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Editorial
 
Citrullinated Antigens: Just Diagnostic Tools or Pathogenic Targets in Rheumatoid Arthritis? EUGEN FEIST, MD,
Harvard Medical School, Boston, Massachusetts, USA; GERD R. BURMESTER, MD, Address reprint requests to Dr. G. Burmester, Humboldt University of Berlin, Department of Rheumatology and Clinical Immunology, Schumannstrasse 20/21, D-10098 Berlin, Germany. E-mail: gerd.burmester@charite.de The diagnostic procedures of rheumatoid arthritis (RA), being the former domain of clinical and imaging findings, were significantly improved with the introduction of novel immunoassays. Thus, autoantibodies against citrullinated antigens were confirmed by numerous studies to represent powerful markers for established RA, and moreover were found to be highly specific for early and undifferentiated disease manifestations1-3. Moreover, identification of citrullination as an important posttranslational modification of autoantigens in RA has not only provided a valuable diagnostic tool, but, surprisingly, has also opened a door for several old, as well as novel, promising antigens. However, the pivotal question remains: Is this only an epiphenomenon of the complex autoimmune disorder RA, or a part of the pathogenesis? Citrullination is a posttranslational modification of arginine residues catalyzed by a family of calcium-binding enzymes, the peptidylarginine deiminases, of which 5 different but strongly related isoforms have been identified to date4. The product of citrullination is the non-standard amino acid citrulline, which contributes to the backbone of certain proteins. By decreasing the net positive charge, citrullination can alter the primary, secondary, and tertiary structure of a protein, with potential influence on intermolecular interactions. Such a modification of proteins is involved in several physiological processes, e.g., conversion of filaggrin in keratinocyte differentiation or of vimentin in apoptosis5,6. Interestingly, distinct haplotypes of the peptidylarginine deiminase 4 gene were found to be related to the manifestation of RA in Asian but not European populations, and the enzyme itself was identified as an autoantigen7-10. It was shown that citrullination occurs within the inflamed synovial tissue11. However, filaggrin as well as the synthetic antigen cyclic citrullinated peptide (CCP) are not expressed in the synovium, and therefore are unlikely to represent the primary targets of the autoimmune response. Subsequently, citrullinated fibrin, as a cleavage product of fibrinogen, was identified as the major target of antibodies against citrullinated antigens in RA, exhibiting a close cross-reactivity to filiggrin12,13. Fibrinogen is one of the predominantly citrullinated proteins found in synovial tissue; it was also detectable as a circulating antigen in synovial fluid of patients with RA14. Interestingly, it was also shown that synovial exosomes contain citrullinated proteins including fibrin derived molecules that could play a role in the induction and distribution process of citrullinated autoantigens15. In this issue of The Journal, Hill, et al provide further important evidence that citrullinated fibrinogen represents a major autoantigen in established RA16; moreover, their results confirmed a high disease specificity for this antibody response. By using in vitro citrullinated fibrinogen as an antigen in ELISA, the sensitivity of the assay was 75%, with a specificity of 98% for RA, making it comparable to anti-CCP. Although the cohort of patients with RA analyzed was relatively small, appropriate control patients with other rheumatic disorders were included. Importantly, the antibody reactivities against citrullinated fibrinogen were consistent with the anti-CCP results, with the exception of only one patient. The results of Hill, et al are in good agreement with a recently published study revealing a similar diagnostic performance for anti-citrullinated fibrinogen antibodies and the second generation of CCP-ELISA17. Citrullinated fibrinogen was also shown to provide a similar sensitivity and specificity compared to CCP in patients with early RA; moreover, both markers were good predictors of radiographic progression18. Another study revealed an association between the HLA-DRB1*0404 genotype and the generation of anti-citrullinated fibrinogen antibodies. Further, a frequent T cell response was observed against fibrinogen in RA19. Citrullinated fibrinogen is immunogenic, but the antibody