Citrullination is an inflammation-dependent process.
Journal: 2006/September - Annals of the Rheumatic Diseases
ISSN: 0003-4967
Abstract:
OBJECTIVE
To study the presence of citrullinated proteins in inflammatory conditions and in clinically non-affected tissues of controls.
METHODS
Synovial biopsy specimens from 19 patients with rheumatoid arthritis and 10 healthy controls were investigated by immunohistochemistry. Additionally, muscle tissue from 5 patients with polymyositis and from 7 healthy controls, intestinal tissue from macroscopically affected and non-affected areas from 10 patients with inflammatory bowel disease (IBD) and tonsil tissues from 4 chronically inflamed tonsils were studied.
RESULTS
Citrullinated proteins were present in all synovial biopsy specimens from patients with rheumatoid arthritis, whereas only three of 10 healthy synovial biopsy specimens showed scarce amounts of citrullination. Citrullination was also present in all myositis-affected muscles, whereas it was absent in the muscle tissues of controls. All tonsil biopsy specimens studied were positive for citrulline. Even though more frequently detected in the macroscopically affected colonic areas, no marked difference was observed in the pattern or extent of citrullination between the macroscopically affected and non-affected intestinal IBD tissues.
CONCLUSIONS
Citrullination is present in a wide range of inflammatory tissues, suggesting that this process is inflammation dependent rather than disease dependent.
Relations:
Content
Citations
(84)
References
(15)
Diseases
(3)
Drugs
(1)
Organisms
(1)
Anatomy
(2)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Ann Rheum Dis 65(9): 1219-1222

Citrullination is an inflammation‐dependent process

D Makrygiannakis, E af Klint, I E Lundberg, A‐K Ulfgren, L Klareskog, A I Catrina, Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
R Löfberg, Department of Gastroenterology, Karolinska University Hospital, Huddinge, Karolinska Institutet
Correspondence to: A I Catrina
Department of Medicine, Rheumatology Unit, CMM, L8‐04, Karolinska University Hospital, Solna, S‐17176 Stockholm, Sweden; Anca.Catrina@ki.se
Copyright © 2006 BMJ Publishing Group Ltd & European League Against Rheumatism
D Makrygiannakis, E af Klint, I E Lundberg, A‐K Ulfgren, L Klareskog, A I Catrina, Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, SwedenR Löfberg, Department of Gastroenterology, Karolinska University Hospital, Huddinge, Karolinska InstitutetCorrespondence to: A I Catrina
Department of Medicine, Rheumatology Unit, CMM, L8‐04, Karolinska University Hospital, Solna, S‐17176 Stockholm, Sweden; Anca.Catrina@ki.se
Copyright © 2006 BMJ Publishing Group Ltd & European League Against Rheumatism
Accepted 2006 Mar 2.

Abstract

Objectives

To study the presence of citrullinated proteins in inflammatory conditions and in clinically non‐affected tissues of controls.

Methods

Synovial biopsy specimens from 19 patients with rheumatoid arthritis and 10 healthy controls were investigated by immunohistochemistry. Additionally, muscle tissue from 5 patients with polymyositis and from 7 healthy controls, intestinal tissue from macroscopically affected and non‐affected areas from 10 patients with inflammatory bowel disease (IBD) and tonsil tissues from 4 chronically inflamed tonsils were studied.

Results

Citrullinated proteins were present in all synovial biopsy specimens from patients with rheumatoid arthritis, whereas only three of 10 healthy synovial biopsy specimens showed scarce amounts of citrullination. Citrullination was also present in all myositis‐affected muscles, whereas it was absent in the muscle tissues of controls. All tonsil biopsy specimens studied were positive for citrulline. Even though more frequently detected in the macroscopically affected colonic areas, no marked difference was observed in the pattern or extent of citrullination between the macroscopically affected and non‐affected intestinal IBD tissues.

Conclusion

Citrullination is present in a wide range of inflammatory tissues, suggesting that this process is inflammation dependent rather than disease dependent.

Keywords: citrullination, arthritis, polymyositis, inflammatory bowel disease
Abstract

Rheumatoid arthritis is an inflammatory disease that is characterised by the presence of antibodies against citrullinated peptides that may have an important role in the pathogenesis of rheumatoid arthritis.1 Citrullination represents the calcium‐dependent conversion of peptidylarginine to peptidylcitrulline, which is catalysed by peptidylarginine deiminase (PAD) enzymes. This enzymatic conversion normally occurs in processes such as epidermal differentiation,2 formation of the hair follicle3 and differentiation of the myelin sheath during development of the central nervous system.4 The presence of citrullinated proteins was initially considered specific to the synovium in patients with rheumatoid arthritis.5 However, recent reports showed that citrullinated proteins are also present in non‐rheumatoid arthritis inflammatory synovitis,67 suggesting that citrullination of specific antigenic targets rather than citrullination as such is a disease‐specific process. Moreover, citrullination occurs in autoimmune neurodegenerative diseases such as multiple sclerosis48 and Alzheimer's disease.9 In the light of these observations, we asked whether citrullination occurs in types of inflammation other than arthritis and to what extent citrullination is present in the normal joint. To investigate this, we evaluated the presence of citrullinated proteins in inflamed and non‐inflamed tissues.

Acknowledgements

We thank Marianne Engström for excellent technical assistance. This study was supported by grants from the Swedish Medical Research Council, the Swedish Rheumatism Association, the Insurance Company AFA, the The King Gustav V's 80 years Foundation, and the Söderberg Foundation.

Acknowledgements

Abbreviations

IBD - inflammatory bowel disease

PAD - peptidylarginine deiminase

Abbreviations

Footnotes

Competing interests: None declared.

Footnotes

References

  • 1. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J. et al 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 20065438–46. [[PubMed]
  • 2. Tsuji Y, Akiyama M, Arita K, Senshu T, Shimizu HChanging pattern of deiminated proteins in developing human epidermis. J Invest Dermatol 2003120817–822. [[PubMed][Google Scholar]
  • 3. Tarcsa E, Marekov L N, Andreoli J, Idler W W, Candi E, Chung S I. et al The fate of trichohyalin. Sequential post‐translational modifications by peptidyl‐arginine deiminase and transglutaminases. J Biol Chem 199727227893–27901. [[PubMed]
  • 4. Moscarello M A, Wood D D, Ackerley C, Boulias CMyelin in multiple sclerosis is developmentally immature. J Clin Invest 199494146–154. [Google Scholar]
  • 5. Baeten D, Peene I, Union A, Meheus L, Sebbag M, Serre G. et al Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies. Arthritis Rheum 2001442255–2262. [[PubMed]
  • 6. Vossenaar E R, Smeets T J, Kraan M C, Raats J M, van Venrooij W J, Tak P PThe presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum 2004503485–3494. [[PubMed][Google Scholar]
  • 7. Chapuy‐Regaud S, Sebbag M, Baeten D, Clavel C, Foulquier C, De Keyser F. et al Fibrin deimination in synovial tissue is not specific for rheumatoid arthritis but commonly occurs during synovitides. J Immunol 20051745057–5064. [[PubMed]
  • 8. Raijmakers R, Vogelzangs J, Croxford J L, Wesseling P, van Venrooij W J, Pruijn G JCitrullination of central nervous system proteins during the development of experimental autoimmune encephalomyelitis. J Comp Neurol 2005486243–253. [[PubMed][Google Scholar]
  • 9. Ishigami A, Ohsawa T, Hiratsuka M, Taguchi H, Kobayashi S, Saito Y. et al Abnormal accumulation of deiminated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer's disease. J Neurosci Res 200580120–128. [[PubMed]
  • 10. Senshu T, Sato T, Inoue T, Akiyama K, Asaga HDetection of citrulline residues in deiminated proteins on polyvinylidene difluoride membrane. Anal Biochem 199220394–100. [[PubMed][Google Scholar]
  • 11. De Rycke L, Nicholas A P, Cantaert T, Kruithof E, Echols J D, Vanderkerchkhova B. et al Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis‐specific humoral autoimmunity. Arthritis Rheum 2005522323–2330. [[PubMed]
  • 12. Floren C H, Benoni C, Willen RHistologic and colonoscopic assessment of disease extension in ulcerative colitis. Scand J Gastroenterol 198722459–462. [[PubMed][Google Scholar]
  • 13. Vossenaar E R, van Venrooij W JCitrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res Ther 20046107–111. [Google Scholar]
  • 14. Samuels J, Ng Y S, Coupillaud C, Paget D, Meffre EImpaired early B cell tolerance in patients with rheumatoid arthritis. J Exp Med 20052011659–1667. [Google Scholar]
  • 15. Hill J A, Southwood S, Sette A, Jevnikar A M, Bell D A, Cairns ECutting edge: the conversion of arginine to citrulline allows for a high‐affinity peptide interaction with the rheumatoid arthritis‐associated HLA‐DRB1*0401 MHC class II molecule. J Immunol 2003171538–541. [[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.