Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies

Y W Song, E H Kang, Y W Song, E H Kang

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease, characterized by chronic, erosive polyarthritis and by the presence of various autoantibodies in serum and synovial fluid. Since rheumatoid factor (RF) was first described, a number of other autoantibodies have been discovered in RA patients. The autoantigens recognized by these autoantibodies include cartilage components, chaperones, enzymes, nuclear proteins and citrullinated proteins. However, the clinical significances and pathogenic roles of these antibodies are largely unknown except for RF and anticitrullinated protein antibodies (ACPAs), whose clinical usefulness has been acknowledged due to their acceptable sensitivities and specificities, and prognostic values. This review presents and discusses the current state of the art regarding RF and ACPA in RA.

References

    1. Waaler E. On the occurrence of a factor in human serum activating the specific agglutination of sheep red corpuscles. Acta Pathol Microbiol Scand. 1940;17:172–88.
    1. Bläss S, Engel JM, Burmester GR. The immunologic homunculus in rheumatoid arthritis. Arthritis Rheum. 1999;42:2499–506.
    1. Simon M, Girbal E, Sebbag M, Gomès-Daudrix V, Vincent C, Salama G, et al. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called ‘antikeratin antibodies’, autoantibodies specific for rheumatoid arthritis. J Clin Invest. 1993;92:1387–93.
    1. Sebbag M, Simon M, Vincent C, Masson-Bessière C, Girbal E, Durieux JJ, et al. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1995;95:2672–9.
    1. Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998;101:273–81.
    1. Girbal-Neuhauser E, Durieux JJ, Arnaud M, Dalbon P, Sebbag M, Vincent C, 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. 1999;162:585–94.
    1. Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000;43:155–63.
    1. Matsumoto I, Maccioni M, Lee DM, Maurice M, Simmons B, Brenner M, et al. How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat Immunol. 2002;3:360–5.
    1. Carson DA, Chen PP, Fox RI, Kipps TJ, Jirik F, Goldfien RD, et al. Rheumatoid factor and immune networks. Annu Rev Immunol. 1987;5:109–26.
    1. Pope RM, Teller DC, Mannik M. Intermediate complexes formed by self-association of IgG-rheumatoid factors. Ann N Y Acad Sci. 1975;256:82–7.
    1. Wernick RM, Lipsky PE, Marban-Arcos E, Maliakkal JJ, Edelbaum D, Ziff M. IgG and IgM rheumatoid factor synthesis in rheumatoid synovial membrane cell cultures. Arthritis Rheum. 1985;28:742–52.
    1. Jones V, Taylor PC, Jacoby RK, Wallington TB. Synovial synthesis of rheumatoid factors and immune complex constituents in early arthritis. Ann Rheum Dis. 1984;43:235–9.
    1. Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann M, et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis. 2005;64:1731–6.
    1. Børretzen M, Chapman C, Natvig JB, Thompson KM. Differences in mutational patterns between rheumatoid factors in health and disease are related to variable heavy chain family and germ-line gene usage. Eur J Immunol. 1997;27:735–41.
    1. Jónsson T, Steinsson K, Jónsson H, Geirsson AJ, Thorsteinsson J, Valdimarsson H. Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis. Rheumatol Int. 1998;18:119–22.
    1. Jónsson T, Arinbjarnarson S, Thorsteinsson J, Steinsson K, Geirsson AJ, Jónsson H, et al. Raised IgA rheumatoid factor (RF) but not IgM RF or IgG RF is associated with extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol. 1995;24:372–5.
    1. Jorgensen C, Legouffe MC, Bologna C, Brochier J, Sany J. IgA isotype rheumatoid factor in rheumatoid arthritis: clinical implications. Clin Exp Rheumatol. 1996;14:301–4.
    1. Päi S, Päi L, Birkenfeldt R. Correlation of serum IgA rheumatoid factor levels with disease severity in rheumatoid arthritis. Scand J Rheumatol. 1998;27:252–6.
    1. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.
    1. Welch MJ, Fong S, Vaughan J, Carson D. Increased frequency of rheumatoid factor precursor B lymphocytes after immunization of normal adults with tetanus toxoid. Clin Exp Immunol. 1983;51:299–304.
    1. Slaughter L, Carson DA, Jensen FC, Holbrook TL, Vaughan JH. In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med. 1978;148:1429–34.
    1. Izui S, Eisenberg RA, Dixon FJ. IgM rheumatoid factors in mice injected with bacterial lipopolysaccharides. J Immunol. 1979;122:2096–102.
    1. Van Snick JL, Van Roost E, Markowetz B, Cambiaso CL, Masson PL. Enhancement by IgM rheumatoid factor of in vitro ingestion by macrophages and in vivo clearance of aggregated IgG or antigen-antibody complexes. Eur J Immunol. 1978;8:279–85.
