Plasma levels of immune system activation markers Neopterin and Kynurenine-to-Tryptophan Ratio, and oral health among community-dwelling adults in Norway: a population-based, cohort study
DOI:
https://doi.org/10.2340/aos.v84.43535Keywords:
Biomarker, chronic periodontitis, epidemiologyAbstract
Objective: Periodontitis is a condition characterised by inflammation. Neopterin and kynurenine-to-tryptophan ratio (KTR) are markers of immune system activation in response to inflammation whose elevated levels are linked to higher incidence and poorer prognosis of various systemic diseases. Their potential association with oral health remains underexplored. The aim of this study was to prospectively investigate the associations between these biomarkers and periodontal health status among community-dwelling adults in Hordaland County, Norway.
Materials and methods: Neopterin and KTR were measured in 1,298 participants of the Hordaland Health Study, 1997–1999. Information on oral health indicators was obtained from the ‘Hordaland-Oral Health Survey’, 2020–2022. Ordinal logistic regression and negative binomial regression were used to explore the association between biomarkers and periodontitis, tooth loss, and current inflammation (extend of sites with pocket depth ≥4mm and bleeding on probing) and odds ratios (OR) and incidence rate ratios (IRR), along with respective 95% confidence intervals (CI) were reported.
Results: No association was found between biomarker levels and periodontitis [neopterin: OR = 0.96, 95% CI: 0.69–1.33 for fourth (Q4) vs. first quartile (Q1); KTR: OR = 0.85, 95% CI: 0.61–1.18 for Q4 vs. Q1], tooth loss [neopterin: IRR = 1.00, 95% CI: 0.94–1.06 for Q4 vs. Q1; KTR: IRR = 0.97, 95% CI: 0.91–1.03 for Q4 vs. Q1) or extend of inflammation [neopterin: OR = 0.87, 95% CI: 0.70–1.09 for Q4 vs. Q1; KTR: OR = 0.98, 95% CI: 0.78–1.23 for Q4 vs. Q1].
Conclusion: Plasma levels of neopterin and KTR were not prospectively associated with periodontal health and number of missing teeth.
Downloads
References
Bernabe E, Marcenes W, Hernandez CR, Bailey J, Abreu LG, Alipour V, et al. Global, regional, and national levels and trends in burden of oral conditions from 1990 to 2017: a systematic analysis for the global burden of disease 2017 study. J Dent Res. 2020;99:362–73. DOI: https://doi.org/10.1177/0022034520908533
Trindade D, Carvalho R, Machado V, Chambrone L, Mendes JJ, Botelho J. Prevalence of periodontitis in dentate people between 2011 and 2020: a systematic review and meta-analysis of epidemiological studies. J Clin Periodontol. 2023;50:604–26. https://doi.org/10.1111/jcpe.13769 DOI: https://doi.org/10.1111/jcpe.13769
Tonetti MS, Jepsen S, Jin L, Otomo-Corgel J. Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: a call for global action. J Clin Periodontol. 2017;44:456–62. https://doi.org/10.1111/jcpe.12732 DOI: https://doi.org/10.1111/jcpe.12732
Herrero ER, Fernandes S, Verspecht T, Ugarte-Berzal E, Boon N, Proost P, et al. Dysbiotic biofilms deregulate the periodontal inflammatory response. J Dent Res. 2018;97:547–55. https://doi.org/10.1177/0022034517752675 DOI: https://doi.org/10.1177/0022034517752675
Cecoro G, Annunziata M, Iuorio MT, Nastri L, Guida L. Periodontitis, low-grade inflammation and systemic health: a scoping review. Medicina (Kaunas). 2020;56(6):272. https://doi.org/10.3390/medicina56060272 DOI: https://doi.org/10.3390/medicina56060272
Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontology 2000. 1997;14:9–11. https://doi.org/10.1111/j.1600-0757.1997.tb00189.x DOI: https://doi.org/10.1111/j.1600-0757.1997.tb00189.x
Hajishengallis G, Chavakis T, Lambris JD. Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontology 2000. 2020;84:14–34. https://doi.org/10.1111/prd.12331 DOI: https://doi.org/10.1111/prd.12331
Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M, Fine DH, et al. Periodontitis: consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Periodontol. 2018;89(Suppl 1):S173–S82.
