Skip to main content
SpringerLink
Log in

Protein Citrullination: The Link Between Rheumatoid Arthritis and Periodontitis?

  • Chapter
  • First Online:
Protein Deimination in Human Health and Disease

Abstract

Autoimmunity to citrullinated proteins is very specific for rheumatoid arthritis and is considered to be of pathogenic significance. Porphyromonas gingivalis, a major pathogen in gum disease (periodontitis), is hypothesized to play a role in the pathogenesis of rheumatoid arthritis by its unique ability to citrullinate endogenous and host proteins. The immune system in patients with a periodontal infection with Porphyromonas gingivalis is exposed to citrullinated antigens that might become systemic immunogens, eventually leading to rheumatoid arthritis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 159.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aggarwal R, Liao K, Nair R, Ringold S, Costenbader KH (2009) Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Rheum 61(11):1472–1483

    Article  PubMed  Google Scholar 

  • Al-Katma MK, Bissada NF, Bordeaux JM, Sue J, Askari AD (2007) Control of periodontal infection reduces the severity of active rheumatoid arthritis. J Clin Rheumatol 13(3):134–137

    Article  PubMed  Google Scholar 

  • Armitage GC (2003) Diagnosis of periodontal diseases. J Periodontol 74(8):1237–1247

    Article  PubMed  Google Scholar 

  • Baeten D, Peene I, Union A, Meheus L, Sebbag M, Serre G et al (2001) Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies. Arthritis Rheum 44(10):2255–2262

    Article  PubMed  CAS  Google Scholar 

  • Berglundh T, Donati M (2005) Aspects of adaptive host response in periodontitis. J Clin Periodontol 32(Suppl 6):87–107

    Article  PubMed  CAS  Google Scholar 

  • Berthelot JM, Le GB (2010) Rheumatoid arthritis and periodontal disease. Joint Bone Spine 77(6):537–541

    Article  PubMed  CAS  Google Scholar 

  • Bonfil JJ, Dillier FL, Mercier P, Reviron D, Foti B, Sambuc R et al (1999) A “case control” study on the role of HLA DR4 in severe periodontitis and rapidly progressive periodontitis. Identification of types and subtypes using molecular biology (PCR.SSO). J Clin Periodontol 26(2):77–84

    Article  PubMed  CAS  Google Scholar 

  • Brito F, de Barros FC, Zaltman C, Carvalho AT, Carneiro AJ, Fischer RG et al (2008) Prevalence of periodontitis and DMFT index in patients with Crohn’s disease and ulcerative colitis. J Clin Periodontol 35(6):555–560

    Article  PubMed  Google Scholar 

  • Chiu B (1999) Multiple infections in carotid atherosclerotic plaques. Am Heart J 138(5 Pt 2):S534–S536

    Article  PubMed  CAS  Google Scholar 

  • Christan C, Dietrich T, Hagewald S, Kage A, Bernimoulin JP (2002) White blood cell count in generalized aggressive periodontitis after non-surgical therapy. J Clin Periodontol 29(3):201–206

    Article  PubMed  Google Scholar 

  • Correa FO, Goncalves D, Figueredo CM, Bastos AS, Gustafsson A, Orrico SR (2010) Effect of periodontal treatment on metabolic control, systemic inflammation and cytokines in patients with type 2 diabetes. J Clin Periodontol 37(1):53–58

    Article  PubMed  CAS  Google Scholar 

  • de Smit M, Westra J, Vissink A, van der Doornbos MB, Brouwer E, van Winkelhoff AJ (2012a) Periodontitis in established rheumatoid arthritis patients: a cross-sectional clinical, microbiological and serological study. Arthritis Res Ther 14(5):R222

    Article  PubMed  Google Scholar 

  • de Smit MJ, Brouwer E, Westra J, Nesse W, Vissink A, van Winkelhoff AJ (2012b) [Effect of periodontal treatment on rheumatoid arthritis and vice versa]. Ned Tijdschr Tandheelkd 119(4):191–7

    Article  PubMed  Google Scholar 

  • De-Gennaro LA, Lopes JD, Mariano M (2006) Autoantibodies directed to extracellular matrix components in patients with different clinical forms of periodontitis. J Periodontol 77(12):2025–2030

    Article  PubMed  CAS  Google Scholar 

  • DePablo P, Dietrich T, McAlindon TE (2008) Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. J Rheumatol 35(1):70–76

    Google Scholar 

  • Dissick A, Redman RS, Jones M, Rangan BV, Reimold A, Griffiths GR et al (2010) Association of periodontitis with rheumatoid arthritis: a pilot study. J Periodontol 81(2):223–230

