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Rheumatology Advance Access originally published online on April 21, 2006
Rheumatology 2006 45(11):1364-1369; doi:10.1093/rheumatology/kel113
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inhibitory characteristics of citrullinated telopeptides of type I and II collagens for autoantibody binding in patients with rheumatoid arthritis

M.-K. Koivula, S. Åman1, E. Alasaarela1, A. Karjalainen1, M. Hakala2 and J. Risteli

Department of Clinical Chemistry, 1Division of Rheumatology, Department of Internal Medicine, University of Oulu, Oulu and 2Rheumatism Foundation Hospital, Heinola, Finland.

Correspondence to: Juha Risteli, MD, PhD, Professor of Clinical Chemistry, University of Oulu, PL 5000, FI-90014 Oulun yliopisto, Finland. E-mail: juha.risteli{at}oulu.fi


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To study how soluble citrullinated telopeptides of type I and II collagens inhibit the binding of autoantibodies to the respective antigens immobilized onto solid phase, and to use modifications of previous methods to re-analyse rheumatoid arthritis (RA) and control serum samples.

Methods. Autoantibody binding was inhibited with normal or citrullinated carboxytelopeptides using enzyme-linked immunosorbent assay (ELISA) methods. Serum samples were available from 120 patients with RA and 81 controls.

Results. Autoantibodies that bind normal C-telopeptides were not inhibited with soluble normal or citrullinated telopeptides. However, the antibodies that bind only citrullinated telopeptides could be inhibited with corresponding citrullinated telopeptides. Thus, it is not necessary to study the binding of autoantibodies to normal collagens if the specificity of their binding is assessed by immunological inhibition. For type I telopeptide, there are two arginines, the latter of which, when citrullinated, is important for binding. For type II telopeptide, there is one arginine, which is important when citrullinated. The other amino acids, e.g. the last alanine, have only a slight effect on binding. These improved methods differentiate better between RA patients, who have specific citrullinated autoantibodies, and controls than previous ELISA methods.

Conclusions. Based on inhibition assay, it is possible to measure the autoantibodies binding specifically to citrullinated telopeptides of type I and II collagens. When only one assay is involved, variance is decreased and the overall performance is easier than before.

KEY WORDS: Anti-CCP antibodies, Autoantibodies, Citrullination, Rheumatoid arthritis, Telopeptide, Type I collagen, Type II collagen


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Citrullination of proteins in normal individuals occurs late during the protein lifespan, e.g. in vimentin and filaggrin during apoptosis. Citrullination has recently been an object of interest in rheumatology, since several specific autoantibodies found in rheumatoid arthritis (RA) are mainly directed to proteins where certain arginine residues are modified to citrulline [1, 2]. This post-translational modification is enzyme-dependent, and there are at least five genetically different forms of enzyme peptidylarginine deiminases (PADs) [3, 4]. Two isotypes, PAD-2 and PAD-4, have been found in monocytes and/or macrophages of inflamed synovium, and there is a polymorphism that is related to RA [5–7]. The hypothesis is that during rheumatic synovitis PAD is released into the extracellular space and may induce citrullination of arginine residues locally in several proteins, such as vimentin, fibrin and fibrinogen and fibronectin [1, 2, 8]. Rheumatoid factors (RF) have been considered the most characteristic autoantibodies in RA, but their specificity is far from optimal. RA-associated autoantibodies with higher specificity include an antiperinuclear factor discovered about 40 years ago [9] and an antikeratin antibody [10]. During the last decade, it has turned out that the antigen to which these autoantibodies are bound is actually citrullinated (pro)filaggrin [11, 12]. Since there is no filaggrin in serum and joints, these autoantibodies probably reflect an immunological cross-reaction with citrullinated antigens. However, the presence of antifilaggrin antibodies is highly specific for RA, and a modification of the antifilaggrin assay, called ‘anti-cyclic citrullinated protein assay (anti-CCP assay)’, has been widely used for diagnostic purposes [13–15].

