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The peculiar features, diversity and impact of citrulline-reactive autoantibodies

Abstract

Since entering the stage 25 years ago as a highly specific serological biomarker for rheumatoid arthritis, anti-citrullinated protein antibodies (ACPAs) have been a topic of extensive research. This hallmark B cell response arises years before disease onset, displays interpatient autoantigen variability, and is associated with poor clinical outcomes. Technological and scientific advances have revealed broad clonal diversity and intriguing features including high levels of somatic hypermutation, variable-domain N-linked glycosylation, hapten-like peptide interactions, and clone-specific multireactivity to citrullinated, carbamylated and acetylated epitopes. ACPAs have been found in different isotypes and subclasses, in both circulation and tissue, and are secreted by both plasmablasts and long-lived plasma cells. Notably, although some disease-promoting features have been reported, results now demonstrate that certain monoclonal ACPAs therapeutically block arthritis and inflammation in mouse models. A wealth of functional studies using patient-derived polyclonal and monoclonal antibodies have provided evidence for pathogenic and protective effects of ACPAs in the context of arthritis. To understand the roles of ACPAs, one needs to consider their immunological properties by incorporating different facets such as rheumatoid arthritis B cell biology, environmental triggers and chronic antigen exposure. The emerging picture points to a complex role of citrulline-reactive autoantibodies, in which the diversity and dynamics of antibody clones could determine clinical progression and manifestations.

Key points

  • Citrulline B cell responses are diverse but share important features that might be linked to rheumatoid arthritis-associated B cell dysregulation as well as environmental triggers, antigen exposure and the evolution of chronic immune reactions.

  • Anti-citrullinated protein antibodies (ACPAs) are extensively multireactive towards citrullinated, carbamylated and acetylated proteins, have high somatic hypermutation, and carry N-linked glycosylations in the variable regions.

  • More than 100 patient-derived human monoclonal ACPAs have been generated from different B cell compartments and patients, providing invaluable insights into citrulline autoimmunity and antibody function.

  • Although disease-causative autoantigens are presently unknown, ACPAs can target different synovial cells and are likely to form pathogenic immune complexes.

  • Results from studies using human monoclonal ACPAs reveal that some clones can completely block arthritis and inflammation in mouse models, while showing moderate pathogenic properties in other settings.

  • Different ACPA clones with different immunological features and antigen-binding patterns might mediate disease-promoting effects or have protective roles.

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Fig. 1: Diversity of ACPAs, their distinct characteristics and multireactivities.
Fig. 2: ACPA+ B cells are likely to originate from different immune reactions.
Fig. 3: ACPAs influence a diversity of in vitro and in vivo phenotypes.
Fig. 4: Different ACPA features could be linked to disease progression.

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References

  1. Aletaha, D. et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 62, 2569–2581 (2010).

    Article  PubMed  Google Scholar 

  2. Rose, H. M., Ragan, C., Pearce, E. & Lipman, M. O. Differential agglutination of normal and sensitized sheep erythrocytes by sera of patients with rheumatoid arthritis. Proc. Soc. Exp. Biol. Med. 68, 1–6 (1948).

    Article  CAS  PubMed  Google Scholar 

  3. Nienhuis, R. L. F., Mandema, E. & Smids, C. New serum factor in patients with rheumatoid arthritis: the antiperinuclear factor. Ann. Rheum. Dis. 23, 302 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Young, B. J., Mallya, R. K., Leslie, R. D., Clark, C. J. & Hamblin, T. J. Anti-keratin antibodies in rheumatoid arthritis. Br. Med. J. 2, 97 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 

  7. Vossenaar, E. R. et al. Multiplex analysis of antinuclear antibodies by flow cytometry using FIDIS. Arthritis Res. Ther. 6, 8 (2004).

    Google Scholar 

  8. Masson-Bessière, C. et al. The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the α- and β-chains of fibrin. J. Immunol. 166, 4177–4184 (2001).

    Article  PubMed  Google Scholar 

  9. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Hefton, A. et al. Autoantibodies against citrullinated serum albumin in patients with rheumatoid arthritis. J. Transl. Autoimmun. 2, 100023 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Rakieh, C. et al. Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study. Ann. Rheum. Dis. 74, 1659 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Studenic, P. et al. Prospective studies on the risk of rheumatoid arthritis: the European risk RA registry. Front. Med. 9, 824501 (2022).

    Article  Google Scholar 

  16. Stadt et al. Monoclonal anti-citrullinated protein antibodies selected on citrullinated fibrinogen have distinct targets with different cross-reactivity patterns. Rheumatology 52, 631–635 (2013).

    Article  PubMed  Google Scholar 

  17. Titcombe, P. J. et al. Pathogenic citrulline‐multispecific B cell receptor clades in rheumatoid arthritis. Arthritis Rheumatol. 70, 1933–1945 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Steen, J. et al. Recognition of amino acid motifs, rather than specific proteins, by human plasma cell–derived monoclonal antibodies to posttranslationally modified proteins in rheumatoid arthritis. Arthritis Rheumatol. 71, 196–209 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kongpachith, S. et al. Affinity maturation of the anti–citrullinated protein antibody paratope drives epitope spreading and polyreactivity in rheumatoid arthritis. Arthritis Rheumatol. 71, 507–517 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Elliott, S. E. et al. B cells in rheumatoid arthritis synovial tissues encode focused antibody repertoires that include antibodies that stimulate macrophage TNF-α production. Clin. Immunol. 212, 108360 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hensvold, A. et al. The human bone marrow plasma cell compartment in rheumatoid arthritis — clonal relationships and anti-citrulline autoantibody producing cells. J. Autoimmun. 136, 103022 (2023).

    Article  CAS  PubMed  Google Scholar 

  22. Joshua, V. et al. Rheumatoid arthritis-specific autoimmunity in the lung before and at the onset of disease. Arthritis Rheumatol. 75, 1910–1922 (2023).

    Article  CAS  PubMed  Google Scholar 

  23. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Petkova, S. B. et al. Human antibodies induce arthritis in mice deficient in the low-affinity inhibitory IgG receptor FcγRIIB. J. Exp. Med. 203, 275–280 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 5, 178ra40 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Krishnamurthy, A. et al. Combination of two monoclonal anti–citrullinated protein antibodies induced tenosynovitis, pain, and bone loss in mice in a peptidyl arginine deiminase‐4-dependent manner. Arthritis Rheumatol. 75, 164–170 (2023).