response is not necessarily accompanied by an arthritogenic phenotype in rodents20,21. However, it was recently shown that induction of tolerance to a citrullinated peptide led to a significant reduction in susceptibility to collagen induced arthritis in mice22. Further, administration of monoclonal antibodies against citrullinated fibrinogen was able to overcome the protective tolerance to substantially enhance arthritis. By demonstrating pathogenicity in an animal model, these encouraging results clearly support the link between altered antigenic properties due to citrullination of fibrinogen and the manifestation of arthritis. However, many questions remain. First, in order to establish anti-citrullinated fibrinogen antibodies as a diagnostic marker, standardized assays must be introduced. Subsequently, it will be necessary to conduct multicenter studies in larger cohorts including early and undifferentiated disease manifestations, as well as comprehensive followup analyses, in order to clarify the significance of these antibodies in correlation to disease activity and outcome. 1. van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum 2004;50:709-15. [MEDLINE] 2. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis 2006;65:845-51. Epub 2006 Apr 10. [MEDLINE] 3. Zendman AJ, van Venrooij WJ, Pruijn GJ. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology Oxford 2006;45:20-5. [MEDLINE] 4. Gyorgy B, Toth E, Tarcsa E, Falus A, Buzas EI. Citrullination: A posttranslational modification in health and disease. Int J Biochem Cell Biol 2006;38:1662-77. Epub 2006 Mar 30. [MEDLINE] 5. Senshu T, Kan S, Ogawa H, Manabe M, Asaga H. Preferential deimination of keratin K1 and filaggrin during the terminal differentiation of human epidermis. Biochem Biophys Res Commun 1996;225:712-9. [MEDLINE] 6. Asaga H, Yamada M, Senshu T. Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 1998;24;243:641-6. 7. Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003; 34:395-402. [MEDLINE] 8. Barton A, Bowes J, Eyre S, et al. A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 2004;50:1117-21. [MEDLINE] 9. Caponi L, Petit-Teixeira E, Sebbag M, et al. A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann Rheum Dis 2005; 64:587-93. Epub 2004 Oct 14. [MEDLINE] 10. Takizawa Y, Sawada T, Suzuki A, Yamada R, Inoue T, Yamamoto K. Peptidylarginine deiminase 4 (PADI4) identified as a conformation-dependent autoantigen in rheumatoid arthritis. Scand J Rheumatol 2005;34:212-5. [MEDLINE] 11. Chapuy-Regaud S, Sebbag M, Baeten D, et al. Fibrin deimination in synovial tissue is not specific for rheumatoid arthritis but commonly occurs during synovitides. J Immunol 2005;174:5057-64. [MEDLINE] 12. Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, et al. The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol 2001;166:4177-84. [MEDLINE] 13. Sebbag M, Moinard N, Auger I, et al. Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins. Eur J Immunol 2006;36:2250-63. [MEDLINE] 14. Takizawa Y, Suzuki A, Sawada T, et al. Citrullinated fibrinogen detected as a soluble citrullinated autoantigen in rheumatoid arthritis synovial fluids. Ann Rheum Dis 2006;65:1013-20. Epub 2006 Jan 31. [MEDLINE] 15. Skriner K, Adolph K, Jungblut PR, Burmester GR. Citrullinated proteins are associated with synovial exosomes. Arthritis Rheum 2006; in press. 16. Hill JA, Al-Bishri J, Gladman DD, Cairns E, Bell DA. Serum autoantibodies that bind citrullinated fibrinogen are frequently found in patients with rheumatoid arthritis. J Rheumatol 2006;33:2115-9. 17. Vander Cruyssen B, Cantaert T, Nogueira L, et al. Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays. Arthritis Res Ther 2006 Jul 19;8:R122. 18. Nielen MM, van der Horst AR, van Schaardenburg D, et al. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis. Ann Rheum Dis 2005;64:1199-204. Epub 2005 Jan 7. [MEDLINE] 19. Auger I, Sebbag M, Vincent C, et al. Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum 2005;52:3424-32. [MEDLINE] 20. Duplan V, Foulquier C, Clavel C, et al. In the rat, citrullinated autologous fibrinogen is immunogenic but the induced autoimmune response is not arthritogenic. Clin Exp Immunol 2006;145:502-12. [MEDLINE] 21. Rubin B, Sonderstrup G. Citrullination of self-proteins and autoimmunity. Scand J Immunol 2004;60:112-20. Erratum in: Scand J Immunol 2005;61:298. [MEDLINE] 22. Kuhn KA, Kulik L, Tomooka B, et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 2006;116:961-73. [MEDLINE]
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