Our previous studies have indicated that there are autoantibodies in RA against citrullinated collagens [16, 17]. These antibodies are directed against the carboxyterminal telopeptides of both type I and II collagens, and similar antibodies could react with both collagens, which is very interesting, since both cartilage and bone are involved in RA [16]. Other scientists have found out that citrullinated residues could also be located in the trimeric, helical regions of type II collagen (amino acid residues 359–369) [18]. In addition, human acid-soluble type I and II collagens were treated in vitro with PAD-2 in another study, and several arginine residues were found to be citrullinated [19]. In rats, citrullination can break down the tolerance against self-antigens (rat serum albumin) and increase the arthritogenic properties of cartilage type II collagen [20].

There are also antibodies against normal type I and II collagens [21, 22] in RA. These are by no means specific for RA, and their formation could be secondary to the destruction of connective tissues. Consequently, to detect specific antibodies against citrullinated collagens, two assays are currently applied using both arginine- and citrulline-containing type I and II carboxytelopeptides. The aim of these experiments was to further study the autoantibodies against arginine- and citrulline-containing C-telopeptides in RA. The specificity of the binding of these antibodies was tested by inhibition with corresponding soluble identical antigens. Based on these experiments, it was found unnecessary to measure the binding to normal, arginine-containing peptides. It is sufficient to perform the assays with the citrullinated forms of telopeptides and, in addition, to confirm that these antibodies could be inhibited with corresponding soluble antigens.


   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients and controls
The serum samples from 120 RA patients were from the Division of Rheumatology of Oulu University Hospital, and that of the 81 controls were from age- and sex-matched healthy persons [16]. An experienced rheumatologist made the clinical diagnosis of RA on clinical grounds, since the patients were in the early stages of the disease. The study was approved by the Ethical Committee of Oulu University Hospital. The study was performed according to the Declaration of Helsinki.

Peptide antigens
Different lengths of synthetic arginine- or citrulline-containing peptides derived from carboxytelopeptide of type I and type II collagens, some of which were also biotinylated, were synthesized by NeoMPS (Strasbourg, France). Their sequences (nomenclature: SP + number) are shown in Table 1.


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  		TABLE 1. Synthetic peptides used in this study derived from carboxytelopeptides of type I and II collagens

 
Enzyme-linked in immunosorbent assay (ELISA) methods
The biotinylated peptides were coupled to streptavidin-coated 96-well assay plates (BioBind Assembly, Thermo Labsystems Oy, Vantaa, Finland) at a concentration of 10 µg/well. The coupling was performed at room temperature, pH 7.5, for 2 h. The streptavidin-coated wells had been blocked by the manufacturer to prevent unspecific binding.

The sera were diluted in assay buffer [10 mM Tris-HCl, 350 mM NaCl, 1% BSA, 1% (vol/vol) Triton X-100, 0.5% (wt/vol) Na-deoxycholate, 0.1% SDS; pH 7.6] supplemented with 1% rabbit serum and incubated in the well for 1 h at room temperature (100 µl/well). After washing [three times with PBS/0.05% (vol/vol) Tween-20], 100 µl of anti-human IgG conjugated to peroxidase (Product # 31412, Pierce, Rockford, IL, USA) diluted 1:40 000 in GuardianTM Peroxidase Conjugate Stabilizer/Diluent (Product # 37548, Pierce) was added. After incubation for 1 h at room temperature, the plates were washed (three times with PBS/Tween-20). The bound antibodies were detected with 3,3'-5,5'-tetramethyl-benzidine (Sigma–Aldrich, St Louis, MN, USA) as a substrate (0.01 mg/100 µl per well in 100 mM sodium acetate trihydrate, 1.5 mM citric acid monohydrate, 0.0015% H2O2). After 30 min, the reaction was stopped by adding 100 µl of 2M sulphuric acid/well. The absorbances at a wavelength of 450 nm were read in a Victor2 instrument (Wallac, Turku, Finland), and the results were calculated by Multicalc (Wallac). All sera were tested in duplicate. The coefficients of variation were generally <10%.

Anti-CCP-ELISA (anti-CCP Mark2 assay) was used according to the procedure described by the manufacturer (Euro-Diagnostica, Malmö, Sweden). All sera, calibrators and controls were measured in duplicate, and the results were averaged.

Inhibition tests
To assess antibody specificity, assays with type I and II carboxytelopeptides were done using selected patient sera (n = 14) (Table 2), which showed increased binding in the previous ELISA [16]. The sera were diluted in assay buffer to such dilutions that, in each assay, the initial binding could be noticeably (at least 20%) inhibited by different soluble peptides. Serial dilutions of competitive peptides [arginine and citrulline forms of C-telopeptide of the {alpha}1(I) and {alpha}1(II) collagen antigens] were added. The extent of competition was plotted as percentage inhibition against the soluble peptide concentration. The signal (absorbance at wavelength of 450 nm) obtained with human serum only (initial binding) was defined as 0% inhibition, and the signal of the blank (no serum, but competitive peptide) was defined as 100% inhibition.


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  		TABLE 2. Individual patient sera showing different binding to normal and citrullinated carboxytelopeptides of type I and II collagens and filaggrin sequence-derived cyclic citrullinated peptide. Positive titres (anti-{alpha}1(I)Arg ≥ 0.572, anti-{alpha}1(I)Cit ≥ 0.548, anti-{alpha}1(II)Arg ≥ 0.335 and anti-{alpha}1(II)Cit ≥ 0.285) are based on titres, as described in the previous article [16]. For anti-CCP, positive titre is more than 25 U/ml

 
After these experiments, all RA and control sera were tested with citrullinated type I and II carboxytelopeptides under standard conditions (see previous explanation) and with added corresponding soluble antigens (one concentration 200 µg/ml). For each serum, the differences without and with inhibition were calculated and compared with control sera.

Statistical methods
The data were analysed by using the Statistical Package for the Social Sciences (SPSS) for Windows version 12.0.1 (SPSS, SPSS Inc., Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
When selected sera from RA patients were tested on arginine- and citrulline-containing telopeptides and anti-CCP assay, different patterns emerged (Table 2). In three out of 14 patients, antibody binding to all telopeptides was positive, in four out of 14, binding to only citrulline-containing type I and II collagen telopeptides and assay for anti-CCP were positive, and in six out of 14, binding to citrulline-containing type I collagen and assay for anti-CCP were positive. This series included only one patient (T.S.) who had antibodies to citrulline-containing type II collagen telopeptide and was anti-CCP-positive (Table 2). When the sera of the three patients positive for all antibodies were inhibited in the arginine telopeptides assays with corresponding soluble peptides, no inhibition was found (Fig. 1), nor did the citrulline-containing peptide inhibit antibody binding in these patients in normal peptide-containing assays. Two of them (H-O.I and M.V.) had anti-CCP antibodies, while one was negative (P.A.). When the sera of the patients, in whom the arginine- and citrulline-containing assays were positives, were inhibited in the citrulline telopeptides assays with both soluble antigens, no inhibition was seen (Fig. 2, the first three patients). When the sera of the patients with antibodies that were only inhibited with citrulline-containing peptide were assayed with normal and citrullinated peptides, inhibition was seen in the presence the citrulline-containing peptide, but no inhibition was induced by the arginine peptides (Fig. 2, the last 10 patients). With respect to type II telopeptides, similar results were obtained (Fig. 3). These patients, whose sera bound to both normal and citrulline-containing telopeptides, showed no inhibition (Fig. 3, the first three patients), but we did see inhibition in the sera where only the binding to citrulline-containing peptide was positive (Fig. 3, the last five patients). It thus seems that autoantibodies binding to normal, arginine-containing peptide could not be inhibited with arginine or citrullinated peptides. However, in the patients whose sera bound only to citrullinated peptides, the antibodies could be inhibited with corresponding soluble peptides.


Figure 1
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  		FIG. 1. ELISA assessment of the inhibition of the binding of RA autoantibodies to arginine-containing type I and II collagen. (A) Type I collagen carboxytelopeptide: white columns, standard assay without inhibition; grey columns, the same assay containing 200 µg/ml of soluble peptide SP65; and black columns, the same assay containing 200 µg/ml of soluble peptide SP66. (B) Type II collagen carboxytelopeptide: white columns, standard assay without inhibition; grey columns, the same assay containing 200 µg/ml of soluble peptide SP40; and black columns, the same assay containing 200 µg/ml of soluble peptide SP41. The strength of antibody binding is expressed on the linear y-axis as absorbance values of 1:100 diluted sera at 450 nm wavelength. Serum of patient P.A. was diluted at 1:200 because of very high initial absorbance.