    Article  CAS  PubMed  Google Scholar 

  29. Chirivi, R. G. S. et al. Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases. Cell Mol. Immunol. 18, 1528–1544 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Raposo, B. et al. Divergent and dominant anti-inflammatory effects of patient-derived anticitrullinated protein antibodies (ACPA) in arthritis development. Ann. Rheum. Dis. 82, 724–726 (2023).

    Article  CAS  PubMed  Google Scholar 

  31. He, Y. et al. A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis. Nat. Commun. 14, 691 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gomez, A. M. et al. Anti‐citrullinated protein antibodies with multiple specificities ameliorate collagen antibody‐induced arthritis in a time‐dependent manner. Arthritis Rheumatol. 76, 181–191 (2023).

    Article  PubMed  Google Scholar 

  33. Falkenburg, W. J. J. et al. Identification of clinically and pathophysiologically relevant rheumatoid factor epitopes by engineered IgG targets. Arthritis Rheumatol. 72, 2005–2016 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Oskam, N. et al. Rheumatoid factor autoantibody repertoire profiling reveals distinct binding epitopes in health and autoimmunity. Ann. Rheum. Dis. 82, 945–956 (2023).

    Article  CAS  PubMed  Google Scholar 

  35. Mergaert, A. M. et al. Rheumatoid factor and anti-modified protein antibody reactivities converge on IgG epitopes. Arthritis Rheumatol. 74, 984–991 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. 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 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Verheul, M. K. et al. Triple positivity for anti-citrullinated protein autoantibodies, rheumatoid factor, and anti-carbamylated protein antibodies conferring high specificity for rheumatoid arthritis. Arthritis Rheumatol. 70, 1721–1731 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Pecani, A. et al. Prevalence, sensitivity and specificity of antibodies against carbamylated proteins in a monocentric cohort of patients with rheumatoid arthritis and other autoimmune rheumatic diseases. Arthritis Res. Ther. 18, 276 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Grönwall, C. et al. A comprehensive evaluation of the relationship between different IgG and IgA anti-modified protein autoantibodies in rheumatoid arthritis. Front. Immunol. 12, 627986 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Figueiredo, C. P. et al. Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs. Ann. Rheum. Dis. 76, 399 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Studenic, P. et al. Presence of anti-acetylated peptide antibodies (AAPA) in inflammatory arthritis and other rheumatic diseases suggests discriminative diagnostic capacity towards early rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis. 13, 1759720X211022533 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Grönwall, C. et al. Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis. J. Autoimmun. 84, 29–45 (2017).

    Article  PubMed  Google Scholar 

  45. Thiele, G. M. et al. Malondialdehyde‐acetaldehyde adducts and anti–malondialdehyde‐acetaldehyde antibodies in rheumatoid arthritis. Arthritis Rheumatol. 67, 645–655 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mikuls, T. R. et al. Malondialdehyde–acetaldehyde antibody concentrations in rheumatoid arthritis and other rheumatic conditions. Int. Immunopharmacol. 56, 113–118 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Sahlström, P. et al. Autoreactive B cells against malondialdehyde-induced protein cross-links are present in the joint, lung, and bone marrow of rheumatoid arthritis patients. J. Biol. Chem. 299, 105320 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Harris, M. L. et al. Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis. Arthritis Rheum. 58, 1958–1967 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hassfeld, W. et al. Autoantibody to the nuclear antigen RA33: a marker for early rheumatoid arthritis. Rheumatology 32, 199–203 (1993).

    Article  CAS  Google Scholar 

  50. Yang, X. et al. Diagnostic accuracy of anti-RA33 antibody for rheumatoid arthritis: systematic review and meta-analysis. Clin. Exp. Rheumatol. 34, 539–547 (2015).

    Google Scholar 

  51. Konig, M. F., Giles, J. T., Nigrovic, P. A. & Andrade, F. Antibodies to native and citrullinated RA33 (hnRNP A2/B1) challenge citrullination as the inciting principle underlying loss of tolerance in rheumatoid arthritis. Ann. Rheum. Dis. 75, 2022 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Cappelli, L. C., Hines, D., Wang, H., Bingham, C. O. & Darrah, E. Anti-peptidylarginine deiminase 4 autoantibodies and disease duration as predictors of treatment response in rheumatoid arthritis. ACR Open. Rheumatol. 6, 81–90 (2024).

    Article  PubMed  Google Scholar 

  53. Lönnblom, E. et al. Autoantibodies to disease‐related proteins in joints as novel biomarkers for the diagnosis of rheumatoid arthritis. Arthritis Rheumatol. 75, 1110–1119 (2023).

    Article  PubMed  Google Scholar 

  54. Mullazehi, M., Wick, M. C., Klareskog, L., van Vollenhoven, R. & Rönnelid, J. Anti-type II collagen antibodies are associated with early radiographic destruction in rheumatoid arthritis. Arthritis Res. Ther. 14, R100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Steenbergen, H. W., van, Cope, A. P., Mil, A. H. M. & van der, H. Rheumatoid arthritis prevention in arthralgia: fantasy or reality? Nat. Rev. Rheumatol. 19, 767–777 (2023).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Jilani, A. A. & Mackworth-Young, C. G. The role of citrullinated protein antibodies in predicting erosive disease in rheumatoid arthritis: a systematic literature review and meta-analysis. Int. J. Rheumatol. 2015, 728610 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Berglin, E. et al. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann. Rheum. Dis. 65, 453 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Mewar, D. et al. Independent associations of anti-cyclic citrullinated peptide antibodies and rheumatoid factor with radiographic severity of rheumatoid arthritis. Arthritis Res. Ther. 8, R128 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kaltenhäuser, S. et al. Antibodies against cyclic citrullinated peptide are associated with the DRB1 shared epitope and predict joint erosion in rheumatoid arthritis. Rheumatology 46, 100–104 (2007).

    Article  PubMed  Google Scholar 

  61. 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 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Minocha, A., Kukran, S., Yee, P. & Nisar, M. The differential effect of antibodies on radiographic progression in rheumatoid arthritis. Mediterr. J. Rheumatol. 31, 393 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Pertsinidou, E. et al. In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation. Ann. Rheum. Dis. 83, 277–287 (2024).

