Automated immunoassays for the autoantibodies to carbamylated or citrullinated telopeptides of type I and II collagens

Jere Häyrynen, Maija Kärkkäinen, Aulikki Kononoff 3 , Leena Arstila, Pia Elfving 3 , Helena Niinisalo, Elina Savolainen 7 , Hannu Kautiainen, Juha Risteli, Oili Kaipiainen-Seppänen 3 ,  and Marja-Kaisa Koivula
  • 1 Institute of Diagnostics, Department of Clinical Chemistry, University of Oulu, Finland
  • 2 Oulu University of Applied Science, Oulu, Finland
  • 3 Department of Medicine, Kuopio University Hospital, Kuopio, Finland
  • 4 Iisalmi Hospital, Iisalmi, Finland
  • 5 Varkaus Hospital, Varkaus, Finland
  • 6 Suonenjoki Health Centre, Suonenjoki, Finland
  • 7 Kuopio Municipal Hospital, Kuopio, Finland
  • 8 Unit of Primary Health Care, Kuopio University Hospital, Kuopio, Finland
  • 9 Unit of Family Practice, Central Finland Central Hospital, Jyväskylä, Finland
  • 10 Northern Finland Laboratory Center NordLab, Oulu University Hospital, Oulu, Finland
  • 11 Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland
Jere Häyrynen, Maija Kärkkäinen, Aulikki Kononoff, Leena Arstila, Pia Elfving, Helena Niinisalo, Elina Savolainen, Hannu Kautiainen, Juha Risteli, Oili Kaipiainen-Seppänen and Marja-Kaisa Koivula

Abstract

Background: The aim of the study was to describe automated immunoassays for autoantibodies to homocitrulline or citrulline containing telopeptides of type I and II collagen in various disease categories in an early arthritis series.

Methods: Serum samples were collected from 142 patients over 16 years of age with newly diagnosed inflammatory joint disease. All samples were analyzed with an automated inhibition chemiluminescence immunoassay (CLIA) using four different peptide pairs, each consisting of a biotinylated antigen and an inhibiting peptide. Assays were performed with an IDS-iSYS analyzer. Autoantibodies binding to homocitrulline and citrulline containing C-telopeptides of type I (HTELO-I, TELO-I) and type II collagens (HTELO-II, TELO-II) were analyzed.

Results: The mean ratio of HTELO-I inhibition in seropositive and seronegative rheumatoid arthritis (RA) was 3.07 (95% CI 1.41–11.60), p=0.003, and in seropositive and seronegative undifferentiated arthritis (UA) 4.90 (1.85–14.49), p<0.001. The respective mean ratios in seropositive and seronegative RA and UA were in TELO-I 8.72 (3.68–58.01), p<0.001 and 3.13 (1.49–6.16), p=0.008, in HTELO-II 7.57 (3.18–56.60), p<0.001 and 2.97 (1.23–6.69), p=0.037, and in TELO-II 3.01 (1.30–9.51), p=0.002 and 3.64 (1.86–7.65), p=0.008. In reactive arthritis, ankylosing spondylitis, psoriatic arthritis and unspecified spondyloarthritis the inhibition levels were similar to those observed in seronegative RA or UA.

Conclusions: Autoantibodies binding to homocitrulline or citrulline containing telopeptides of type I and II collagen did not differ significantly. They were highest among patients with seropositive disease and they differentiated seropositive and seronegative arthritis.

  • 1.

    Isomäki H, Raunio J, von Essen R, Hämeenkorpi R. Incidence of inflammatory rheumatic diseases in Finland. Scand J Rheumatol 1978;7:188–92.

    • Crossref
    • PubMed
    • Export Citation
  • 2.

    Savolainen E, Kaipiainen-Seppänen O, Kröger L, Luosujärvi R. Total incidence and distribution of inflammatory joint diseases in a defined population. – Results from the Kuopio 2000 Arthritis Survey. J Rheumatol 2003;30:2460–8.

  • 3.

    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.

    • Crossref
    • Export Citation
  • 4.

    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69:1580–8.

  • 5.

    van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, de Jong BA, Breedveld FC, Verweij CL, et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis. A prospective cohort study. Arthritis Rheum 2004;50:709–15.

    • Crossref
    • Export Citation
  • 6.

    de Hair MJ, Lehmann KA, van de Sande MG, Maijer KI, Gerlag DM, Tak PP. The clinical picture of rheumatoid arthritis according to the 2010 American College of Rheumatology/European League against Rheumatism criteria: is this still the same disease? Arthritis Rheum 2012;64:389–93.

    • Crossref
    • Export Citation
  • 7.

    Burkhardt H, Sehnert B, Bockermann R, Engstrom A, Kalden JR, Holmdahl R. Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis. Eur J Immunol 2005;35:1643–52.

    • Crossref
    • PubMed
    • Export Citation
  • 8.

    Suzuki A, Yamada R, Ohtake-Yamanaka M, Okazaki Y, Sawada T, Yamamoto K. Anti-citrullinated collagen type I antibody is a target of autoimmunity in rheumatoid arthritis. Biochem Biophys Res Commun 2005;333:418–26.

    • Crossref
    • Export Citation
  • 9.

    Koivula MK, Åman S, Karjalainen A, Hakala M, Risteli J. Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis? Ann Rheum Dis 2005;64:1443–50.

    • Crossref
    • PubMed
    • Export Citation
  • 10.

    Koivula MK, Ramberg J, Åman S, Karjalainen A, Hakala M, Risteli J. Sensitive immunoassays for the autoantibodies reacting against citrullinated carboxy-terminal telopeptides of type I and type II collagens in patients with rheumatoid arthritis. Clin Chem Lab Med 2005;43:1400–5.

    • Crossref
    • PubMed
    • Export Citation
  • 11.

    Koivula MK, Åman S, Alasaarela E, Karjalainen A, Hakala M, Risteli J. Inhibitory characteristics of citrullinated telopeptides of type I and II collagens for autoantibody binding in patients with rheumatoid arthritis. Rheumatology 2006;45:1364–9.

    • Crossref
    • PubMed
    • Export Citation
  • 12.

    Koivula MK, Heliövaara M, Ramberg J, Knekt P, Rissanen H, Palosuo T, et al. Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis. Ann Rheum Dis 2007;66:1450–5.

    • Crossref
    • PubMed
    • Export Citation
  • 13.

    György B, Tóth E, Tarcsa E, Falus A, Buzás EI. Citrullination: a posttranslational modification in health and disease. Int J Biochem Cell Biol 2006;38:1662–77.

    • Crossref
    • Export Citation
  • 14.

    Wang Z, Nicholls SJ, Rodriguez ER, Kummu O, Hörkkö S, Barnard J, et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat Med 2007;13:1176–84.

    • Crossref
    • PubMed
    • Export Citation
  • 15.

    Kraus LM, Kraus AP Jr. Carbamylation of amino acids and proteins in uremia. Kidney Int Suppl 2001;78:S102–7.

    • Crossref
    • Export Citation
  • 16.

    Lundberg K, Nijenhuis S, Vossenaar ER, Palmblad K, van Venrooij WJ, Klareskog L, et al. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res Ther 2005;7:R458–67.

    • Crossref
    • Export Citation
  • 17.

    Turunen S, Koivula MK, Risteli L, Risteli J. Anticitrulline antibodies can be caused by homocitrulline-containing proteins in rabbits. Arthritis Rheum 2010;62:3345–52.

    • Crossref
    • PubMed
    • Export Citation
  • 18.

    Mydel P, Wang Z, Brisslert M, Hellvard A, Dahlberg LE, Hazen SL, et al. Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis. J Immunol 2010;184:6882–90.

    • Crossref
    • Export Citation
  • 19.

    Jaisson S, Larreta-Garde V, Bellon G, Hornebeck W, Garnotel R, Gillery P. Carbamylation differentially alters type I collagen sensitivity to various collagenases. Matrix Biol 2007;26:190–6.

    • Crossref
    • PubMed
    • Export Citation
  • 20.

    Klareskog L, Padyukov L, Rönnelid J, Alfredsson L. Genes, environment and immunity in the development of rheumatoid arthritis. Curr Opin Immunol 2006;18:650–5.

    • Crossref
    • PubMed
    • Export Citation
  • 21.

    Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al, and the Epidemiological Investigation of Rheumatoid Arthritis Study Group. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54:38–46.

    • Crossref
    • Export Citation
  • 22.

    Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GM, van Veelen PA, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci USA 2011;108:17372–7.

    • Crossref
    • Export Citation
  • 23.

    Kärkkäinen M. Automated detection method for antibodies against homocitrullinated proteins: establishment of the assay and its validation. Available from: https://www.theseus.fi/bitstream/handle/10024/.../Karkkainen_Maija.pdf [in Finnish with English abstract]. Accessed 23 September, 2014.

  • 24.

    van Venrooij W, Drijfhout J, van Boekel M, Pruijn G. Patent application EP 1 693 673 A2. Detection of auto-antibodies from patients suffering from rheumatoid arthritis.

  • 25.

    Risteli J, Koivula MK, Risteli J. Citrullinated collagens in the pathogenesis of rheumatoid arthritis. Expert Rev Clin Immunol 2007;3:184–94.

    • Crossref
    • Export Citation
  • 26.

    Aho K, Palosuo T, Raunio V, Puska P, Aromaa A, Salonen TJ. When does rheumatoid arthritis start? Arthritis Rheum 1985;28:485–9.

    • Crossref
    • PubMed
    • Export Citation
  • 27.

    Rantapaa-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003;48:2741–9.

    • Crossref
    • Export Citation
  • 28.

    Nielen MM, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004;50:380–6.

    • Crossref
    • Export Citation
  • 29.

    Shi J, van de Stadt LA, Levarht EW, Huizinga TW, Toes RE, Trouw LA, et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum 2013;65:911–5.

    • Crossref
    • PubMed
    • Export Citation
  • 30.

    Shi J, van de Stadt LA, Nivine Levarht EW, Huizinga TW, Hamann D, van Schaardenburg D, et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann Rheum Dis 2014;73:4780–3.

    • Crossref
    • Export Citation
  • 31.

    Scott DL. Prognostic factors in early rheumatoid arthritis. Rheumatology 2000;39(Suppl 1):24–9.

    • Crossref
    • Export Citation
  • 32.

    Turunen S, Koivula MK, Melkko J, Alasaarela E, Lehenkari P, Risteli J. Different amounts of protein-bound citrulline and homocitrulline in foot joint tissues of a patient with anti-citrullinated protein antibody positive erosive rheumatoid arthritis. J Transl Med 2013;11:224.

    • Crossref
    • PubMed
    • Export Citation
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Clinical Chemistry and Laboratory Medicine ( CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. CCLM welcomes contributions on the progress in fundamental and applied research and cutting-edge clinical laboratory medicine. It is one of the leading journals in the field, with an impact factor of over three. CCLM is the official journal of nine national clinical societies and associated with EFLM.

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