    Article  PubMed  Google Scholar 

  • Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al BR, Mechin MC et al (2007) Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum 56(11):3541–3553

    Article  PubMed  CAS  Google Scholar 

  • Getts MT, Miller SD (2010) 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: triggering of autoimmune diseases by infections. Clin Exp Immunol 160(1):15–21

    Article  PubMed  CAS  Google Scholar 

  • Griffen AL, Becker MR, Lyons SR, Moeschberger ML, Leys EJ (1998) Prevalence of Porphyromonas gingivalis and periodontal health status. J Clin Microbiol 36(11):3239–3242

    PubMed  CAS  Google Scholar 

  • Hayashi J, Masaka T, Ishikawa I (1999) Increased levels of soluble CD14 in sera of periodontitis patients. Infect Immun 67(1):417–420

    PubMed  CAS  Google Scholar 

  • Hendler A, Mulli TK, Hughes FJ, Perrett D, Bombardieri M, Houri-Haddad Y et al (2010) Involvement of autoimmunity in the pathogenesis of aggressive periodontitis. J Dent Res 89(12):1389–1394

    Article  PubMed  CAS  Google Scholar 

  • Hirsch HZ, Tarkowski A, Koopman WJ, Mestecky J (1989) Local production of IgA- and IgM-rheumatoid factors in adult periodontal disease. J Clin Immunol 9(4):273–278

    Article  PubMed  CAS  Google Scholar 

  • Hitchon CA, Chandad F, Ferucci ED, Willemze A, Ioan-Facsinay A, van der WD et al (2010) Antibodies to porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives. J Rheumatol 37(6):1105–12

    Article  PubMed  CAS  Google Scholar 

  • Hutter JW, van der Velden U, Varoufaki A, Huffels RA, Hoek FJ, Loos BG (2001) Lower numbers of erythrocytes and lower levels of hemoglobin in periodontitis patients compared to control subjects. J Clin Periodontol 28(10):930–936

    Article  PubMed  CAS  Google Scholar 

  • Jansson H (2006) Studies on periodontitis and analyses of individuals at risk for periodontal diseases. Swed Dent J Suppl 180:5–49

    PubMed  Google Scholar 

  • Kallberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, van der Helm-van Mil AH et al (2007) Gene–gene and gene–environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet 80(5):867–875

    Article  PubMed  Google Scholar 

  • Kinloch A, Lundberg K, Wait R, Wegner N, Lim NH, Zendman AJ et al (2008) Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis. Arthritis Rheum 58(8):2287–2295

    Article  PubMed  CAS  Google Scholar 

  • Loos BG, Craandijk J, Hoek FJ, van Dillen Wertheim PM, Van der Velden U (2000) Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol 71(10):1528–34

    Article  PubMed  CAS  Google Scholar 

  • Lundberg K, Kinloch A, Fisher BA, Wegner N, Wait R, Charles P et al (2008) Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum 58(10):3009–3019

    Article  PubMed  CAS  Google Scholar 

  • Madianos PN, Lieff S, Murtha AP, Boggess KA, Auten RL Jr, Beck JD et al (2001) Maternal periodontitis and prematurity. Part II: maternal infection and fetal exposure. Ann Periodontol 6(1):175–182

    Article  PubMed  CAS  Google Scholar 

  • Marotte H, Farge P, Gaudin P, Alexandre C, Mougin B, Miossec P (2006) The association between periodontal disease and joint destruction in rheumatoid arthritis extends the link between the HLA-DR shared epitope and severity of bone destruction. Ann Rheum Dis 65(7):905–909

    Article  PubMed  CAS  Google Scholar 

  • Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C, Senshu T et al (2001) The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol 166(6):4177–4184

    PubMed  CAS  Google Scholar 

  • McGraw WT, Potempa J, Farley D, Travis J (1999) Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect Immun 67(7):3248–3256

    PubMed  CAS  Google Scholar 

  • Mealey BL, Oates TW (2006) Diabetes mellitus and periodontal diseases. J Periodontol 77(8):1289–1303

    Article  PubMed  CAS  Google Scholar 

  • Mercado F, Marshall RI, Klestov AC, Bartold PM (2000) Is there a relationship between rheumatoid arthritis and periodontal disease? J Clin Periodontol 27(4):267–272

    Article  PubMed  CAS  Google Scholar 

  • Mercado FB, Marshall RI, Klestov AC, Bartold PM (2001) Relationship between rheumatoid arthritis and periodontitis. J Periodontol 72(6):779–787