    1. Brown PB, Nardella FA, Mannik M. Human complement activation by self-associated IgG rheumatoid factors. Arthritis Rheum. 1982;25:1101–7.
    1. Tighe H, Chen PP, Tucker R, Kipps TJ, Roudier J, Jirik FR, et al. Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice. J Exp Med. 1993;177:109–18.
    1. Firestein GS. Rheumatoid synovitis and pannus. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatology. 3rd. Philadelphia, USA: Mosby; 2003. pp. 855–84.
    1. Schmidt D, Goronzy JJ, Weyand CM. CD4+ CD7− CD28− T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest. 1996;97:2027–37.
    1. Ziff M. Role of endothelium in the pathogenesis of rheumatoid synovitis. Int J Tissue React. 1993;15:135–7.
    1. Roosnek E, Lanzavecchia A. Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells. J Exp Med. 1991;173:487–9.
    1. Suzuki K, Sawada T, Murakami A, Matsui T, Tohma S, Nakazono K, et al. High diagnostic performance of ELISA detection of antibodies to citrullinated antigens in rheumatoid arthritis. Scand J Rheumatol. 2003;32:197–204.
    1. Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van't; Hof M, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2000;43:1831–5.
    1. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Toes RE, Huizinga TW. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther. 2005;7:R949–58.
    1. Im CH, Kang EH, Ryu HJ, Lee JH, Lee EY, Lee YJ, et al. Anti-cyclic citrullinated peptide antibody is associated with radiographic erosion in rheumatoid arthritis independently of shared epitope status. Rheumatol Int. 2009;29:251–6.
    1. Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays. 2003;25:1106–18.
    1. Reparon-Schuijt CC, van Esch WJ, van Kooten C, Schellekens GA, de Jong BA, van Venrooij WJ, et al. Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum. 2001;44:41–7.
    1. Masson-Bessière C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C, Senshu T, 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.
    1. Koivula MK, Aman S, Karjalainen A, Hakala M, Risteli J. Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis? Ann Rheum Dis. 2005;64:1443–50.
    1. Vossenaar ER, Despres N, Lapointe E, van der Heijden A, Lora M, Senshu T, et al. Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res Ther. 2004;6:R142–50.
    1. Nakashima K, Hagiwara T, Yamada M. Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem. 2002;277:49562–8.
    1. Goëb V, Thomas-L'o;tellier M, Daveau R, Charlionet R, Fardellone P, Le Loët X, et al. Candidate autoantigens identified by mass spectrometry in early rheumatoid arthritis are chaperones and citrullinated glycolytic enzymes. Arthritis Res Ther. 2009;11:R38.
    1. Zhao X, Okeke NL, Sharpe O, Batliwalla FM, Lee AT, Ho PP, et al. Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis. Arthritis Res Ther. 2008;10:R94.
    1. Vossenaar ER, Nijenhuis S, Helsen MM, van der Heijden A, Senshu T, van den Berg WB, et al. Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum. 2003;48:2489–500.
    1. van Gaalen FA, van Aken J, Huizinga TW, Schreuder GM, Breedveld FC, Zanelli E, et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum. 2004;50:2113–21.
    1. Kaltenhäuser S, Pierer M, Arnold S, Kamprad M, Baerwald C, Häntzschel H, et al. Antibodies against cyclic citrullinated peptide are associated with the DRB1 shared epitope and predict joint erosion in rheumatoid arthritis. Rheumatology. 2007;46:100–4.
    1. Berglin E, Padyukov L, Sundin U, Hallmans G, Stenlund H, Van Venrooij WJ, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther. 2004;6:R303–8.
    1. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30:1205–13.
    1. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol. 2003;171:538–41.
    1. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 2006;54:1117–21.
    1. Huizinga TW, Amos CI, van der Helm-van Mil AH, Chen W, van Gaalen FA, Jawaheer D, et al. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 2005;52:3433–8.
    1. Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, 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. 2006;54:38–46.
    1. Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, et al. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: a mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum. 2007;56:1745–53.
    1. Xue Y, Zhang J, Chen YM, Guan M, Zheng SG, Zou HJ. The HLA-DRB1 shared epitope is not associated with antibodies against cyclic citrullinated peptide in Chinese patients with rheumatoid arthritis. Scand J Rheumatol. 2008;37:183–7.
    1. Boki KA, Drosos AA, Tzioufas AG, Lanchbury JS, Panayi GS, Moutsopoulos HM. Examination of HLA-DR4 as a severity marker for rheumatoid arthritis in Greek patients. Ann Rheum Dis. 1993;52:517–9.