    Article  PubMed  Google Scholar 

  64. Ajeganova, S. et al. The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor. Ann. Rheum. Dis. 76, 112 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. García-Moreno, C., Gómara, M. J., Castellanos-Moreira, R., Sanmartí, R. & Haro, I. Peptides bearing multiple post-translational modifications as antigenic targets for severe rheumatoid arthritis patients. Int. J. Mol. Sci. 22, 13290 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Regueiro, C. et al. Increased disease activity in early arthritis patients with anti-carbamylated protein antibodies. Sci. Rep. 11, 9945 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Nijjar, J. S. et al. The impact of autoantibodies against citrullinated, carbamylated, and acetylated peptides on radiographic progression in patients with new-onset rheumatoid arthritis: an observational cohort study. Lancet Rheumatol. 3, e284–e293 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Truchetet, M. et al. Association of the presence of anti–carbamylated protein antibodies in early arthritis with a poorer clinical and radiologic outcome. Arthritis Rheumatol. 69, 2292–2302 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Lo, K. C. et al. Comprehensive profiling of the rheumatoid arthritis antibody repertoire. Arthritis Rheumatol. 72, 242–250 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Zheng, Z. et al. Disordered antigens and epitope overlap between anti-citrullinated protein antibodies and rheumatoid factor in rheumatoid arthritis. Arthritis Rheumatol. 72, 262–272 (2020).

    Article  CAS  PubMed  Google Scholar 

  71. Willemze, A. et al. The interaction between HLA shared epitope alleles and smoking and its contribution to autoimmunity against several citrullinated antigens. Arthritis Rheum. 63, 1823–1832 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. 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 

  73. Hansson, M. et al. Validation of a multiplex chip-based assay for the detection of autoantibodies against citrullinated peptides. Arthritis Res. Ther. 14, R201 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Beers et al. ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression. Arthritis Res. Ther. 15, R140–R140 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 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 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Too, C. L. et al. Differences in the spectrum of anti-citrullinated protein antibody fine specificities between Malaysian and Swedish patients with rheumatoid arthritis: implications for disease pathogenesis. Arthritis Rheumatol. 69, 58–69 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Rönnelid, J. et al. Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive rheumatoid arthritis patients with distinct genetic and environmental determinants. Ann. Rheum. Dis. 77, 203 (2018).

    Article  PubMed  Google Scholar 

  78. Scherer, H. U. et al. Distinct ACPA fine specificities, formed under the influence of HLA shared epitope alleles, have no effect on radiographic joint damage in rheumatoid arthritis. Ann. Rheum. Dis. 70, 1461 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Nielen, M. M. J. 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 

  80. 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 (2010).

    Article  PubMed  Google Scholar 

  81. 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  PubMed  Google Scholar 

  82. Bos, W. H., van de Stadt, L. A., Sohrabian, A., Rönnelid, J. & van Schaardenburg, D. Development of anti-citrullinated protein antibody and rheumatoid factor isotypes prior to the onset of rheumatoid arthritis. Arthritis Res. Ther. 16, 405 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Tanner, S. et al. A prospective study of the development of inflammatory arthritis in the family members of indigenous North American people with rheumatoid arthritis. Arthritis Rheumatol. 71, 1494–1503 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Kelmenson, L. B. et al. Timing of elevations of autoantibody isotypes prior to diagnosis of rheumatoid arthritis. Arthritis Rheumatol. 72, 251–261 (2020).

    Article  CAS  PubMed  Google Scholar 

  85. Brink, M. et al. Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis. Arthritis Res. Ther. 18, 43 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Lingampalli, N. et al. Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis. Clin. Immunol. 195, 119–126 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Kissel, T. et al. IgG anti-citrullinated protein antibody variable domain glycosylation increases before the onset of rheumatoid arthritis and stabilizes thereafter: a cross‐sectional study encompassing ~1,500 samples. Arthritis Rheumatol. 74, 1147–1158 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kissel, T. et al. On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis. Ann. Rheum. Dis. 78, 1616 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Hafkenscheid, L. et al. N‐linked glycans in the variable domain of IgG anti–citrullinated protein antibodies predict the development of rheumatoid arthritis. Arthritis Rheumatol. 71, 1626–1633 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. O’Neil, L. J., Meng, X., Mcfadyen, C., Fritzler, M. J. & El-Gabalawy, H. S. Serum proteomic networks associate with pre-clinical rheumatoid arthritis autoantibodies and longitudinal outcomes. Front. Immunol. 13, 958145 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  91. 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  Google Scholar 

  92. Gunasekera, S. et al. Stabilized cyclic peptides as scavengers of autoantibodies: neutralization of anticitrullinated protein/peptide antibodies in rheumatoid arthritis. ACS Chem. Biol. 13, 1525–1535 (2018).

    Article  CAS  PubMed  Google Scholar 

  93. Szarka, E. et al. Affinity purification and comparative biosensor analysis of citrulline-peptide-specific antibodies in rheumatoid arthritis. Int. J. Mol. Sci. 19, 326 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Willemze, A. et al. The concentration of anticitrullinated protein antibodies in serum and synovial fluid in relation to total immunoglobulin concentrations. Ann. Rheum. Dis. 72, 1059 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. 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 

  96. Cîrciumaru, A. et al. Anti-citrullinated protein antibody reactivity towards neutrophil-derived antigens: clonal diversity and inter-individual variation. Biomolecules 13, 630 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Raats, J. M. H., Wijnen, E. M., Pruijn, G. J. M., van den Hoogen, F. H. J. & van Venrooij, W. J. Recombinant human monoclonal autoantibodies specific for citrulline-containing peptides from phage display libraries derived from patients with rheumatoid arthritis. J. Rheumatol. 30, 1696–1711 (2003).

    CAS  PubMed  Google Scholar 

  98. Elliott, S. E. et al. Affinity maturation drives epitope spreading and generation of proinflammatory anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis Rheumatol. 70, 1946–1958 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lu, D. R. et al. T cell-dependent affinity maturation and innate immune pathways differentially drive autoreactive B cell responses in rheumatoid arthritis. Arthritis Rheumatol. 70, 1732–1744 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kissel, T. et al. Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications. Ann. Rheum. Dis. 79, 472 (2020).