    Article  PubMed  CAS  Google Scholar 

  • Mikuls TR, Payne JB, Reinhardt RA, Thiele GM, Maziarz E, Cannella AC et al (2009) Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int Immunopharmacol 9(1):38–42

    Article  PubMed  CAS  Google Scholar 

  • Montebugnoli L, Servidio D, Miaton RA, Prati C, Tricoci P, Melloni C et al (2005) Periodontal health improves systemic inflammatory and haemostatic status in subjects with coronary heart disease. J Clin Periodontol 32(2):188–192

    Article  PubMed  CAS  Google Scholar 

  • Nesse W, Dijkstra PU, Abbas F, Spijkervet FK, Stijger A, Tromp JA et al (2010) Increased prevalence of cardiovascular and autoimmune diseases in periodontitis patients: a cross-sectional study. J Periodontol 81(11):1622–1628

    Article  PubMed  Google Scholar 

  • Nesse W, Westra J, van der Wal JE, Abbas F, Nicholas AP, Vissink A et al (2012) The periodontium of periodontitis patients contains citrullinated proteins which may play a role in ACPA (anti-citrullinated protein antibody) formation. J Clin Periodontol 39(7):599–607

    Article  PubMed  CAS  Google Scholar 

  • Nielen MM, van SD, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH et al (2004) Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 50(2):380–6

    Article  PubMed  Google Scholar 

  • Nienhuis RL, Mandema E (1964) A new serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Ann Rheum Dis 23:302–305

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly PG, Claffey NM (2000) A history of oral sepsis as a cause of disease. Periodontol 2000 23:13–18

    Article  PubMed  Google Scholar 

  • Ogrendik M, Kokino S, Ozdemir F, Bird PS, Hamlet S (2005) Serum antibodies to oral anaerobic bacteria in patients with rheumatoid arthritis. MedGenMed 7(2):2

    PubMed  Google Scholar 

  • Ortiz P, Bissada NF, Palomo L, Han YW, Al-Zahrani MS, Panneerselvam A et al (2009) Periodontal therapy reduces the severity of active rheumatoid arthritis in patients treated with or without tumor necrosis factor inhibitors. J Periodontol 80(4):535–540

    Article  PubMed  CAS  Google Scholar 

  • Pancholi V, Fischetti VA (1998) alpha-enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci. J Biol Chem 273(23):14503–15

    Article  PubMed  CAS  Google Scholar 

  • Prete M, Racanelli V, Digiglio L, Vacca A, Dammacco F, Perosa F (2011) Extra-articular manifestations of rheumatoid arthritis: an update. Autoimmun Rev 11(2):123–131

    Article  PubMed  Google Scholar 

  • Rajapakse PS, Dolby AE (2004) Evidence for local production of antibodies to auto and non-self antigens in periodontal disease. Oral Dis 10(2):99–105

    Article  PubMed  CAS  Google Scholar 

  • Rosenstein ED, Greenwald RA, Kushner LJ, Weissmann G (2004) Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation 28(6):311–318

    Article  PubMed  Google Scholar 

  • Scannapieco FA, Bush RB, Paju S (2003) Associations between periodontal disease and risk for atherosclerosis, cardiovascular disease, and stroke. A systematic review. Ann Periodontol 8(1):38–53

    Article  PubMed  Google Scholar 

  • Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC et al (2000) The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43(1):155–163

    Article  PubMed  CAS  Google Scholar 

  • Scher JU, Ubeda C, Equinda M, Khanin R, Buischi Y, Viale A et al (2012) Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum 64(10):3083–94. doi:10.1002/art.34539

    Article  PubMed  Google Scholar 

  • Shirai H, Blundell TL, Mizuguchi K (2001) A novel superfamily of enzymes that catalyze the modification of guanidino groups. Trends Biochem Sci 26(8):465–468

    Article  PubMed  CAS  Google Scholar 

  • Tobon GJ, Youinou P, Saraux A (2010) The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis. J Autoimmun 35(1):10–14

    Article  PubMed  Google Scholar 

  • Tolo K, Jorkjend L (1990) Serum antibodies and loss of periodontal bone in patients with rheumatoid arthritis. J Clin Periodontol 17(5):288–291

    Article  PubMed  CAS  Google Scholar 

  • van de Stadt LA, van der Horst AR, de Koning MH, Bos WH, Wolbink GJ, van de Stadt RJ et al (2011) The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia. Ann Rheum Dis 70(1):128–133

    Article  PubMed  Google Scholar 

  • van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Toes RE, Huizinga TW (2005) Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther 7(5):R949–R958