 

Figure 2
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  		FIG. 2. ELISA assessment of the inhibition of the binding of RA autoantibodies to citrulline-containing type I collagen carboxytelopeptide. White columns, standard assay without any inhibition; grey columns, the same assay containing 200 µg/ml of soluble peptide SP65; and black columns, the same assay containing 200 µg/ml of soluble peptide SP66. Serum of patients P.A., K.H., K-M.V., L.J. and N.S. were diluted at 1:200, F.S. 1:400 and P.H. 1:800 because of very high initial absorbances.

 

Figure 3
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  		FIG. 3. ELISA assessment of the inhibition of the binding of RA autoantibodies in ELISA to citrulline-containing type II collagen carboxytelopeptide. White columns, standard assay without inhibition; grey columns, the same assay containing 200 µg/ml of soluble peptide SP40; and black columns, the same assay containing 200 µg/ml of soluble peptide SP41.

 
These sera could also be used to study which amino acids could be important in the linear epitopes for antibody binding. For type I collagen telopeptide (Table 3), it seems that the last citrulline (SP66) is important, since antibodies seem to bind to the second citrulline residue (SP72) to a lesser extent than to the first. It also seems that, in some cases (e.g. H.B., K.H., A.E. and especially F.S. and K.T.), the last alanine could be important, while in other cases it does not have any effect. If the first citrulline from the carboxyterminal end is truncated (Table 3, SP77), antibodies are more efficiently inhibited by this peptide than by the full-length peptide (SP72). For type II collagen telopeptides (Table 4), citrulline was obviously necessary, and the last alanine increased overall binding only slightly (2–15%).


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  		TABLE 3. Inhibitory characteristics of citrullinated carboxytelopeptides of type I collagens in different patient sera

 

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  		TABLE 4. Inhibitory characteristics of citrullinated carboxytelopeptides of type II collagens in different patient sera

 
Finally, we tested our previous series of RA patients and controls [16, 17] using the new inhibitory modification of the methods (Table 5 and Fig. 4). The power of discrimination between normal and diseased cases was much better than before (Table 5). Figure 4 shows a summary of the results of both {alpha}1 telopeptide chains of type I and II collagens when the sera were inhibited with corresponding soluble antigens (one concentration 200 µg/ml). In the case of type I collagen assay, there were 48 sera of RA patients (40%) who showed increased specific binding, and three sera of controls were also positive (more than upper level of reference range 17.6%; based on the mean + 2S.D. of controls). The mean of the controls was 6.9% and that of the RA patients 22.6%. In the case of type II collagen assay, the corresponding figures for positive findings were 36 sera of RA patients (30%) and one control serum (more than upper level of reference range 13.8%; based on the mean + 2S.D. of controls). With type II collagen, the mean of the controls was 5.4% and that of the RA patients 14.5%.


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  		TABLE 5. Performance characteristics of ELISA methods based on inhibition by citrullinated collagen peptides (present study), two ELISAs with arginine- and citrulline-containing peptides [16] and an automatic version of the latter [17]. P-values and Student's test values (t) between patients with RA (n = 120) and controls (n = 81). Positives indicate how many RA patients had positives in a certain assay modifications

 

