The PerioGene North Study Reveals That Periodontal Inflammation and Advanced Jawbone Loss in Periodontitis Associate with Serum Gingipain Antibodies but Not with Systemic Autoimmunity

Overview

Journal Front Immunol

Date 2025 Jan 29

PMID 39877342

Authors

Elin Kindstedt

Charlotte de Vries

Magnus Wanman

Barbara Aleksandra Potempa

Jan Potempa

Susanne Lindquist

Anders Esberg

Karin Lundberg

Pernilla Lundberg

Affiliations

Soon will be listed here.

Abstract

Introduction: Periodontitis is associated with rheumatoid arthritis (RA). One hypothesis posits that this connection arises from the formation of autoantibodies against citrullinated proteins (ACPA) in inflamed gums, possibly triggered by . We previously demonstrated an increased antibody response to arginine gingipains (anti-Rgp IgG), not only in individuals with severe periodontitis compared to controls, but in RA versus controls, with an association to ACPA. In the present study, we set out to further explore the relationship between anti-Rgp IgG, ACPA and periodontitis, including clinical periodontal parameters, in the large and well-characterized PerioGene North case-control study.

Methods: We measured serum levels of anti-Rgp and ACPA IgG by enzyme-linked immunosorbent assay (ELISA), in 478 patients with periodontitis and 509 periodontally healthy controls within PerioGene North. Subsequently, anti-Rgp IgG levels and ACPA status were analysed in relation to periodontitis and clinical periodontal parameters.

Results: Serum anti-Rgp IgG levels were elevated in cases versus controls (p< 0.001). However, receiver operating characteristic (ROC) curve analysis revealed that anti-Rgp IgG could not efficiently discriminate cases from controls (AUC= 0.63; 95% CI: 0.60 - 0.66). Among cases, increased anti-Rgp IgG levels associated with high periodontal inflammation and advanced alveolar bone loss (p<0.001 for both). An ACPA response was detected in 15 (3.1%) cases and 6 (1.2%) controls (p=0.033), but no association to periodontitis was evident after adjustment for age and smoking and anti-Rgp IgG levels did not differ between ACPA-positive and ACPA-negative individuals.

Conclusion: We show that anti-Rgp IgG identifies a subgroup of periodontitis patients with high degree of periodontal inflammation and advanced alveolar bone loss, but we do not find support for a link between periodontitis or anti-Rgp IgG and ACPA status in PerioGene North. Given the association between anti-Rgp and alveolar bone loss, the mechanistic role of gingipains in bone resorption should be experimentally explored.

References

Guo Y, Nguyen K, Potempa J . Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon's knife to a meat chopper-like brutal degradation of proteins. Periodontol 2000. 2010; 54(1):15-44. PMC: 2924770. DOI: 10.1111/j.1600-0757.2010.00377.x. View

Totaro M, Cattani P, Ria F, Tolusso B, Gremese E, Fedele A . Porphyromonas gingivalis and the pathogenesis of rheumatoid arthritis: analysis of various compartments including the synovial tissue. Arthritis Res Ther. 2013; 15(3):R66. PMC: 4060366. DOI: 10.1186/ar4243. View

Huang N, Shimomura E, Yin G, Tran C, Sato A, Steiner A . Immunization with cell-free-generated vaccine protects from Porphyromonas gingivalis-induced alveolar bone loss. J Clin Periodontol. 2018; 46(2):197-205. PMC: 7891626. DOI: 10.1111/jcpe.13047. View

McGraw W, Potempa J, Farley D, Travis J . Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect Immun. 1999; 67(7):3248-56. PMC: 116503. DOI: 10.1128/IAI.67.7.3248-3256.1999. View

Kharlamova N, Jiang X, Sherina N, Potempa B, Israelsson L, Quirke A . Antibodies to Porphyromonas gingivalis Indicate Interaction Between Oral Infection, Smoking, and Risk Genes in Rheumatoid Arthritis Etiology. Arthritis Rheumatol. 2015; 68(3):604-13. PMC: 4767537. DOI: 10.1002/art.39491. View

Rafiei M, Kiani F, Sayehmiri K, Sayehmiri F, Tavirani M, Dousti M . Prevalence of Anaerobic Bacteria (P.gingivalis) as Major Microbial Agent in the Incidence Periodontal Diseases by Meta-analysis. J Dent (Shiraz). 2018; 19(3):232-242. PMC: 6092461. View

Smit M, Rahajoe P, Raveling-Eelsing E, Lisotto P, Harmsen H, Kertia N . Influence of Oral Microbiota on the Presence of IgA Anti-Citrullinated Protein Antibodies in Gingival Crevicular Fluid. Front Oral Health. 2022; 3:904711. PMC: 9243218. DOI: 10.3389/froh.2022.904711. View

Dominy S, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A . in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019; 5(1):eaau3333. PMC: 6357742. DOI: 10.1126/sciadv.aau3333. View

Eke P, Dye B, Wei L, Slade G, Thornton-Evans G, Borgnakke W . Update on Prevalence of Periodontitis in Adults in the United States: NHANES 2009 to 2012. J Periodontol. 2015; 86(5):611-22. PMC: 4460825. DOI: 10.1902/jop.2015.140520. View

10.

Kindstedt E, Johansson L, Palmqvist P, Koskinen Holm C, Kokkonen H, Johansson I . Association Between Marginal Jawbone Loss and Onset of Rheumatoid Arthritis and Relationship to Plasma Levels of RANKL. Arthritis Rheumatol. 2017; 70(4):508-515. DOI: 10.1002/art.40394. View

11.

Reichert S, Haffner M, Keysser G, Schafer C, Stein J, Schaller H . Detection of oral bacterial DNA in synovial fluid. J Clin Periodontol. 2013; 40(6):591-8. DOI: 10.1111/jcpe.12102. View

12.

Nik Eezammuddeen N, Vaithilingam R, Hassan N . Influence of periodontitis on levels of autoantibodies in rheumatoid arthritis patients: A systematic review. J Periodontal Res. 2022; 58(1):29-42. DOI: 10.1111/jre.13065. View

13.

Leite F, Nascimento G, Scheutz F, Lopez R . Effect of Smoking on Periodontitis: A Systematic Review and Meta-regression. Am J Prev Med. 2018; 54(6):831-841. DOI: 10.1016/j.amepre.2018.02.014. View

14.

Hirai K, Yamaguchi-Tomikawa T, Eguchi T, Maeda H, Takashiba S . Identification and Modification of Cysteine Protease, Gingipain, Ideal for Screening Periodontitis. Front Immunol. 2020; 11:1017. PMC: 7290125. DOI: 10.3389/fimmu.2020.01017. View

15.

Takahashi J, Saito A, Nakagawa T, Yamada S, Ishihara K, Okuda K . Dynamics of serum immunoglobulin G avidity for Porphyromonas gingivalis in adult periodontitis. J Periodontol. 1998; 69(3):367-73. DOI: 10.1902/jop.1998.69.3.367. View

16.

Dye B, Herrera-Abreu M, Lerche-Sehm J, Vlachojannis C, Pikdoken L, Pretzl B . Serum antibodies to periodontal bacteria as diagnostic markers of periodontitis. J Periodontol. 2009; 80(4):634-47. DOI: 10.1902/jop.2009.080474. View

17.

Potempa J, Mydel P, Koziel J . The case for periodontitis in the pathogenesis of rheumatoid arthritis. Nat Rev Rheumatol. 2017; 13(10):606-620. DOI: 10.1038/nrrheum.2017.132. View

18.

Brewer R, Lanz T, Hale C, Sepich-Poore G, Martino C, Swafford A . Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Sci Transl Med. 2023; 15(684):eabq8476. PMC: 10496947. DOI: 10.1126/scitranslmed.abq8476. View

19.

Sherina N, de Vries C, Kharlamova N, Sippl N, Jiang X, Brynedal B . Antibodies to a Citrullinated Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells: Implications for a Bacterial Origin in RA Etiology. Front Immunol. 2022; 13:804822. PMC: 9066602. DOI: 10.3389/fimmu.2022.804822. View

20.

Hocevar K, Potempa J, Turk B . Host cell-surface proteins as substrates of gingipains, the main proteases of Porphyromonas gingivalis. Biol Chem. 2018; 399(12):1353-1361. DOI: 10.1515/hsz-2018-0215. View