changes in the lungs, including inflammatory infiltrates.

Peptidyl-arginine deiminases

(PADs). Citrullination (also known as deimination) of peptides and proteins is mediated by the calcium-dependent PADs.

Periodontitis

An inflammatory disease affecting the gum (peridontium). Severe periodontitis leads to alveolar bone loss and subsequent loss of teeth.

Molecular mimicry

Occurs when sequence similarity can lead to immune system cross-reactions, such as a foreign antigen triggering a response that is subsequently propagated by a self-antigen. The sequences do not need to be identical, but share certain crucial residues.

ACR/EULAR criteria

Classification criteria for rheumatoid arthritis from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR). The latest criteria include positive status for antibodies to citrullinated protein antigens.

PTPN22

This gene encodes the protein tyrosine phosphatase LYP. A functional polymorphism in PTPN22 shows genetic association to several inflammatory diseases, including rheumatoid arthritis.

Replacement mutations

In contrast to silent mutations, replacement mutations lead to amino acid changes. When these changes occur in the complementarity-determining regions of antibodies, they are likely to affect how antigen is recognized by the antibody.

Osteoclasts

Bone lining cells that absorb bone during growth and healing. They are identified by their multiple nuclei and positive staining for tartrate resistant acid phosphatase (TRAP). Osteoclasts differentiate in the presence of the cytokine RANKL from myeloid cells.

Osteopaenia

Loss of bone density.

Fibroblast-like synoviocytes

The specialized fibroblasts that are part of the normal lining of the joint synovial membrane. These cells can undergo large-scale proliferation in rheumatoid arthritis.

Collagen-induced arthritis (CIA) model

A murine model of polyarthritis that is induced after immunization with collagen type II, which is the major structural component of cartilage.

Neutrophil extracellular traps

(NETs). Neutrophils can extrude their nuclear content through the process of NETosis. The released DNA–histone complexes can have antibacterial effects, but also lead to exposure of nuclear contents to the immune system. NETs are abundant in the synovial fluid of patients with rheumatoid arthritis.

Rituximab

A monoclonal antibody targeting CD20 that is a B cell-depleting agent. B cell-depletion therapy is an approved treatment for rheumatoid arthritis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Malmström, V., Catrina, A. & Klareskog, L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol 17, 60–75 (2017). https://doi.org/10.1038/nri.2016.124

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri.2016.124

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing