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. 2005 Oct;64(10):1443–1450. doi: 10.1136/ard.2004.031211

Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis?

M Koivula 1, S Aman 1, A Karjalainen 1, M Hakala 1, J Risteli 1
PMCID: PMC1755220  PMID: 16162901

Abstract

Objectives: To assess the possible presence in patients with rheumatoid arthritis (RA) of autoantibodies recognising citrullinated peptides derived from type I and II collagens.

Methods: Firstly, the binding of four pairs of synthetic peptides (arginine-containing and artificially citrullinated forms) related to different regions of human type II collagen were tested with sera from 120 patients with RA and 81 controls. Secondly, two similar pairs of peptides related to the carboxy terminal telopeptides of the α1 and α2 chains of human type I collagen were tested.

Results: 42–53% of the RA sera showed increased binding of arginine peptides related to type II collagen. However, 12 RA sera bound the citrullinated form of the α1(II) telopeptide more strongly than the corresponding arginine peptide. 20 RA sera bound the citrullinated carboxytelopeptide from the α1 chain of type I collagen (α1(I) telopeptide) more strongly than the respective arginine peptide. The correlation between the autoantibodies to type I and II collagen telopeptides was rs = 0.576, p<0.001. Anti-cyclic citrullinated peptide (anti-CCP) assay was positive in 71/120 (59%) patients with RA. An anti-CCP assay detects a different subgroup of antibodies than anti-telopeptide assays. However, both anti-telopeptide and anti-CCP antibodies were increased in patients with RA.

Conclusion: Some patients with RA were identified whose sera contained antibodies that specifically bound citrullinated peptides related to the carboxy terminal telopeptides of the α1 and α2 chains of type I collagen and the α1 chains of type II collagen (sequences YYXA, FYXA, and YMXA, where X stands for citrulline).

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Figure 1.

Figure 1

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 Sequences and localisations of the synthetic peptides used in the study. (A) Localisation of the peptides CC1-CC4 in human type II collagen; the numbers in brackets refer to arginine residues. (B) Sequences of the peptides CC1-CC4. (C) Detailed structure of the carboxy terminal telopeptide of type II collagen; the 12 carboxy terminal amino acids represent the peptide CC1. (D) Sequences of the peptides related to the carboxy terminal telopeptides of the α1 and α2 chains of human type I collagen.

Figure 5.

Figure 5

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 Competition assays. One human serum sample was tested in three different ELISAs: anti-carboxytelopeptides of the α1 chain of type I (A) and II collagens (B) and anti-CCP assays (C). The inhibitors were EKAHDGGRYYRA (open triangles), EKAHDGGRYYXA (closed triangles), EKGPDPLQYMRA (open squares), and EKGPDPLQYMXA (closed squares).

Figure 4.

Figure 4

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 Differences in absorbance between the corresponding citrulline and arginine peptides in the patients with RA and controls for all peptide pairs tested. C = controls, RA = patients with rheumatoid arthritis, each circle represents one serum sample. The circles in the upper part indicate the sera that bind citrullinated peptide more strongly than arginine peptide and vice versa for those in the lower part. The figures in the upper and lower parts indicate the numbers of the cases with preferential binding to either citrullinated or arginine peptide, respectively (exceeding ±2SD of the differences of control sera).

Figure 2.

Figure 2

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 Binding of the peptides CC1 to CC4 to the individual sera of 120 patients with RA. The numbers on the abscissa refer to the serum samples; normal peptides are shown as light grey columns and citrullinated peptides as dark grey columns. The ordinate shows the absorbance measured. For the peptides of CC3 and CC4, no serum bound more strongly to the citrullinated peptide than to the normal peptide. For the CC2 peptide two cases and for the CC1 peptide 12 cases of preferential binding to the citrullinated peptide form were seen.

Figure 3.

Figure 3

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 Correlation between the bindings (absorbance units) of the carboxy terminal telopeptides of the α1 chains of type I and II collagens to the sera from patients with RA.

Selected References

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