    1. Linn-Rasker SP, van der Helm-van Mil AH, van Gaalen FA, Kloppenburg M, de Vries RR, le Cessie S, et al. Smoking is a risk factor for anti-CCP antibodies only in RA patients that carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis. 2006;65:366–71.
    1. Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008;67:1488–92.
    1. Lee HS, Lee AT, Criswell LA, Seldin MF, Amos CI, Carulli JP, et al. Several regions in the major histocompatibility complex confer risk for anti-CCP-antibody positive rheumatoid arthritis, independent of the DRB1 locus. Mol Med. 2008;14:293–300.
    1. Ding B, Padyukov L, Lundström E, Seielstad M, Plenge RM, Oksenberg JR, et al. Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region. Arthritis Rheum. 2009;60:30–8.
    1. Vignal C, Bansal AT, Balding DJ, Binks MH, Dickson MC, Montgomery DS, et al. Genetic association of the major histocompatibility complex with rheumatoid arthritis implicates two non-DRB1 loci. Arthritis Rheum. 2009;60:53–62.
    1. Feitsma AL, Toes RE, Begovich AB, Chokkalingam AP, de Vries RR, Huizinga TW, et al. Risk of progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele in anti-citrullinated peptide antibody positive patients. Rheumatology. 2007;46:1092–5.
    1. Kokkonen H, Johansson M, Innala L, Jidell E, Rantapää-Dahlqvist S. The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern Sweden. Arthritis Res Ther. 2007;9:R56.
    1. Iwamoto T, Ikari K, Nakamura T, Kuwahara M, Toyama Y, Tomatsu T, et al. Association between PADI4 and rheumatoid arthritis: a meta-analysis. Rheumatology. 2006;45:804–7.
    1. Thabet MM, Huizinga TW, Marques RB, Stoeken-Rijsbergen G, Bakker AM, Kurreeman FA, et al. The contribution of Fc gamma receptor IIIA gene 158V/F polymorphism and copy number variation to the risk of ACPA positive rheumatoid arthritis. Ann Rheum Dis. 2008 Nov 19; Epub ahead of print.
    1. Irigoyen P, Lee AT, Wener MH, Li W, Kern M, Batliwalla F, et al. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum. 2005;52:3813–8.
    1. Verpoort KN, van Gaalen FA, van der Helm-van Mil AH, Schreuder GM, Breedveld FC, Huizinga TW, et al. Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. Arthritis Rheum. 2005;52:3058–62.
    1. Kraan MC, Versendaal H, Jonker M, Bresnihan B, Post WJ, t Hart BA, et al. Asymptomatic synovitis precedes clinically manifest arthritis. Arthritis Rheum. 1998;41:1481–8.
    1. Rantapää-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741–9.
    1. Nielen MM, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50:380–6.
    1. 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.
    1. De Rycke L, Peene I, Hoffman IE, Kruithof E, Union A, Meheus L, et al. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis. 2004;63:1587–93.
    1. Korkmaz C, Us T, Kaşifoğlu T, Akgün Y. Anti-cyclic citrullinated peptide (CCP) antibodies in patients with long-standing rheumatoid arthritis and their relationship with extra-articular manifestations. Clin Biochem. 2006;39:961–5.
    1. Bongartz T, Cantaert T, Atkins SR, Harle P, Myers JL, Turesson C, et al. Citrullination in extra-articular manifestations of rheumatoid arthritis. Rheumatology. 2007;46:70–5.
    1. Berglin E, Johansson T, Sundin U, Jidell E, Wadell G, Hallmans G, 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. 2006;65:453–8.
    1. Mewar D, Coote A, Moore DJ, Marinou I, Keyworth J, Dickson MC, et al. Independent associations of anti-cyclic citrullinated peptide antibodies and rheumatoid factor with radiographic severity of rheumatoid arthritis. Arthritis Res Ther. 2006;8:R128.
    1. De Rycke L, Verhelst X, Kruithof E, Van den Bosch F, Hoffman IE, Veys EM, et al. Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis. 2005;64:299–302.
    1. Bos WH, Bartelds GM, Wolbink GJ, de Koning MH, van de Stadt RJ, van Schaardenburg D, et al. Differential response of the rheumatoid factor and anticitrullinated protein antibodies during adalimumab treatment in patients with rheumatoid arthritis. J Rheumatol. 2008;35:1972–7.
    1. Mikuls TR, O'D;ell JR, Stoner JA, Parrish LA, Arend WP, Norris JM, et al. Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti-cyclic citrullinated peptide antibody. Arthritis Rheum. 2004;50:3776–82.
    1. Cambridge G, Leandro MJ, Edwards JC, Ehrenstein MR, Salden M, Bodman-Smith M, et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum. 2003;48:2146–54.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere