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  • Review Article
  • Published:

Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis

Key Points

  • Autoantibodies against post-translational modified citrullinated proteins, so-called anti-citrullinated protein antibodies (ACPAs), define a distinct clinical RA phenotype; this phenotype is characterized by an increased frequency of early inflammatory lung changes

  • The presence of ACPAs before signs of inflammation in joints suggests that immunity against citrullinated proteins is initiated outside the joint

  • Changes in the lung and enrichment of ACPAs in the lungs (bronchoalveolar lavage fluid) occur in both individuals at risk of developing RA as well as patients with early RA

  • The lung, therefore, might be a site of initiation of immunity to citrullinated proteins

  • Early targeting of the immune reactions in the lung might be a new approach to modulate disease

Abstract

Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.

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Figure 1: A schematic model of initiation of RA-associated immunity against citrullinated proteins in the lungs.
Figure 2: Summary of the pathogenic roles of ACPAs in RA.

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References

  1. Weinblatt, M. E. et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818–822 (1985).

    Article  CAS  PubMed  Google Scholar 

  2. Feldmann, M. & Maini, R. N. Anti-TNFα therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19, 163–196 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Nishimoto, N. & Kishimoto, T. Interleukin 6: from bench to bedside. Nat. Clin. Pract. Rheumatol. 2, 619–626 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Smolen, J. S., Aletaha, D., Koeller, M., Weisman, M. H. & Emery, P. New therapies for treatment of rheumatoid arthritis. Lancet 370, 1861–1874 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Arend, W. P. & Firestein, G. S. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat. Rev. Rheumatol. 8, 573–586 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Waaler, E. On the occurrence of a factor in human serum activating the specific agglutintion of sheep blood corpuscles. 1939. APMIS 115, 422–438 (2007).

    Article  PubMed  Google Scholar 

  8. Hoet, R. M., Boerbooms, A. M., Arends, M., Ruiter, D. J. & van Venrooij, W. J. Antiperinuclear factor, a marker autoantibody for rheumatoid arthritis: colocalisation of the perinuclear factor and profilaggrin. Ann. Rheum. Dis. 50, 611–618 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Burkhardt, H. et al. Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse. Arthritis Rheum. 46, 2339–2348 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Blass, S. et al. The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis. Arthritis Rheum. 44, 761–771 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Skriner, K. et al. Anti-A2/RA33 autoantibodies are directed to the RNA binding region of the A2 protein of the heterogeneous nuclear ribonucleoprotein complex. Differential epitope recognition in rheumatoid arthritis, systemic lupus erythematosus, and mixed connective tissue disease. J. Clin. Invest. 100, 127–135 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 

  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).

    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. Verpoort, K. N. et al. Fine specificity of the anti-citrullinated protein antibody response is influenced by the shared epitope alleles. Arthritis Rheum. 56, 3949–3952 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Shoda, H. et al. Detection of autoantibodies to citrullinated BiP in rheumatoid arthritis patients and pro-inflammatory role of citrullinated BiP in collagen-induced arthritis. Arthritis Res. Ther. 13, R191 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Snir, O. et al. Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles. Ann. Rheum. Dis. 68, 736–743 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. 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 

  20. Chandra, P. E. et al. Novel multiplex technology for diagnostic characterization of rheumatoid arthritis. Arthritis Res. Ther. 13, R102 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lundberg, K. et al. Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile. Ann. Rheum. Dis. 72, 652–658 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Shi, J. et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum. 65, 911–915 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Snir, O. et al. Multifunctional T cell reactivity with native and glycosylated type II collagen in rheumatoid arthritis. Arthritis Rheum. 64, 2482–2488 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Trembleau, S. et al. Immunodominant T-cell epitopes of hnRNP-A2 associated with disease activity in patients with rheumatoid arthritis. Eur. J. Immunol. 40, 1795–1808 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Corrigall, V. M., Vittecoq, O. & Panayi, G. S. Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development. Immunology 128, 218–226 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. 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 

  28. 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 

  29. Kurki, P., Aho, K., Palosuo, T. & Heliovaara, M. Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease. Arthritis Rheum. 35, 914–917 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. 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).

    Article  PubMed  Google Scholar 

  32. Chibnik, L. B., Mandl, L. A., Costenbader, K. H., Schur, P. H. & Karlson, E. W. Comparison of threshold cutpoints and continuous measures of anti-cyclic citrullinated peptide antibodies in predicting future rheumatoid arthritis. J. Rheumatol. 36, 706–711 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Majka, D. S. et al. Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. Ann. Rheum. Dis. 67, 801–807 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. 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 

  36. 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 

  37. 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 (2012).

    Article  PubMed  Google Scholar 

  38. van de Stadt, L. A. et al. Development of the anti-citrullinated protein antibody repertoire prior to the onset of rheumatoid arthritis. Arthritis Rheum. 63, 3226–3233 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Coulie, P. G. & Van Snick, J. Rheumatoid factor (RF) production during anamnestic immune responses in the mouse. III. Activation of RF precursor cells is induced by their interaction with immune complexes and carrier-specific helper T cells. J. Exp. Med. 161, 88–97 (1985).

    Article  CAS  PubMed  Google Scholar 

  40. Tarkowski, A., Czerkinsky, C. & Nilsson, L. A. Simultaneous induction of rheumatoid factor- and antigen-specific antibody-secreting cells during the secondary immune response in man. Clin. Exp. Immunol. 61, 379–387 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. Pedersen, M. et al. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides. Arthritis Res. Ther. 8, R133 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Karlson, E. W. et al. Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Ann. Rheum. Dis. 69, 54–60 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Too, C. L. et al. Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated protein antibody-positive rheumatoid arthritis: results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA). Arthritis Res. Ther. 14, R89 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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 

  48. Too, C. L. et al. Gene–environment interaction between HLA-DRB1 shared epitope and occupational textile dust exposure in the risk of ACPA-positive rheumatoid arthritis in female patients: evidence from the Malaysian Epidemiological Investigation Of Rheumatoid Arthritis Case–Control Study [abstract]. Arthritis Rheum. 65, S457–S458 (2013).

    Article  CAS  Google Scholar 

  49. Hart, J. E., Laden, F., Puett, R. C., Costenbader, K. H. & Karlson, E. W. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ. Health Perspect. 117, 1065–1069 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hart, J. E. et al. Ambient air pollution exposures and risk of rheumatoid arthritis: results from the Swedish EIRA case-control study. Ann. Rheum. Dis. 72, 888–894 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Hart, J. E. et al. Ambient air pollution exposures and risk of rheumatoid arthritis. Arthritis Care Res. (Hoboken) 65, 1190–1196 (2013).

    Article  CAS  Google Scholar 

  52. Carlens, C. et al. Smoking, use of moist snuff, and risk of chronic inflammatory diseases. Am. J. Respir. Crit. Care Med. 181, 1217–1222 (2010).

    Article  PubMed  Google Scholar 

  53. 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 

  54. Haj Hensvold, A. 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. http://dx.doi.org/10.1136/annrheumdis-2013-203947.

  55. 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 

  56. Reynisdottir, G. et al. Structural lung changes and local anti-citrulline immunity are early features of anti citrullinated-proteins antibodies positive rheumatoid arthritis. Arthritis Rheum. 66, 31–39 (2013).

    Article  CAS  Google Scholar 

  57. Joshua, V. et al. Characterization of lung inflammation and identification of shared citrullinated targets in the lungs and joints of early RA [abstract]. Arthritis Rheum. 65, S392–S392 (2013).

    Google Scholar 

  58. Fischer, A. et al. Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir. Med. 106, 1040–1047 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  59. 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 

  60. 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 

  61. 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 

  62. Ytterberg, A. J. et al. Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-204912.

  63. Harlow, L. et al. Identification of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheum. 65, 869–879 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Mohamed, B. M. et al. Citrullination of proteins: a common post-translational modification pathway induced by different nanoparticles in vitro and in vivo. Nanomedicine 7, 1181–1195 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Matsuo, K. et al. Identification of novel citrullinated autoantigens of synovium in rheumatoid arthritis using a proteomic approach. Arthritis Res. Ther. 8, R175 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. van Beers, J. J. et al. The rheumatoid arthritis synovial fluid citrullinome reveals novel citrullinated epitopes in apolipoprotein E, myeloid nuclear differentiation antigen, and beta-actin. Arthritis Rheum. 65, 69–80 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Makrygiannakis, D. et al. Citrullination is an inflammation-dependent process. Ann. Rheum. Dis. 65, 1219–1222 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Arnson, Y., Shoenfeld, Y. & Amital, H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J. Autoimmun 34, J258–265 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Larsen, J. M. et al. Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota. PLoS ONE 7, e31976 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Demoruelle, M. K., Norris, J. M., Holers, V. M., Harris, J. K. & Deane, K. D. The lung microbiome differs in asymptomatic subjects at elevated risk of future rheumatoid arthritis compared with healthy control subjects. Ann. Am. Thorac. Soc. 11 (Suppl. 1), S74 (2014).

    Article  Google Scholar 

  71. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mikuls, T. R. et al. Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. Arthritis Rheum. 64, 3522–3530 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Nesse, W. et al. The periodontium of periodontitis patients contains citrullinated proteins which may play a role in ACPA (anti-citrullinated protein antibody) formation. J. Clin. Periodontol. 39, 599–607 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Scher, J. U. et al. Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum. 64, 3083–3094 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Harvey, G. P. et al. Expression of peptidylarginine deiminase-2 and -4, citrullinated proteins and anti-citrullinated protein antibodies in human gingiva. J. Periodontal Res. 48, 252–261 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  78. Liu, X., Zou, Q., Zeng, B., Fang, Y. & Wei, H. Analysis of fecal Lactobacillus community structure in patients with early rheumatoid arthritis. Curr. Microbiol. 67, 170–176 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. 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 

  80. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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 

  84. Costenbader, K. H., Chang, S. C., De Vivo, I., Plenge, R. & Karlson, E. W. Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene–environment interactions with heavy cigarette smoking. Arthritis Res. Ther. 10, R52 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Rieck, M. et al. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J. Immunol. 179, 4704–4710 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. 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 

  87. Arechiga, A. F. et al. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J. Immunol. 182, 3343–3347 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat. Genet. 37, 1317–1319 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Swanberg, M. et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat. Genet. 37, 486–494 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Suzuki, A. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Kang, C. P. et al. A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum. 54, 90–96 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Darrah, E. et al. Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity. Sci. Transl. Med. 5, 186ra65 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Uysal, H. et al. Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. J. Exp. Med. 206, 449–462 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Harre, U. et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 122, 1791–1802 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kleyer, A. et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann. Rheum. Dis. 73, 854–860 (2014).

    Article  PubMed  Google Scholar 

  97. Kinloch, A. J. et al. Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian α-enolase and arthritis in DR4-I E-transgenic mice. Arthritis Rheum. 63, 3818–3823 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Haag, S., Uysal, H., Backlund, J., Tuncel, J. & Holmdahl, R. Human α-enolase is immunogenic, but not arthritogenic, in HLA-DR4-transgenic mice: comment on the article by Kinloch et al. Arthritis Rheum. 64, 1689–1691; author reply 1691–1692 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Trouw, L. A. et al. Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways. Arthritis Rheum. 60, 1923–1931 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Wright, H. L., Moots, R. J., Bucknall, R. C. & Edwards, S. W. Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 49, 1618–1631 (2010).

    Article  CAS  Google Scholar 

  101. De Rycke, L. et al. Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis-specific humoral autoimmunity. Arthritis Rheum. 52, 2323–2330 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Snir, O. et al. Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients. Arthritis Rheum. 62, 44–52 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Humby, F. et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med. 6, e1 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  104. 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 

  105. Hedstrom, A. K. et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain 134, 653–664 (2011).

    Article  PubMed  Google Scholar 

  106. Chinoy, H. et al. Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study. Ann. Rheum. Dis. 71, 961–965 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

A.I.C. acknowledges support from the Swedish Foundation for Strategic Research, the Initial Training Networks 7th framework programme Osteoimmune (289150), the European 7th framework programme (FP7/2007–2013) Euro-TEAM (305549), the Innovative Medicine Initiative Be The Cure (115142-2) and the Swedish Research Council. A.J.Y. acknowledges grant support from the Swedish Foundation for Strategic Research. L.K. acknowledges support from the Swedish Foundation for Strategic Research, the European 7th framework programme (FP7/2007–2013) Euro-TEAM (305549), the Innovative Medicine Initiative Be The Cure (115142-2) and the Swedish Research Council.

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All authors made substantial contributions to researching data for the article and made substantial contributions to discussions of content and writing the article. A.I.C. and L.K. had the main responsibility for reviewing and/or editing of the article before submission.

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Correspondence to Anca I. Catrina.

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Catrina, A., Ytterberg, A., Reynisdottir, G. et al. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat Rev Rheumatol 10, 645–653 (2014). https://doi.org/10.1038/nrrheum.2014.115

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