Huber C, Batchelor JR, Fuchs D, Hausen A, Lang A, Niederwieser D, et al. Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. J Exp Med. 1984;160:310–6. https://doi.org/10.1084/jem.160.1.310 DOI: https://doi.org/10.1084/jem.160.1.310
Schröcksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta. 2006;364:82–90. https://doi.org/10.1016/j.cca.2005.06.013 DOI: https://doi.org/10.1016/j.cca.2005.06.013
Ozaki Y, Edelstein MP, Duch DS. Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. Proc Natl Acad Sci U S A. 1988;85:1242–6. https://doi.org/10.1073/pnas.85.4.1242 DOI: https://doi.org/10.1073/pnas.85.4.1242
Reibnegger G, Egg D, Fuchs D, Günther R, Hausen A, Werner ER, et al. Urinary neopterin reflects clinical activity in patients with rheumatoid arthritis. Arthritis Rheum. 1986;29:1063–70. https://doi.org/10.1002/art.1780290902 DOI: https://doi.org/10.1002/art.1780290902
Sulo G, Vollset SE, Nygård O, Midttun Ø, Ueland PM, Eussen SJ, et al. Neopterin and kynurenine-tryptophan ratio as predictors of coronary events in older adults, the Hordaland Health Study. Int J Cardiol. 2013;168:1435–40. https://doi.org/10.1016/j.ijcard.2012.12.090
Zuo H, Tell GS, Vollset SE, Ueland PM, Nygard O, Midttun O, et al. Interferon-gamma-induced inflammatory markers and the risk of cancer: the Hordaland Health Study. Cancer. 2014;120:3370–7. https://doi.org/10.1002/cncr.28869 DOI: https://doi.org/10.1002/cncr.28869
Pedersen ER, Midttun Ø, Ueland PM, Schartum-Hansen H, Seifert R, Igland J, et al. Systemic markers of interferon-γ-mediated immune activation and long-term prognosis in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2011;31:698–704. https://doi.org/10.1161/ATVBAHA.110.219329 DOI: https://doi.org/10.1161/ATVBAHA.110.219329
Ray KK, Morrow DA, Sabatine MS, Shui A, Rifai N, Cannon CP, et al. Long-term prognostic value of neopterin: a novel marker of monocyte activation in patients with acute coronary syndrome. Circulation. 2007;115:3071–8. https://doi.org/10.1161/CIRCULATIONAHA.106.666511 DOI: https://doi.org/10.1161/CIRCULATIONAHA.106.666511
Solvang SH, Nordrehaug JE, Aarsland D, Lange J, Ueland PM, McCann A, et al. Kynurenines, neuropsychiatric symptoms, and cognitive prognosis in patients with mild dementia. Int J Tryptophan Res. 2019;12:1178646919877883. https://doi.org/10.1177/1178646919877883 DOI: https://doi.org/10.1177/1178646919877883
Prasanna JS, Sumadhura C, Karunakar P. Neopterin as a diagnostic biomarker for diagnosis of inflammatory diseases like periodontitis. J Oral Res Rev. 2017;9:45–9. https://doi.org/10.4103/2249-4987.201406 DOI: https://doi.org/10.4103/2249-4987.201406
Ozmeriç N, Baydar T, Bodur A, Engin AB, Uraz A, Eren K, et al. Level of neopterin, a marker of immune cell activation in gingival crevicular fluid, saliva, and urine in patients with aggressive periodontitis. J Periodontol. 2002;73:720–5. https://doi.org/10.1902/jop.2002.73.7.720 DOI: https://doi.org/10.1902/jop.2002.73.7.720
Nisapakultorn K, Makrudthong J, Sa-Ard-Iam N, Rerkyen P, Mahanonda R, Takikawa O. Indoleamine 2,3-dioxygenase expression and regulation in chronic periodontitis. J Periodontol. 2009;80:114–21. https://doi.org/10.1902/jop.2009.080315 DOI: https://doi.org/10.1902/jop.2009.080315
Kurgan S, Onder C, Balci N, Akdogan N, Altingoz SM, Serdar MA, et al. Influence of periodontal inflammation on tryptophan-kynurenine metabolism: a cross-sectional study. Clin Oral Investig. 2022;26:5721–32. https://doi.org/10.1007/s00784-022-04528-4 DOI: https://doi.org/10.1007/s00784-022-04528-4
Heneberk O, Wurfelova E, Radochova V. Neopterin, the cell-mediated immune response biomarker, in inflammatory periodontal diseases: a narrative review of a more than fifty years old biomarker. Biomedicines. 2023;11:1294. https://doi.org/10.3390/biomedicines11051294 DOI: https://doi.org/10.3390/biomedicines11051294
Heneberk O, Vernerova A, Kujovska Krcmova L, Wurfelova E, Radochova V. Neopterin levels in periodontitis and after nonsurgical periodontal therapy: evaluation of gingival crevicular fluid, oral fluid, serum and urinary samples – a case-control study. Biomedicines. 2022;10(32):3200. https://doi.org/10.3390/biomedicines10123200 DOI: https://doi.org/10.3390/biomedicines10123200
