Anti-citrullinated protein antibody

Citrulline

Anti-citrullinated protein antibodies (ACPA) or anti-cyclic citrullinated protein antibodies (anti-CCP) are autoantibodies (antibodies directed against one or more of an individual’s own proteins) that are frequently detected in the blood of rheumatoid arthritis patients. The main epitope for these antibodies is filaggrin,^[1] and there is cross-reactivity between ACPA and anti-keratin and anti-perinuclear factor.^[2]

During inflammation, arginine residues in proteins such as vimentin can be enzymatically converted into citrulline ones (a process called citrullination), and, if their shapes are significantly altered, the proteins may be seen as antigens by the immune system, thereby generating an immune response.^[3] ACPAs have proved to be powerful biomarkers that allow the diagnosis of rheumatoid arthritis (RA) to be made at a very early stage.

In July 2010, the 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria were introduced.^[4] 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.^[5][6] 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,^[7][8][9] 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)^[10][11] and viral citrullinated peptides (VCP-assay).

In 2010, ACPA testing has become substantial part of The 2010 ACR-EULAR classification criteria for rheumatoid arthritis.^[4]

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%.^[12] 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.^{[13] [14]} Unfortunately, these artificial antigens are not expressed in the affected tissue, and therefore are probably not directly involved in the pathogenesis of RA.^{[citation needed]}

In the more recent time^{[clarification needed]}, novel test systems utilizing ACPA have been developed. Citrullinated vimentin is a very promising autoantigen in RA, and a very 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).^{[15] [16]} A newly developed ELISA system utilises genetically modified citrullinated vimentin (MCV), a naturally occurring isoform of vimentin to optimize the performance of the test.^[7][17] 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.

Given that ACPA are more specific than rheumatoid factor, they are used to distinguish various causes of arthritis.^[18] Novel assays may be useful for monitoring disease activity and effects of RA therapy.^[19]

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

Negative	Low/weak positive	Moderate positive	High/strong positive	Unit
< 20[20]	20 – 39[20]	40 - 59[20]	> 60[20]	EU[20]

References

1. ^ Detrick, Barbara (2006). Manual of molecular and clinical laboratory immunology. Washington D.C.: ASM Press. pp. 1037. ISBN 1-55581-364-X. 
2. ^ Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ (January 1998). "Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies". J. Clin. Invest. 101 (1): 273–81. doi:10.1172/JCI1316. PMC 508564. PMID 9421490. http://www.jci.org/articles/view/1316.  Full text at PMC: 508564
3. ^ Raptopoulou A, Sidiropoulos P, Katsouraki M, Boumpas DT (2007). "Anti-citrulline antibodies in the diagnosis and prognosis of rheumatoid arthritis: evolving concepts". Crit Rev Clin Lab Sci 44 (4): 339–63. doi:10.1080/10408360701295623. PMID 17558653. http://www.informaworld.com/openurl?genre=article&doi=10.1080/10408360701295623&magic=pubmed%7C%7C1B69BA326FFE69C3F0A8F227DF8201D0. 
4. ^ ^{a b} Aletaha D, Neogi T, Silman AJ, et al. (September 2010). "2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative". Ann. Rheum. Dis. 69 (9): 1580–8. doi:10.1136/ard.2010.138461. PMID 20699241. http://www.rheumatology.org/practice/clinical/classification/ra/2010_revised_criteria_classification_ra.pdf. 
5. ^ Young BJ, Mallya RK, Leslie RD, Clark CJ, Hamblin TJ (July 1979). "Anti-keratin antibodies in rheumatoid arthritis". Br Med J 2 (6182): 97–9. doi:10.1136/bmj.2.6182.97. PMC 1596039. PMID 111762. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1596039. 
6. ^ Sebbag M, Simon M, Vincent C, et al. (June 1995). "The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies". J. Clin. Invest. 95 (6): 2672–9. doi:10.1172/JCI117969. PMC 295950. PMID 7539459. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=295950. 
7. ^ ^{a b} Vossenaar ER, Després N, Lapointe E, et al. (2004). "Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin". Arthritis Res. Ther. 6 (2): R142–50. doi:10.1186/ar1149. PMC 400433. PMID 15059278. http://arthritis-research.com/content/6/2/R142. 
8. ^ Pratesi F, Tommasi C, Anzilotti C, Chimenti D, Migliorini P (March 2006). "Deiminated Epstein-Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis". Arthritis Rheum. 54 (3): 733–41. doi:10.1002/art.21629. PMID 16508937. 
9. ^ Bang H, Egerer K, Gauliard A, et al. (August 2007). "Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis". Arthritis Rheum. 56 (8): 2503–11. doi:10.1002/art.22817. PMID 17665451. http://www3.interscience.wiley.com/journal/114298035/abstract. 
10. ^ MeSH cyclic+citrullinated+peptide
11. ^ Nishimura K, Sugiyama D, Kogata Y, et al. (June 2007). "Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis". Annals of Internal Medicine 146 (11): 797–808. PMID 17548411. 
12. ^ Coenen D, Verschueren P, Westhovens R, Bossuyt X (March 2007). "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. doi:10.1373/clinchem.2006.078063. PMID 17259232. http://www.clinchem.org/cgi/content/full/53/3/498. 
13. ^ van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE (1 November 2005). "The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis". J. Immunol. 175 (9): 5575–80. PMID 16237041. http://www.jimmunol.org/cgi/content/full/175/9/5575. 
14. ^ Greiner A, Plischke H, Kellner H, Gruber R (June 2005). "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. doi:10.1196/annals.1313.031. PMID 16014545. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2005&volume=1050&spage=295. 
15. ^ Asaga H, Yamada M, Senshu T (February 1998). "Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages". Biochem. Biophys. Res. Commun. 243 (3): 641–6. doi:10.1006/bbrc.1998.8148. PMID 9500980. http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(98)98148-7. 
16. ^ Mor-Vaknin N, Punturieri A, Sitwala K, Markovitz DM (January 2003). "Vimentin is secreted by activated macrophages". Nat. Cell Biol. 5 (1): 59–63. doi:10.1038/ncb898. PMID 12483219. http://www.nature.com/ncb/journal/v5/n1/abs/ncb898.html. 
17. ^ Soós L, Szekanecz Z, Szabó Z, et al. (August 2007). "Clinical evaluation of anti-mutated citrullinated vimentin by ELISA in rheumatoid arthritis". J. Rheumatol. 34 (8): 1658–63. PMID 17611988. http://www.jrheum.com/subscribers/07/08/1658.html. 
18. ^ Avouac J, Gossec L, Dougados M (July 2006). "Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review". Ann. Rheum. Dis. 65 (7): 845–51. doi:10.1136/ard.2006.051391. PMC 1798205. PMID 16606649. http://ard.bmj.com/cgi/content/full/65/7/845. 
19. ^ Nicaise Roland P, Grootenboer Mignot S, Bruns A, et al. (2008). "Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in anti-CCP-negative patients and for monitoring infliximab therapy". Arthritis Res. Ther. 10 (6): R142. doi:10.1186/ar2570. PMC 2656247. PMID 19077182. http://arthritis-research.com/content/10/6/R142. 
20. ^ ^{a b c d e} chronolab.com > Autoantibodies associated with rheumatic diseases > Reference ranges Retrieved on April 29, 2010