Antibodies against citrullinated proteins

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Antibodies against citrullinated proteins (English: anti citrullinated protein antibodies , hence ACPAs for short ) are autoantibodies ( antibodies against components of the own body) that occur in patients with rheumatoid arthritis (RA). In recent times, the test systems for the serological detection of ACPAs have decisively improved classic serodiagnostics using rheumatoid factors . The most prominent representatives of the ACPA test systems are the detection of autoantibodies against mutated citrullinated vimentin ( anti-MCV -ELISA) and the CCP assay. Both achieve sensitivities of almost 80% and specificities of almost 98%.

Basics

The discovery and identification of citrullinated autoantigens in the mid-1970s was a significant improvement in serological RA diagnostics. The starting point was the discovery of so-called anti-keratin antibodies (AKA) and the observation that the detection of these autoantibodies is highly specific for the serological diagnosis of rheumatoid arthritis.

Fillagrin , a structural protein that is exclusively formed by keratin-producing epithelial cells , was identified as the target antigen . Further investigations showed that the AKA only bind to the citrullinated fillagrin and not to the original (non-citrullinated) protein.

The citrullination of proteins is a physiological (i.e., naturally expiring in the body..) Process; it takes place enzymatically through the deamination of the amino acid arginine to the amino acid citrulline . Citrullination changes the charge of the molecule, which changes the three-dimensional structure and the antigenic properties of the protein. As a result, the citrullinated, modified endogenous protein is viewed by the immune system as foreign. This leads to the formation of autoreactive ("directed against itself") antibodies that attack the own tissue and initiate an inflammatory reaction. The result is an autoimmune disease .

meaning

For certain ACPAs, a connection between the antibody titer (the "concentration" of autoantibodies in the blood serum ) and the disease activity has been proven, which makes them a good tool for the treating rheumatologist for the prognosis of the disease and a good basis for individual therapy decisions power.

In addition to their importance for early diagnosis, ACPA are also important for the prognosis of joint damage in rheumatoid arthritis. In patients with this condition who are positive for ACPA, joint destruction generally progresses faster than in patients with rheumatoid arthritis without ACPA.

Historical

After it was known that the citrulline residues are the actual target for the antibodies, a first commercial detection test for RA diagnostics with artificially produced peptides was developed. Synthetic citrullinated peptide fragments were used, the ends of which were joined to form small peptide rings. These artificially generated cyclic citrullinated peptides form the basis of the so-called anti-CCP tests, which are still used routinely for the diagnosis of rheumatoid arthritis.

The good diagnostic properties of anti-citrulline detection are also increasingly used for the detection of antibodies against citrullinated proteins that are not artificially but generated, synthesized and citrullinated in vivo , i.e. in the human body. It is now assumed that citrullination is an essential part of the pathogenesis (disease development) of rheumatoid arthritis.

For example, for the detection of antibodies against citrullinated fibrin, a high specificity and sensitivity for the diagnosis of early rheumatoid arthritis has been proven, whereby the diagnostic performance (sensitivity approx. 75%, specificity approx. 98%) of these tests is similar to that of the anti-CCP - Evidence is. The same was also shown for the anti- fibrinogen detection in early RA and for the detection of antibodies against alpha-enolase. The detection of antibodies against mutated citrullinated vimentin is now recognized as highly specific serological evidence for prognosis and diagnosis, especially of the early forms of rheumatoid arthritis.

Individual evidence

  1. ↑ K Egerer, E Feist, G Burmester: The Serological Diagnosis of Rheumatoid Arthritis - Antibodies to citrullinated Antigens . In: Dtsch Arztebl Int 2009; 106 (10): 159-163 . August. doi : 10.3238 / arztebl.2009.0159 .
  2. ↑ Walther J. van Venrooij, Ger JM Pruijn: Citrullination: a small change for a protein with great Consequences for rheumatoid arthritis . In: Arthritis Research & Therapy . tape 2 , no. 4 , May 24, 2000, pp. 249 , doi : 10.1186 / ar95 , PMID 11094435 .
  3. ↑ a b G. A. Schellekens, BA de Jong, FH van den Hoogen, LB van de Putte, WJ van Venrooij: Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. In: Journal of Clinical Investigation . tape 101 , no. 1 , January 1, 1998, pp. 273–281 , doi : 10.1172 / JCI1316 , PMID 9421490 , PMC 508564 (free full text).
  4. ^ Bence György, Erzsébet Tóth, Edit Tarcsa, András Falus, Edit I. Buzás: Citrullination: A posttranslational modification in health and disease . In: The International Journal of Biochemistry & Cell Biology . tape 38 , no. 10 , 2006, p. 1662-1677 , doi : 10.1016 / j.biocel.2006.03.008 .
  5. ↑ L Innala, Kokkonen H, C Eriksson, E Jidell, E Berglin, SR. Dahlqvst: Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides . In: J Rheumatol . 2008; 35: 1002-1008. . August.
  6. ↑ a b JJ Luime, EM Colin, JM Hazes, E. Lubberts: Does anti-MCV has additional value as serological marker in the diagnostic and prognostic work-up of patients with rheumatoid arthritis? A systematic review. . In: Ann Rheum Dis . 2009 Mar 15 . August.
  7. ↑ B Vander Cruyssen, T Cantaert, L Nogueira, C Clavel, L De Rycke, A Dendoven, M Sebag, D Deforce, C Vincent, D Elewaut, G Serre, F. De Keyser: Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays. . In: Arthritis Res Ther. 2006; 8 (4): R122. . August. PMID 16859515 .
  8. ↑ MM Nielen, AR van der Horst, D van Schaardenburg, IE van der Horst-Bruinsma, RJ van de Stadt, L Aarden, BA Dijkmans, D. Hamann: Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis . In: Ann Rheum Dis. 2005 Aug; 64 (8): 1199-1204. . August. PMID 15640269 .
  9. ^ A Kinloch, V Tatzer, R Wait, D Peston, K Lundberg, P Donatien, D Moyes, PC Taylor, PJ. Venables: Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis . In: Arthritis Res Ther. 2005; 7 (6): R1421-R1429. Epub 2005 Oct 19 . 53, No. 3, 2007, pp. 498-504. PMID 16277695 .
  10. ↑ V Saulot, O Vittecoq, R Charlionet, P Fardellone, C Lange, L Marvin, N Machour, X Le Loët, D Gilbert, F Tron: Presence of autoantibodies to the glycolytic enzyme alpha-enolase in sera from patients with early rheumatoid arthritis . In: Arthritis Rheum . 2002; 46 (5): 1196-1201. . August.
  11. ↑ H Bang, K Egerer, A Gauliard, K Lüthke, PE Rudolph, G Fredenhagen, W Berg, E Feist, GR. Burmester: Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis . In: Arthritis Rheum. 2007 Aug; 56 (8): 2503-2511 . August.
  12. ↑ SW Syversen, GL Goll, D van der Heijde, R Landewé, BA Lie, S Odegard, T Uhlig, PI Gaarder, TK. Kvien: Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a ten-year prospective study . In: Ann Rheum Dis. 2009 July 30 . August.