    Article  CAS  PubMed  Google Scholar 

  101. Reijm, S. et al. Cross-reactivity of IgM anti-modified protein antibodies in rheumatoid arthritis despite limited mutational load. Arthritis Res. Ther. 23, 230 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Traggiai, E. et al. An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat. Med. 10, 871–875 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lloyd, K. A. et al. Variable domain N‐linked glycosylation and negative surface charge are key features of monoclonal ACPA: implications for B‐cell selection. Eur. J. Immunol. 48, 1030–1045 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Germar, K. et al. Generation and characterization of anti-citrullinated protein antibody-producing B cell clones from rheumatoid arthritis patients. Arthritis Rheumatol. 71, 340–350 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. Sahlström, P. et al. Different hierarchies of anti-modified protein autoantibody reactivities in rheumatoid arthritis. Arthritis Rheumatol. 72, 1643–1657 (2020).

    Article  PubMed  Google Scholar 

  106. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Tiller, T. et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112–124 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Amara, K. et al. A refined protocol for identifying citrulline-specific monoclonal antibodies from single human B cells from rheumatoid arthritis patient material. Bio Protoc. 9, e3347 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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 (2016).

    Article  CAS  PubMed  Google Scholar 

  110. 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 

  111. Amara, K. et al. Retraction: monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J. Exp. Med. 216, 245–245 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hardt, U. et al. Integrated single cell and spatial transcriptomics reveal autoreactive differentiated B cells in joints of early rheumatoid arthritis. Sci. Rep. 12, 11876 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tan, Y. 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 

  114. Amara, K. et al. B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis. J. Autoimmun. 81, 34–43 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sherina, N. et al. Antibodies to a citrullinated Porphyromonas gingivalis epitope are increased in early rheumatoid arthritis, and can be produced by gingival tissue B cells: implications for a bacterial origin in RA etiology. Front. Immunol. 13, 804822 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rispens, T. & Huijbers, M. G. The unique properties of IgG4 and its roles in health and disease. Nat. Rev. Immunol. 23, 763–778 (2023).

    Article  CAS  PubMed  Google Scholar 

  117. Lloyd, K. A. et al. Differential ACPA binding to nuclear antigens reveals a PAD-independent pathway and a distinct subset of acetylation cross-reactive autoantibodies in rheumatoid arthritis. Front. Immunol. 9, 3033 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Ge, C. et al. Structural basis of cross‐reactivity of anti-citrullinated protein antibodies. Arthritis Rheumatol. 71, 210–221 (2019).

    Article  CAS  PubMed  Google Scholar 

  119. Suwannalai, P. et al. Anti-citrullinated protein antibodies have a low avidity compared with antibodies against recall antigens. Ann. Rheum. Dis. 70, 373 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Yamada, H. et al. Low avidity observed for anti-citrullinated peptide antibody is not a general phenomenon for autoantibodies. Ann. Rheum. Dis. 82, 1637–1638 (2023).

    Article  CAS  PubMed  Google Scholar 

  121. Tilvawala, R. et al. The rheumatoid arthritis-associated citrullinome. Cell Chem. Biol. 25, 691–704.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kissel, T. et al. Surface Ig variable domain glycosylation affects autoantigen binding and acts as threshold for human autoreactive B cell activation. Sci. Adv. 8, eabm1759 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ferdous, S., Kelm, S., Baker, T. S., Shi, J. & Martin, A. C. R. B-cell epitopes: discontinuity and conformational analysis. Mol. Immunol. 114, 643–650 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Hardt, U. et al. Analysis of IGH allele content in a sample group of rheumatoid arthritis patients demonstrates unrevealed population heterogeneity. Front. Immunol. 14, 1073414 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Avnir, Y. et al. IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity. Sci. Rep. 6, 20842 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lee, J. H. et al. Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor naïve human B cells. NPJ Vaccines 6, 113 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Pushparaj, P. et al. Immunoglobulin germline gene polymorphisms influence the function of SARS-CoV-2 neutralizing antibodies. Immunity 56, 193–206.e7 (2023).

    Article  CAS  PubMed  Google Scholar 

  128. Förster, M. et al. Genetic control of antibody production during collagen‐induced arthritis development in heterogeneous stock mice. Arthritis Rheum. 64, 3594–3603 (2012).

    Article  PubMed  Google Scholar 

  129. Raposo, B. et al. Epitope-specific antibody response is controlled by immunoglobulin VH polymorphisms. J. Exp. Med. 211, 405–411 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  131. Dekkers, G., Rispens, T. & Vidarsson, G. Novel concepts of altered immunoglobulin G galactosylation in autoimmune diseases. Front. Immunol. 9, 553 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  132. van de Bovenkamp, F. S. et al. Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. Proc. Natl Acad. Sci. USA 115, 1901–1906 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Hafkenscheid, L. et al. Structural analysis of variable domain glycosylation of anti-citrullinated protein antibodies in rheumatoid arthritis reveals the presence of highly sialylated glycans. Mol. Cell. Proteom. 16, 278–287 (2017).

    Article  CAS  Google Scholar 

  134. Vergroesen, R. D. et al. B-cell receptor sequencing of anti-citrullinated protein antibody (ACPA) IgG-expressing B cells indicates a selective advantage for the introduction of N-glycosylation sites during somatic hypermutation. Ann. Rheum. Dis. 77, 956 (2018).

    PubMed  Google Scholar 

  135. Bovenkamp, F. S., van de, Hafkenscheid, L., Rispens, T. & Rombouts, Y. The emerging importance of IgG Fab glycosylation in immunity. J. Immunol. 196, 1435–1441 (2016).

    Article  PubMed  Google Scholar 

  136. Hamza, N. et al. Ig gene analysis reveals altered selective pressures on Ig-producing cells in parotid glands of primary Sjögren’s syndrome patients. J. Immunol. 194, 514–521 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Visser, A., Hamza, N., Kroese, F. G. M. & Bos, N. A. Acquiring new N-glycosylation sites in variable regions of immunoglobulin genes by somatic hypermutation is a common feature of autoimmune diseases. Ann. Rheum. Dis. 77, e69 (2018).

    Article  PubMed  Google Scholar 

  138. Koers, J. et al. Differences in IgG autoantibody Fab glycosylation across autoimmune diseases. J. Allergy Clin. Immunol. 151, 1646–1654 (2023).

    Article  CAS  PubMed  Google Scholar 

  139. van de Bovenkamp, F. S. et al. Variable domain N-linked glycans acquired during antigen-specific immune responses can contribute to immunoglobulin G antibody stability. Front. Immunol. 9, 740 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Coloma, M. J., Trinh, R. K., Martinez, A. R. & Morrison, S. L. Position effects of variable region carbohydrate on the affinity and in vivo behavior of an anti-(1→6) dextran antibody. J. Immunol. 162, 2162–2170 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Oskam, N. et al. Factors affecting IgG4-mediated complement activation. Front. Immunol. 14, 1087532 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kawataka, M. et al. N -glycan in the monoclonal ACPA, CCP-Ab1 the variable region promotes the exacerbation of experimental arthritis. Rheumatology https://doi.org/10.1093/rheumatology/kead130 (2023).

    Article  PubMed  Google Scholar 

  143. Zhang, F. et al. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature 623, 616–624 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Samuels, J., Ng, Y.-S., Coupillaud, C., Paget, D. & Meffre, E. Impaired early B cell tolerance in patients with rheumatoid arthritis. J. Exp. Med. 201, 1659–1667 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wang, Y. et al. Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance. Sci. Rep. 9, 19995 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Rincón‐Arévalo, H. et al. Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthritis. Clin. Exp. Immunol. 204, 221–238 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Cowan, G. J. M. et al. In human autoimmunity, a substantial component of the B cell repertoire consists of polyclonal, barely mutated IgG+ve B cells. Front. Immunol. 11, 395 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wing, E. et al. Double-negative-2 B cells are the major synovial plasma cell precursor in rheumatoid arthritis. Front. Immunol. 14, 1241474 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Neys, S. F. H. et al. Aberrant B cell receptor signaling in circulating naïve and IgA+ memory B cells from newly-diagnosed autoantibody-positive rheumatoid arthritis patients. J. Autoimmun. 143, 103168 (2023).

    Article  Google Scholar 

  150. Kristyanto, H. et al. Persistently activated, proliferative memory autoreactive B cells promote inflammation in rheumatoid arthritis. Sci. Transl. Med. 12, eaaz5327 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Joshua, V. et al. Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells. Arthritis Res. Ther. 18, 284 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Kerkman, P. F. et al. Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis. Ann. Rheum. Dis. 75, 1170 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Reijm, S. et al. Autoreactive B cells in rheumatoid arthritis include mainly activated CXCR3+ memory B cells and plasmablasts. JCI Insight 8, e172006 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Elsner, R. A. & Shlomchik, M. J. Germinal center and extrafollicular B cell responses in vaccination, immunity, and autoimmunity. Immunity 53, 1136–1150 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Vidal‐Pedrola, G. et al. Characterization of age‐associated B cells in early drug‐naïve rheumatoid arthritis patients. Immunology 168, 640–653 (2023).

    Article  PubMed  Google Scholar 

  156. Horns, F. et al. Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching. eLife 5, e16578 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Cerutti, A. The regulation of IgA class switching. Nat. Rev. Immunol. 8, 421–434 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Braham, M. V. J. et al. A synthetic human 3D in vitro lymphoid model enhancing B-cell survival and functional differentiation. iScience 26, 105741 (2023).

    Article  CAS  PubMed  Google Scholar 

  159. Yoshitomi, H. Peripheral helper T cells, mavericks of peripheral immune responses. Int. Immunol. 36, 9–16 (2023).

    Article  PubMed Central  Google Scholar 

  160. Malmström, V., Catrina, A. I. & Klareskog, L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat. Rev. Immunol. 17, 60–75 (2017).

    Article  PubMed  Google Scholar 

  161. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Pieper, J. et al. Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint. J. Autoimmun. 92, 47–56 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Song, J. et al. Shared recognition of citrullinated tenascin-C peptides by T and B cells in rheumatoid arthritis. JCI Insight 6, e145217 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Rims, C. et al. Citrullinated aggrecan epitopes as targets of autoreactive CD4+ T cells in patients with rheumatoid arthritis. Arthritis Rheumatol. 71, 518–528 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Curran, A. M. et al. Citrullination modulates antigen processing and presentation by revealing cryptic epitopes in rheumatoid arthritis. Nat. Commun. 14, 1061 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 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. 7, 494 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Lim, J. J. et al. The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR. Sci. Immunol. 6, eabe0896 (2021).

    Article  CAS  PubMed  Google Scholar 

  168. Romero, V. et al. Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis. Sci. Transl. Med. 5, 209ra150 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Molberg, Ø. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4, 713–717 (1998).

    Article  CAS  PubMed  Google Scholar 

  170. Darrah, E. et al. Proteolysis by granzyme B enhances presentation of autoantigenic peptidylarginine deiminase 4 epitopes in rheumatoid arthritis. J. Proteome Res. 16, 355–365 (2017).

    Article  CAS  PubMed  Google Scholar 

  171. Musters, A. et al. In rheumatoid arthritis inflamed joints share dominant patient-specific B-cell clones. Front. Immunol. 13, 915687 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 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 

  173. 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 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 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 (2015).

    Article  PubMed  Google Scholar 

  175. Karlson, E. W. et al. A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals. Arthritis Rheum. 42, 910–917 (1999).

    Article  CAS  PubMed  Google Scholar 

  176. 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 

  177. 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 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Wouters, F. et al. Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis. Ann. Rheum. Dis. 81, 48–55 (2022).

    Article  CAS  PubMed  Google Scholar 

  179. Kilsgård, O. et al. Peptidylarginine deiminases present in the airways during tobacco smoking and inflammation can citrullinate the host defense peptide LL-37, resulting in altered activities. Am. J. Resp. Cell Mol. 46, 240–248 (2011).

    Article  Google Scholar 

  180. Lugli, E. B. et al. Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smokers: implications for autoimmunity in rheumatoid arthritis. Arthritis Res. Ther. 17, 9 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  181. 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 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hedström, A. K., Rönnelid, J., Klareskog, L. & Alfredsson, L. Complex relationships of smoking, HLA–DRB1 genes, and serologic profiles in patients with early rheumatoid arthritis: update from a Swedish population‐based case–control study. Arthritis Rheumatol. 71, 1504–1511 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Ishikawa, Y. et al. Shared epitope defines distinct associations of cigarette smoking with levels of anticitrullinated protein antibody and rheumatoid factor. Ann. Rheum. Dis. 78, 1480 (2019).

    Article  CAS  PubMed  Google Scholar 

  185. Demoruelle, M. K. et al. Anti-citrullinated protein antibodies are associated with neutrophil extracellular traps in the sputum in relatives of rheumatoid arthritis patients. Arthritis Rheumatol. 69, 1165–1175 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. 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).

    Article  CAS  PubMed  Google Scholar 

  187. Ytterberg, A. J. et al. Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. Ann. Rheum. Dis. 74, 1772 (2015).

    Article  CAS  PubMed  Google Scholar 

  188. Roelsgaard, I. K. et al. Smoking cessation is associated with lower disease activity and predicts cardiovascular risk reduction in rheumatoid arthritis patients. Rheumatology 59, 1997–2004 (2019).

    Article  PubMed Central  Google Scholar 

  189. Giuseppe, D. D., Orsini, N., Alfredsson, L., Askling, J. & Wolk, A. Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in women. Arthritis Res. Ther. 15, R56 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Liu, X. et al. Impact and timing of smoking cessation on reducing risk of rheumatoid arthritis among women in the Nurses’ Health Studies. Arthritis Care Res. 71, 914–924 (2019).

    Article  Google Scholar 

  191. Li, S., Yu, Y., Yue, Y., Zhang, Z. & Su, K. Microbial infection and rheumatoid arthritis. J. Clin. Cell Immunol. 4, 174 (2013).

    PubMed  PubMed Central  Google Scholar 

  192. Griffante, G. et al. Human cytomegalovirus-induced host protein citrullination is crucial for viral replication. Nat. Commun. 12, 3910 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Kalla, M. & Hammerschmidt, W. Human B cells on their route to latent infection — early but transient expression of lytic genes of Epstein-Barr virus. Eur. J. Cell Biol. 91, 65–69 (2012).

    Article  CAS  PubMed  Google Scholar 

  194. Sherina, N. et al. Low levels of antibodies against common viruses associate with anti-citrullinated protein antibody-positive rheumatoid arthritis; implications for disease aetiology. Arthritis Res. Ther. 19, 219 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Fechtner, S. et al. Antibody responses to Epstein‐Barr virus in the preclinical period of rheumatoid arthritis suggest the presence of increased viral reactivation cycles. Arthritis Rheumatol. 74, 597–603 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Pratesi, F., Tommasi, C., Anzilotti, C., Chimenti, D. & Migliorini, P. Deiminated Epstein‐Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis Rheum. 54, 733–741 (2006).

    Article  CAS  PubMed  Google Scholar 

  197. Pratesi, F. et al. Antibodies to a new viral citrullinated peptide, VCP2: fine specificity and correlation with anti‐cyclic citrullinated peptide (CCP) and anti‐VCP1 antibodies. Clin. Exp. Immunol. 164, 337–345 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Tsuda, R. et al. Monoclonal antibody against citrullinated peptides obtained from rheumatoid arthritis patients reacts with numerous citrullinated microbial and food proteins. Arthritis Rheumatol. 67, 2020–2031 (2015).

    Article  CAS  PubMed  Google Scholar 

  199. Brewer, R. C. et al. Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Sci. Transl. Med. 15, eabq8476 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Fuggle, N. R., Smith, T. O., Kaul, A. & Sofat, N. Hand to mouth: a systematic review and meta-analysis of the association between rheumatoid arthritis and periodontitis. Front. Immunol. 7, 80 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Mankia, K. et al. Prevalence of periodontal disease and periodontopathic bacteria in anti-cyclic citrullinated protein antibody-positive at-risk adults without arthritis. JAMA Netw. Open. 2, e195394 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  202. 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  Google Scholar 

  203. González‐Febles, J. & Sanz, M. Periodontitis and rheumatoid arthritis: what have we learned about their connection and their treatment? Periodontol. 2000 87, 181–203 (2021).

    Article  PubMed  Google Scholar 

  204. Quirke, A.-M. et al. Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Ann. Rheum. Dis. 73, 263 (2014).

    Article  CAS  PubMed  Google Scholar 

  205. Johansson, L. et al. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. Arthritis Res. Ther. 18, 201 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Jenning, M. et al. Bacterial citrullinated epitopes generated by Porphyromonas gingivalis infection — a missing link for ACPA production. Ann. Rheum. Dis. 79, 1194–1202 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Goulas, T. et al. Structure and mechanism of a bacterial host-protein citrullinating virulence factor, Porphyromonas gingivalis peptidylarginine deiminase. Sci. Rep. 5, 11969 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Kearney, K. J., Ariëns, R. A. S. & Macrae, F. L. The role of fibrin(ogen) in wound healing and infection control. Semin. Thromb. Hemost. 48, 174–187 (2022).

    Article  CAS  PubMed  Google Scholar 

  210. Eckes, B. et al. Impaired wound healing in embryonic and adult mice lacking vimentin. J. Cell Sci. 113, 2455–2462 (2000).

    Article  CAS  PubMed  Google Scholar 

  211. Midwood, K. et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 15, 774–780 (2009).

    Article  CAS  PubMed  Google Scholar 

  212. Engström, M. et al. Increased citrullination and expression of peptidylarginine deiminases independently of P. gingivalis and A. actinomycetemcomitans in gingival tissue of patients with periodontitis. J. Transl. Med. 16, 214 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Courbon, G. et al. Porphyromonas gingivalis experimentally induces periodontis and an anti-CCP2-associated arthritis in the rat. Ann. Rheum. Dis. 78, 594 (2019).

    Article  CAS  PubMed  Google Scholar 

  214. Kim, T. S. et al. Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis. J. Exp. Med. 220, e20221751 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Svärd, A. et al. Antibodies against Porphyromonas gingivalis in serum and saliva and their association with rheumatoid arthritis and periodontitis. Data from two rheumatoid arthritis cohorts in Sweden. Front. Immunol. 14, 1183194 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Bender, P., Bürgin, W. B., Sculean, A. & Eick, S. Serum antibody levels against Porphyromonas gingivalis in patients with and without rheumatoid arthritis — a systematic review and meta-analysis. Clin. Oral. Investig. 21, 33–42 (2017).

    Article  PubMed  Google Scholar 

  217. 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 

  218. Konig, M. F. et al. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci. Transl. Med. 8, 369ra176 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Volkov, M. et al. Comment on “Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis.”. Sci. Transl. Med. 10, eaan8349 (2018).

    Article  PubMed  Google Scholar 

  220. Longman, R. S. & Littman, D. R. The functional impact of the intestinal microbiome on mucosal immunity and systemic autoimmunity. Curr. Opin. Rheumatol. 27, 381–387 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  222. Chriswell, M. E. et al. Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum. Sci. Transl. Med. 14, eabn5166 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Scher, J. U. et al. The lung microbiota in early rheumatoid arthritis and autoimmunity. Microbiome 4, 60 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Zhang, X. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 21, 895–905 (2015).

    Article  CAS  PubMed  Google Scholar 

  225. Alpizar-Rodriguez, D. et al. Prevotella copri in individuals at risk for rheumatoid arthritis. Ann. Rheum. Dis. 78, 590 (2019).

    Article  CAS  PubMed  Google Scholar 

  226. Chen, K., Magri, G., Grasset, E. K. & Cerutti, A. Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA. Nat. Rev. Immunol. 20, 427–441 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. 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–R13 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Ljungberg, K. R. et al. Presence of salivary IgA anti-citrullinated protein antibodies associate with higher disease activity in patients with rheumatoid arthritis. Arthritis Res. Ther. 22, 274 (2020).

    Article  Google Scholar 

  230. Svärd, 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  Google Scholar 

  231. Rahajoe, P. S. et al. Increased IgA anti‐citrullinated protein antibodies in the periodontal inflammatory exudate of healthy individuals compared to rheumatoid arthritis patients. J. Clin. Periodontol. 47, 552–560 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Sokolova, M. V. et al. Antibodies against citrullinated proteins of IgA isotype are associated with progression to rheumatoid arthritis in individuals at-risk. RMD Open. 9, e002705 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Kinslow, J. D. et al. Elevated IgA plasmablast levels in subjects at risk of developing rheumatoid arthritis. Arthritis Rheumatol. Hoboken N. J. 68, 2372–2383 (2016).

    Article  CAS  Google Scholar 

  234. Aleyd, E., Al, M., Tuk, C. W., van der Laken, C. J. & van Egmond, M. IgA complexes in plasma and synovial fluid of patients with rheumatoid arthritis induce neutrophil extracellular traps via FcαRI. J. Immunol. 197, 4552–4559 (2016).

    Article  CAS  PubMed  Google Scholar 

  235. Lundberg, K. et al. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res. Ther. 7, R458–R467 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Sun, M. et al. Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts. Ann. Rheum. Dis. 78, 1621 (2019).

    Article  CAS  PubMed  Google Scholar 

  237. Simon, M. et al. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called “antikeratin antibodies,” autoantibodies specific for rheumatoid arthritis. J. Clin. Investig. 92, 1387–1393 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. 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).

    Article  CAS  PubMed  Google Scholar 

  239. Vincent, C. et al. High diagnostic value in rheumatoid arthritis of antibodies to the stratum corneum of rat oesophagus epithelium, so-called “antikeratin antibodies”. Ann. Rheum. Dis. 48, 712 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Lee, C.-Y. et al. Mining the human tissue proteome for protein citrullination. Mol. Cell. Proteom. 17, 1378–1391 (2018).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  242. 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 (2016).

    Article  CAS  PubMed  Google Scholar 

  243. Engdahl, C. et al. Periarticular bone loss in arthritis is induced by autoantibodies against citrullinated vimentin. J. Bone Min. Res. 32, 1681–1691 (2017).

    Article  CAS  Google Scholar 

  244. Krishnamurthy, A. et al. Citrullination controls dendritic cell transdifferentiation into osteoclasts. J. Immunol. 202, ji1800534 (2019).

    Article  Google Scholar 

  245. Jurczak, A. et al. Antibody-induced pain-like behavior and bone erosion: links to subclinical inflammation, osteoclast activity, and acid-sensing ion channel 3-dependent sensitization. Pain 163, 1542–1559 (2022).

    Article  CAS  PubMed  Google Scholar 

  246. Shindo, S. et al. Extracellular release of citrullinated vimentin directly acts on osteoclasts to promote bone resorption in a mouse model of periodontitis. Cells 12, 1109 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Amulic, B., Cazalet, C., Hayes, G. L., Metzler, K. D. & Zychlinsky, A. Neutrophil function: from mechanisms to disease. Annu. Rev. Immunol. 30, 459–489 (2012).

    Article  CAS  PubMed  Google Scholar 

  248. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    Article  CAS  PubMed  Google Scholar 

  249. Fert‐Bober, J., Darrah, E. & Andrade, F. Insights into the study and origin of the citrullinome in rheumatoid arthritis. Immunol. Rev. 294, 133–147 (2020).

    Article  PubMed  Google Scholar 

  250. Chirivi, R. G. S., Jenniskens, G. J. & Raats, J. M. H. Anti-citrullinated protein antibodies as novel therapeutic drugs in rheumatoid arthritis. J. Clin. Cell. Immunol. S6, 1–13 (2013).

    Google Scholar 

  251. Sohn, D. H. et al. Local joint inflammation and histone citrullination in a murine model of the transition from preclinical autoimmunity to inflammatory arthritis. Arthritis Rheumatol. 67, 2877–2887 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Lande, R. et al. Generation of monoclonal antibodies specific for native LL37 and citrullinated LL37 that discriminate the two LL37 forms in the skin and circulation of cutaneous/systemic lupus erythematosus and rheumatoid arthritis patients. Antibodies 9, 14 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Stork, E. M. et al. Antigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis. Nat. Commun. 15, 3114 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Goldman, J. A. et al. Limited plasmapheresis in rheumatoid arthritis with vasculitis. Arthritis Rheum. 22, 1146–1150 (1979).

    Article  CAS  PubMed  Google Scholar 

  255. Wallace, D. J. et al. Plasmapheresis and lymphoplasmapheresis in the management of rheumatoid arthritis. Arthritis Rheum. 22, 703–710 (1979).

    Article  CAS  PubMed  Google Scholar 

  256. Cheng, Y. et al. Plasmapheresis therapy in combination with TNF-α inhibitor and DMARDs: a multitarget method for the treatment of rheumatoid arthritis. Mod. Rheumatol. 27, 1–17 (2016).

    Google Scholar 

  257. Rothwell, R. S. et al. A controlled study of plasma exchange in the treatment of severe rheumatoid arthritis. Arthritis Rheum. 23, 785–790 (1980).

    Article  CAS  PubMed  Google Scholar 

  258. Dwosh, I. L., Giles, A. R., Ford, P. M., Pater, J. L. & Anastassiades, T. P. Plasmapheresis therapy in rheumatoid arthritis — a controlled, double-blind, crossover trial. N. Engl. J. Med. 308, 1124–1129 (1983).

    Article  CAS  PubMed  Google Scholar 

  259. Felson, D. T. et al. The Prosorba column for treatment of refractory rheumatoid arthritis: a randomized, double‐blind, sham‐controlled trial. Arthritis Rheum. 42, 2153–2159 (1999).

    Article  CAS  PubMed  Google Scholar 

  260. Gendreau, R. M. & Group, P. C. T. A randomized double-blind sham-controlled trial of the Prosorba column for treatment of refractory rheumatoid arthritis. Ther. Apher. 5, 79–83 (2001).

    Article  CAS  PubMed  Google Scholar 

  261. Taylor, P. C. et al. Efficacy and safety of nipocalimab in patients with moderate to severe active rheumatoid arthritis (RA): the multicenter, randomized, double-blinded, placebo controlled phase 2a IRIS-RA study. ACR Convergence 2023 (2023).

  262. 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 

  263. Raposo, B. et al. POS1040 patient-derived ACPA clones display both pro- and anti-inflammatory potential in vivo. Ann. Rheum. Dis. 82, 837 (2023).

    Google Scholar 

  264. Ozawa, T. et al. Physiologic target, molecular evolution, and pathogenic functions of a monoclonal anti–citrullinated protein antibody obtained from a patient with rheumatoid arthritis. Arthritis Rheumatol. 72, 2040–2049 (2020).

    Article  CAS  PubMed  Google Scholar 

  265. Ho, P. P. et al. Autoimmunity against fibrinogen mediates inflammatory arthritis in mice. J. Immunol. 184, 379–390 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  267. Courtenay, J. S., Dallman, M. J., Dayan, A. D., Martin, A. & Mosedale, B. Immunisation against heterologous type II collagen induces arthritis in mice. Nature 283, 283666a0 (1980).

    Article  Google Scholar 

  268. Ge, C. et al. Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage. JCI Insight 2, e93688 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  269. Boissier, M., Chiocchia, G., Ronziere, M., Herbage, D. & Fournier, C. Arthritogenicity of minor cartilage collagens (types IX and XI) in mice. Arthritis Rheum. 33, 1–8 (1990).

    Article  CAS  PubMed  Google Scholar 

  270. Cremer et al. Immunity to type IX collagen in rodents: a study of type IX collagen for autoimmune and arthritogenic activities. Clin. Exp. Immunol. 112, 375–382 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Lu, S., Carlsen, S., Hansson, A.-S. & Holmdahl, R. Immunization of rats with homologous type xi collagen leads to chronic and relapsing arthritis with different genetics and joint pathology than arthritis induced with homologous type II collagen. J. Autoimmun. 18, 199–211 (2002).

    Article  PubMed  Google Scholar 

  272. Svetlicky, N. et al. Anti‐citrullinated‐protein‐antibody‐specific intravenous immunoglobulin attenuates collagen‐induced arthritis in mice. Clin. Exp. Immunol. 182, 241–250 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Clavel, C. et al. Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 58, 678–688 (2008).

    Article  CAS  PubMed  Google Scholar 

  274. 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 

  275. Laurent, L. et al. IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies. Ann. Rheum. Dis. 74, 1425 (2015).

    Article  CAS  PubMed  Google Scholar 

  276. 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 

  277. Duplan, V. et al. In the rat, citrullinated autologous fibrinogen is immunogenic but the induced autoimmune response is not arthritogenic. Clin. Exp. Immunol. 145, 502–512 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Hill, J. A. et al. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. J. Exp. Med. 205, 967–979 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Cantaert, T., Teitsma, C., Tak, P. P. & Baeten, D. Presence and role of anti-citrullinated protein antibodies in experimental arthritis models. Arthritis Rheum. 65, 939–948 (2013).

    Article  CAS  PubMed  Google Scholar 

  280. Thiele, G. M. et al. Citrullinated mouse collagen administered to DBA/1J mice in the absence of adjuvant initiates arthritis. Int. Immunopharmacol. 13, 424–431 (2012).

    Article  CAS  PubMed  Google Scholar 

  281. Ribon, M. et al. Neutrophil extracellular traps exert both pro- and anti-inflammatory actions in rheumatoid arthritis that are modulated by C1q and LL-37. J. Autoimmun. 98, 122–131 (2019).

    Article  CAS  PubMed  Google Scholar 

  282. Yamada, H. et al. Cutting edge: B cells expressing cyclic citrullinated peptide-specific antigen receptor are tolerized in normal conditions. J. Immunol. 201, 3492–3496 (2018).

    Article  PubMed  Google Scholar 

  283. Cope, A. P. et al. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial. Lancet 403, 838–849 (2024).

    Article  CAS  PubMed  Google Scholar 

  284. Rech, J. et al. Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial. Lancet 403, 850–859 (2024).

    Article  CAS  PubMed  Google Scholar 

  285. Jurczak, A. et al. Insights into FcγR involvement in pain-like behavior induced by an RA-derived anti-modified protein autoantibody. Brain Behav. Immun. 113, 212–227 (2023).

    Article  CAS  PubMed  Google Scholar 

  286. Wang, X. et al. Autoantibodies against unmodified and citrullinated human endogenous retrovirus K envelope protein in patients with rheumatoid arthritis. J. Rheumatol. 49, 26–35 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Raposo, B., Klareskog, L., Robinson, W.H. et al. The peculiar features, diversity and impact of citrulline-reactive autoantibodies. Nat Rev Rheumatol 20, 399–416 (2024). https://doi.org/10.1038/s41584-024-01124-6

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