Anti–citrullinated protein antibody explained

Anti-citrullinated protein antibodies (ACPAs) are autoantibodies (antibodies to an individual's own proteins) that are directed against peptides and proteins that are citrullinated. They are present in the majority of patients with rheumatoid arthritis. Clinically, cyclic citrullinated peptides (CCP) are frequently used to detect these antibodies in patient serum or plasma (then referred to as anti–citrullinated peptide antibodies).[1]

During inflammation, arginine amino acid residues can be enzymatically converted into citrulline residues in proteins such as vimentin, by a process called citrullination. If their shapes are significantly altered, the proteins may be seen as antigens by the immune system, thereby generating an immune response.[2]

ACPAs have proved to be powerful biomarkers that allow the diagnosis of rheumatoid arthritis (RA) to be made at a very early stage.[1] In July 2010, the 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria were introduced.[3] These new classification criteria include ACPA testing, and overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis.

History

The presence of autoantibodies against citrullinated proteins in rheumatoid arthritis patients was first described in the mid-1970s when the biochemical basis of antibody reactivity against keratin and filaggrin was investigated.[4] [5] Subsequent studies demonstrated that autoantibodies from RA patients react with a series of different citrullinated antigens, including fibrinogen, deiminated Epstein-Barr Virus Nuclear Antigen 1 and vimentin,[6] [7] [8] which is a member of the intermediate filament family of proteins. Several assays for detecting ACPAs were developed in the following years, employing mutated citrullinated Vimentin (MCV-assay), filaggrin-derived peptides (CCP-assay)[9] and viral citrullinated peptides (VCP-assay).

A 2006 clinical study showed that anti viral citrullinated peptide (VCP) antibodies of the IgG and IgA isotypes represent a discriminating specific marker of rheumatoid arthritis from other chronic arthritides and disease controls, suggesting an independent production of each isotype.[10] In 2010, ACPA testing has become substantial part of The 2010 ACR-EULAR classification criteria for rheumatoid arthritis.[3]

Clinical significance

In a comparative study (in 2007), various detection kits had a sensitivity between 69.6% and 77.5% and a specificity between 87.8% and 96.4%.[11] Despite the excellent performance of these immunoassays, for example CCP-assays, they only provide a sensitivity comparable with that of rheumatoid factor (RF). Moreover, analysis of the correlation of anti-CCP antibody titre with RA disease activity yielded conflicting results.[12] [13]

However, novel test systems utilizing ACPA have been developed. Citrullinated vimentin is a very promising autoantigen in RA, and a suitable tool for studying this systemic autoimmune disease. Vimentin is secreted and citrullinated by macrophages in response to apoptosis, or by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha).[14] [15] A newly developed ELISA system utilises genetically modified citrullinated vimentin (MCV), a naturally occurring isoform of vimentin to optimize the performance of the test.[6] [16] Noteworthy are the findings of a recently published study that highly valuates anti-MCV test systems for diagnosing rheumatoid arthritis in anti-CCP-negative patients. However, data from all around the world vary substantially.[17] Anti-CCP is also very useful in the early diagnosis of rheumatoid arthritis in high-risk groups, such as relatives of RA patients,[18] although Silman and co-workers found that the concordance rate of developing RA was 15.4% among identical (monozygotic) twins and was 3.6% among fraternal (dizygotic) twins.[19]

Given that ACPA are more specific than rheumatoid factor, they are used to distinguish various causes of arthritis.[20] Novel assays may be useful for monitoring disease activity and effects of RA therapy.[21]

The reference ranges for blood tests of anti–citrullinated protein antibodies are:

NegativeLow/weak positiveModerate positiveHigh/strong positiveUnit - < 20[22] 20–39 40–59 > 60 EU

Anti-CCP is part of the 2010 ACR/EULAR classification criteria for Rheumatoid Arthritis. Anti-CCP positivity is also a good prognostic marker for future radiographic damage, and possibly a marker to B-cell therapy responses including rituximab.[23]

Combination of anti-CCP with other serological markers like rheumatoid factor, 14-3-3η (YWHAH) not only enhances the diagnostic capture rate but together with acute phase reactants either in early disease or at the time of diagnosis may be useful in predicting future outcomes.