Figure 4
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  		FIG. 4. Percentages of inhibition among 120 patients with RA and 81 control subjects assessed by ELISA. (A) Inhibition obtained with citrullinated type I collagen C-telopeptide and (B) inhibition obtained with citrullinated type II collagen C-telopeptide. The means are indicated with solid lines, and the means±2S.D. of the controls are indicated with dashed lines.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
Autoantibodies are usually measured by demonstrating their binding against the antigen in question, and the specificity of the antibody reaction is not subjected to further study. RA involves autoantibodies against normal collagens, especially cartilage collagens [21, 22]. These antibodies are possibly related to the breakdown of immunological tolerance against the major proteins in the joints. In our previous study, 45% of RA patients had increased concentrations of antibodies against arginine-containing type II carboxytelopeptide [16]. For type I collagen carboxytelopeptide, this figure was as low as 5% [16], which explains the better performance of type I telopeptide assay in patients with previously diagnosed RA [16, 17]. In a recently published study, 41% of RA patients had anti-human type II collagen antibodies against normal cartilage collagen, and after that, anti-citrullinated type II collagen antibodies were not significantly increased [19]. However, anti-citrullinated human type I collagen antibodies were significantly higher in RA patients’ sera than in normal controls [19]. This process of generation of autoantibodies against normal collagens, especially cartilage collagen, could be due to citrullination, since in rats, for instance, immunization with citrullinated rat serum albumin (RSA) induced autoantibodies against citrullinated RSA, which would also bind normal RSA. When rats were immunized with normal RSA, there were no autoantibodies generated against normal or citrullinated RSA [20]. In our own study on rabbits immunized with citrulline-containing type I carboxytelopeptide, we at first get antibodies against citrullinated type I carboxytelopeptides, but very soon, also antibodies binding to arginine-containing type I carboxytelopeptide.

With regard to the two arginine residues in type I carboxytelopeptide, it could be noted that the first citrulline from the carboxyterminus was apparently crucial for the formation of the linear epitope, while the last alanine was important in some cases, but not in all sera (Table 3). For type II collagen, the last amino acid, alanine, contributes only very slightly to overall binding (Table 4).

The present study showed that, for diagnostic purposes, there is no need to test antibody binding against arginine-containing peptides, since these sera are also positive against citrulline-containing peptides (Figs 1–3GoGo). However, some of the sera contained antibodies that could not be inhibited with a corresponding soluble antigen, possibly due to unspecific binding. Because of this finding, the plain test with citrullinated peptides was considered insufficient, and we decided to include an inhibition test with corresponding soluble antigens. By using this set-up, we have been able to detect antibodies binding specifically to citrullinated peptides of both type I and II collagens.

We applied these improved inhibitory methods to a previously tested serum series and found out superior discrimination compared with earlier assays (Table 5, Fig. 4). In addition, there were more positive reactions compared with the previous methods, which used two ELISA assays (Table 5). With respect to the anti-CCP assay, about one third to one half of the patients with RA have specific serological abnormalities several years before the onset of symptoms, depending on the period between taking the specimen and the onset of disease [14, 23]. We have also addressed this question by analysing sera from patients who later developed RA and matched controls, and based on the preliminarily results obtained by using an automatic version of the assay [17], autoantibodies against citrullinated telopeptide of type II collagen and flaggan predict synergistically the development of seropositive RA (to be published). These phenomena, while offering possibilities to study early immunological activation in RA, also make demands on the collection of control individuals. Of the small number of control subjects used in this study, three had antibodies showing increased inhibition with type I telopeptide assay (mean±2S.D.), while type II telopeptide assay yielded similar findings in only one control case (Fig. 4).

It has long been supposed that autoimmunity against collagens might be involved in the pathogenesis of RA. One problem encountered is that there are autoantibodies against collagens in subjects, who have no RA. Citrullination could explain this discrepancy, since citrulline in collagens will definitively produce autoantibodies. Unfortunately, the RA patients will most likely later produce them against normal collagens which could hamper the findings. However, our results do not exclude the role of collagens in pathogenesis of RA, but further studies are still necessary.


   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Ms Liisa Kaarela and Ms Aino Nykänen for expert technical assistance. We also thank Timo Palosuo, MD, PhD, for constructive comments on the manuscript.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 19 October 2005; revised version accepted 28 February 2006.
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M.-K. Koivula, E. Savolainen, O. Kaipiainen-Seppanen, H. Kautiainen, R. Luosujarvi, M. Hakala, and J. Risteli
Sensitivity and specificity of autoantibodies binding to citrullinated carboxyterminal telopeptides of types I and II collagens in an early arthritis series
Rheumatology, May 1, 2008; 47(5): 656 - 659.
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