    Article  PubMed  Google Scholar 

  • van der Woude D, Houwing-Duistermaat JJ, Toes RE, Huizinga TW, Thomson W, Worthington J et al (2009) Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis. Arthritis Rheum 60(4):916–23

    Article  PubMed  Google Scholar 

  • van Steenbergen TJ, van Winkelhoff AJ, Van d V, De GJ (1989) Taxonomy, virulence and epidemiology of black-pigmented Bacteroides species in relation to oral infections. Infection 17(3):194–6

    Article  PubMed  Google Scholar 

  • van Venrooij WJ, Vossenaar ER, Zendman AJ (2004) Anti-CCP antibodies: the new rheumatoid factor in the serology of rheumatoid arthritis. Autoimmun Rev 3(Suppl 1):S17–S19

    PubMed  Google Scholar 

  • van Winkelhoff AJ, Slots J (1999) Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in nonoral infections. Periodontol 2000 20:122–35

    Article  PubMed  Google Scholar 

  • van Winkelhoff AJ, Loos BG, van der Reijden WA, Van d V (2002) Porphyromonas gingivalis, Bacteroides forsythus and other putative periodontal pathogens in subjects with and without periodontal destruction. J Clin Periodontol 29(11):1023–1028

    Article  PubMed  Google Scholar 

  • Vossenaar ER, van Venrooij WJ (2004) Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res Ther 6(3):107–111

    Article  PubMed  CAS  Google Scholar 

  • Vossenaar ER, Radstake TR, Van der HA, Van Mansum MA, Dieteren C, De Rooij DJ et al (2004a) Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis 63(4):373–81

    Article  PubMed  CAS  Google Scholar 

  • Vossenaar ER, Smeets TJ, Kraan MC, Raats JM, van Venrooij WJ, Tak PP (2004b) The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum 50(11):3485–3494

    Article  PubMed  CAS  Google Scholar 

  • Wegner N, Wait R, Sroka A, Eick S, Nguyen KA, Lundberg K et al (2010) Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum 62(9):2662–2672

    Article  PubMed  CAS  Google Scholar 

  • Wohlfeil M, Scharf S, Siegelin Y, Schacher B, Oremek GM, Sauer-Eppel H et al (2012) Increased systemic elastase and C-reactive protein in aggressive periodontitis (CLOI-D-00160R2). Clin Oral Investig 16(4):1199–1207

    Article  PubMed  Google Scholar 

  • Wygrecka M, Marsh LM, Morty RE, Henneke I, Guenther A, Lohmeyer J et al (2009) Enolase-1 promotes plasminogen-mediated recruitment of monocytes to the acutely inflamed lung. Blood 113(22):5588–5598

    Article  PubMed  CAS  Google Scholar 

  • Yucel-Lindberg T, Engström M, Hermansson M, Nicholas AP, Klareskog L, Catrina A (2010) Detection of citrullinated proteins and PAD-2 in periodontal tissue. Ann Rheum Dis 69:S198

    Article  Google Scholar 

  • Zambon JJ (1996) Periodontal diseases: microbial factors. Ann Periodontol 1(1):879–925

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Dentistry and Oral Hygiene, University Medical Center Groningen, University of Groningen, 30.001, Groningen, 9700 RB, The Netherlands

    M. J. de Smit & A. J. van Winkelhoff

  2. Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, 30.001, Groningen, 9700 RB, The Netherlands

    J. Westra & E. Brouwer

  3. Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, 30.001, Groningen, 9700 RB, The Netherlands

    W. Nesse & A. Vissink

  4. Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 30.001, Groningen, 9700 RB, The Netherlands

    A. J. van Winkelhoff

Authors
  1. M. J. de Smit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Westra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. Nesse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Vissink
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. J. van Winkelhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Brouwer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Brouwer .

Editor information

Editors and Affiliations

  1. Department of Neurology, University of Alabama at Birmingham and The Birmingham Veterans Administration Medical Center, Birmingham, Alabama, USA

    Anthony P. Nicholas

  2. Bascom Palmer Eye Institute, University of Miami, MIAMI, Florida, USA

    Sanjoy K. Bhattacharya

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

de Smit, M.J., Westra, J., Nesse, W., Vissink, A., van Winkelhoff, A.J., Brouwer, E. (2014). Protein Citrullination: The Link Between Rheumatoid Arthritis and Periodontitis?. In: Nicholas, A., Bhattacharya, S. (eds) Protein Deimination in Human Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8317-5_4

Download citation

Publish with us

Policies and ethics

Search

Navigation