Other ACPAs and citrullinated targets in RA

Vimentin, fibrin, filaggrin, enolase and keratin are common citrullination targets. The list of proteins that undergo citrullination and make up the citrullinome continues to increase. The RA associated citrullinome has been reported to include targets from synovial fluid and tissue that range from proteases, receptors, and carrier proteins. These proteins are components of complement, proteolytic activity, cell recognition, endocytosis, and response to biotic stimuli amongst others.[24] 14-3-3η (YWHAH) is also another synovial derived protein that has been reported as a citrullination target.[25]

Notes and References

  1. Puszczewicz M, Iwaszkiewicz C . Role of anti-citrullinated protein antibodies in diagnosis and prognosis of rheumatoid arthritis. . Arch Med Sci . 7 . 2 . 189–94 . May 2011 . 22291756 . 10.5114/aoms.2011.22067 . 3258718.
  2. Raptopoulou A, Sidiropoulos P, Katsouraki M, Boumpas DT . Anti-citrulline antibodies in the diagnosis and prognosis of rheumatoid arthritis: evolving concepts . Crit Rev Clin Lab Sci . 44 . 4 . 339–63 . 2007 . 17558653 . 10.1080/10408360701295623 . 1773519 .
  3. Aletaha D, Neogi T, Silman AJ . 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative . Ann. Rheum. Dis. . 69 . 9 . 1580–8 . September 2010 . 20699241 . 10.1136/ard.2010.138461 . 1191830 . etal. free .
  4. Young BJ, Mallya RK, Leslie RD, Clark CJ, Hamblin TJ . Anti-keratin antibodies in rheumatoid arthritis . Br Med J . 2 . 6182 . 97–9 . July 1979 . 111762 . 1596039 . 10.1136/bmj.2.6182.97 .
  5. Sebbag M, Simon M, Vincent C . The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies . J. Clin. Invest. . 95 . 6 . 2672–9 . June 1995 . 7539459 . 295950 . 10.1172/JCI117969 . etal.
  6. Vossenaar ER, Després N, Lapointe E . Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin . . 6 . 2 . R142–50 . 2004 . 15059278 . 400433 . 10.1186/ar1149 . etal . free .
  7. 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 . 3 . 733–41 . March 2006 . 16508937 . 10.1002/art.21629 .
  8. Bang H, Egerer K, Gauliard A . Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis . Arthritis Rheum. . 56 . 8 . 2503–11 . August 2007 . 17665451 . 10.1002/art.22817 . etal.
  9. Nishimura K, Sugiyama D, Kogata Y . Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis . Annals of Internal Medicine . 146 . 11 . 797–808 . June 2007 . 17548411 . 10.7326/0003-4819-146-11-200706050-00008. 6640507 . etal.
  10. IgG, IgA, IgM antibodies to a viral citrullinated peptide in patients affected by rheumatoid arthritis, chronic arthritides and connective tissue disorders . C. Anzilotti . L. Riente . F. Pratesi . D. Chimenti . A. Delle Sedie . S. Bombardieri . P. Migliorini . . 46 . 10 . October 2007 . 1579–82 . 10.1093/rheumatology/kem193 . 17717033 . 1462-0324 . 173280877 . https://web.archive.org/web/20200830171437/https://academic.oup.com/rheumatology/article/46/10/1579/1789552?searchresult=1 . 30 August 2020 . live.
  11. Coenen D, Verschueren P, Westhovens R, Bossuyt X . Technical and diagnostic performance of 6 assays for the measurement of citrullinated protein/peptide antibodies in the diagnosis of rheumatoid arthritis . Clin. Chem. . 53 . 3 . 498–504 . March 2007 . 17259232 . 10.1373/clinchem.2006.078063 . free .
  12. van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE . The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis . J. Immunol. . 175 . 9 . 5575–80 . 1 November 2005. 16237041 . 10.4049/jimmunol.175.9.5575. free .