Prasanna JS, Sumadhura C. Biochemical analysis of three biological fluids and its response to non-surgical periodontal therapy in pre and postmenopausal women with periodontitis. J Menopausal Med. 2019;25:149–57. https://doi.org/10.6118/jmm.18179 DOI: https://doi.org/10.6118/jmm.18179
Ren J, Chen YB, Zhang YY, Zhou QB, Chen S, Yang JY, et al. Decreased circulating neopterin is associated with increased arterial elasticity: a beneficial role of periodontal treatment. Aust Dent J. 2016;61:76–83. https://doi.org/10.1111/adj.12303 DOI: https://doi.org/10.1111/adj.12303
Fratini A, Izzetti R, Riccetti N, Gennai S, Graziani F, Marchetti E. Diagnostic accuracy of urinary biomarkers in periodontitis: a systematic review and meta-analysis. Int J Dent. 2024;2024:9769772. https://doi.org/10.1155/2024/9769772 DOI: https://doi.org/10.1155/2024/9769772
Midttun Ø, Hustad S, Ueland PM. Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrometry. 2009;23:1371–9. https://doi.org/10.1002/rcm.4013 DOI: https://doi.org/10.1002/rcm.4013
Sulo G, Vollset SE, Nygard O, Midttun O, Ueland PM, Eussen SJ, et al. Neopterin and kynurenine-tryptophan ratio as predictors of coronary events in older adults, the Hordaland Health Study. Int J Cardiol. 2013;168:1435–40. https://doi.org/10.1016/j.ijcard.2012.12.090 DOI: https://doi.org/10.1016/j.ijcard.2012.12.090
Eke PI, Page RC, Wei L, Thornton-Evans G, Genco RJ. Update of the case definitions for population-based surveillance of periodontitis. J Periodontol. 2012;83:1449–54. https://doi.org/10.1902/jop.2012.110664 DOI: https://doi.org/10.1902/jop.2012.110664
Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke WS, et al. Update on prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012. J Periodontol. 2015;86:611–22. https://doi.org/10.1902/jop.2015.140520 DOI: https://doi.org/10.1902/jop.2015.140520
Eke PI, Wei L, Borgnakke WS, Thornton-Evans G, Zhang X, Lu H, et al. Periodontitis prevalence in adults >/= 65 years of age, in the USA. Periodontology 2000. 2016;72:76–95. https://doi.org/10.1111/prd.12145 DOI: https://doi.org/10.1111/prd.12145
Bodur A, Baydar T, Ozmeric N, Engin AB, Uraz A, Eren K, et al. Neopterin profile to evaluate the effectiveness of treatment in aggressive periodontitis. Pteridines. 2003;14:77–81. https://doi.org/10.1515/pteridines.2003.14.3.77 DOI: https://doi.org/10.1515/pteridines.2003.14.3.77
Turgut Cankaya Z, Bodur A, Tacoy G, Erguder I, Aktuna D, Cengel A. The effect of periodontal therapy on neopterin and vascular cell adhesion molecule-1 levels in chronic periodontitis patients with and without acute myocardial infarction: a case-control study. J Appl Oral Sci. 2018;26:e20170199. https://doi.org/10.1590/1678-7757-2017-0199 DOI: https://doi.org/10.1590/1678-7757-2017-0199
Pink C, Kocher T, Meisel P, Dorr M, Markus MR, Jablonowski L, et al. Longitudinal effects of systemic inflammation markers on periodontitis. J Clin Periodontol. 2015;42:988–97. https://doi.org/10.1111/jcpe.12473 DOI: https://doi.org/10.1111/jcpe.12473
Fejerskov O, Escobar G, Jossing M, Baelum V. A functional natural dentition for all--and for life? The oral healthcare system needs revision. J Oral Rehabil. 2013;40:707–22. https://doi.org/10.1111/joor.12082 DOI: https://doi.org/10.1111/joor.12082
Additional Files
Published
Issue
Section
License
Copyright (c) 2025 Sarala Banjara, Ellen Berggreen, Jannicke Igland, Anne-Kristine Åstrøm, Øivind Midttun, Dagmar Bunæs, Gerhard Sulo
This work is licensed under a Creative Commons Attribution 4.0 International License.
Acta Odontologica Scandinavica publishes original research papers as well as critical reviews relevant to the diagnosis, epidemiology, health service, prevention, aetiology, pathogenesis, pathology, physiology, microbiology, development and treatment of diseases affecting tissues of the oral cavity and associated structures including papers on cause and effect or explanatory/associative relationships for experimental or observational studies.