  13. Greiner A, Plischke H, Kellner H, Gruber R . Association of anti-cyclic citrullinated peptide antibodies, anti-citrullin antibodies, and IgM and IgA rheumatoid factors with serological parameters of disease activity in rheumatoid arthritis . Ann. N. Y. Acad. Sci. . 1050 . 295–303 . June 2005 . 16014545 . 10.1196/annals.1313.031 . 12252627 .
  14. Asaga H, Yamada M, Senshu T . Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages . Biochem. Biophys. Res. Commun. . 243 . 3 . 641–6 . February 1998 . 9500980 . 10.1006/bbrc.1998.8148 .
  15. Mor-Vaknin N, Punturieri A, Sitwala K, Markovitz DM . Vimentin is secreted by activated macrophages . Nat. Cell Biol. . 5 . 1 . 59–63 . January 2003 . 12483219 . 10.1038/ncb898 . 30850762 .
  16. Soós L, Szekanecz Z, Szabó Z . Clinical evaluation of anti-mutated citrullinated vimentin by ELISA in rheumatoid arthritis . J. Rheumatol. . 34 . 8 . 1658–63 . August 2007 . 17611988 . etal . 27 March 2009 . https://web.archive.org/web/20080220064623/http://www.jrheum.com/subscribers/07/08/1658.html . 20 February 2008 . dead .
  17. Iwaszkiewicz C, Puszczewicz M, Białkowska-Puszczewicz G . Diagnostic value of the anti-Sa antibody compared with the anti-cyclic citrullinated peptide antibody in rheumatoid arthritis. . International Journal of Rheumatic Diseases . 18 . 1 . 46–51 . January 2015 . 25488711 . 10.1111/1756-185X.12544 . 12677526 .
  18. 20457731 . 10.1093/rheumatology/keq134 . 49 . 8 . Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in rheumatoid arthritis patients and relatives from Brazil. . Aug 2010 . Rheumatology (Oxford) . 1590–3. Goeldner . I. . Skare . T. L. . De Messias Reason . I. T. . Nisihara . R. M. . Silva . M. B. . Utiyama . S. R. . free .
  19. 8402000 . 32 . 10 . Twin concordance rates for rheumatoid arthritis: results from a nationwide study. . Oct 1993 . Br J Rheumatology . 903–7 . 10.1093/rheumatology/32.10.903 . Silman AJ, MacGregor AJ, Thomson W, etal.
  20. 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. . 65 . 7 . 845–51 . July 2006 . 16606649 . 10.1136/ard.2006.051391 . 1798205.
  21. Nicaise Roland P, Grootenboer Mignot S, Bruns A . Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in anti-CCP-negative patients and for monitoring infliximab therapy . Arthritis Research & Therapy . 10 . 6 . R142 . 2008 . 19077182 . 2656247 . 10.1186/ar2570 . etal . free .
  22. http://www.chronolab.com/rheumatic/range.htm chronolab.com > Autoantibodies associated with rheumatic diseases > Reference ranges
  23. Gardette A, Ottaviani S, Tubach F, Roy C, Nicaise-Roland P, Palazzo E, Gill G, Meyer O, Dieudé P . High anti-CCP antibody titres predict good response to rituximab in patients with active rheumatoid arthritis . Joint Bone Spine . 81 . 5 . 416–20 . October 2014 . 24998790 . 10.1016/j.jbspin.2014.06.001 .
  24. Tilvawala R, Nguyen SH, Maurais AJ, Nemmara VV, Nagar M, Salinger AJ, Nagpal S, Weerapana E, Thompson PR . The Rheumatoid Arthritis-Associated Citrullinome . Cell Chem Biol . 25 . 6 . 691–704.e6 . June 2018 . 29628436 . 6014894 . 10.1016/j.chembiol.2018.03.002 .
  25. Maksymowych WP, Marotta A . 14-3-3η: a novel biomarker platform for rheumatoid arthritis . Clin Exp Rheumatol . 32 . 5 Suppl 85 . S–35–9 . 2014 . 25365087 .

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