Impact of Protein Citrullination by Periodontal Pathobionts on Oral and Systemic Health: A Systematic Review of Preclinical and Clinical Studies

Overview

Journal J Clin Med

Specialty General Medicine

Date 2024 Nov 27

PMID 39597974

Authors

Marco Bonilla

Natividad Martin-Morales

Rocio Galvez-Rueda

Enrique Raya-Alvarez

Francisco Mesa

Affiliations

Soon will be listed here.

Abstract

: This review synthesizes the role of () and () in modulating immune responses through citrullination and assesses its impact on periodontitis and systemic conditions. A systematic review was conducted on preclinical and clinical studies focusing on and -induced citrullination and its effects on immune responses, particularly inflammatory pathways, and systemic diseases. The search included PubMed, Scopus, Google Scholar, Web of Science, and gray literature. Quality and risk of bias were assessed using OHAT Rob Toll and QUIN-Tool. The review is registered in PROSPERO (ID: CRD42024579352). 18 articles published up to August 2024 were included. Findings show that and citrullination modulates immune responses, leading to neutrophil dysfunction and chronic inflammation. Key mechanisms include citrullination of antimicrobial peptides, CXCL10, histone H3, α-enolase, and C5a, impairing neutrophil activation and promoting NET formation. This review suggests that and citrullination modulates immune responses and may influence periodontitis and systemic conditions like RA. Beyond ACPA production, these pathogens affect key proteins such as H3, C5a, and CXCL10, as well as antimicrobial peptides, NET formation, and phagocytosis. These interactions lead to neutrophil dysfunction and potentially affect other cells, subsequently disrupting local and systemic inflammatory responses.

References

Deng Q, Pan B, Alam H, Liang Y, Wu Z, Liu B . Citrullinated Histone H3 as a Therapeutic Target for Endotoxic Shock in Mice. Front Immunol. 2020; 10:2957. PMC: 6962130. DOI: 10.3389/fimmu.2019.02957. View

ROGERS G, Simmonds D . Content of citrulline and other amino-acids in a protein of hair follicles. Nature. 1958; 182(4629):186-7. DOI: 10.1038/182186a0. View

Sheth V, Shah N, Jain R, Bhanushali N, Bhatnagar V . Development and validation of a risk-of-bias tool for assessing in vitro studies conducted in dentistry: The QUIN. J Prosthet Dent. 2022; 131(6):1038-1042. DOI: 10.1016/j.prosdent.2022.05.019. View

Ray R . Periodontitis: An Oral Disease with Severe Consequences. Appl Biochem Biotechnol. 2022; 195(1):17-32. DOI: 10.1007/s12010-022-04127-9. View

Xu W, Zhou W, Wang H, Liang S . Roles of Porphyromonas gingivalis and its virulence factors in periodontitis. Adv Protein Chem Struct Biol. 2020; 120:45-84. PMC: 8204362. DOI: 10.1016/bs.apcsb.2019.12.001. View

Mantri C, Chen C, Dong X, Goodwin J, Pratap S, Paromov V . Fimbriae-mediated outer membrane vesicle production and invasion of Porphyromonas gingivalis. Microbiologyopen. 2014; 4(1):53-65. PMC: 4335976. DOI: 10.1002/mbo3.221. View

Reichert S, Schlumberger W, Dahnrich C, Hornig N, Altermann W, Schaller H . Association of levels of antibodies against citrullinated cyclic peptides and citrullinated α-enolase in chronic and aggressive periodontitis as a risk factor of Rheumatoid arthritis: a case control study. J Transl Med. 2015; 13:283. PMC: 4552989. DOI: 10.1186/s12967-015-0625-7. View

Wegner N, Wait R, Sroka A, Eick S, Nguyen K, Lundberg K . Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010; 62(9):2662-72. PMC: 2941529. DOI: 10.1002/art.27552. View

Li W . Phagocyte dysfunction, tissue aging and degeneration. Ageing Res Rev. 2013; 12(4):1005-12. PMC: 3842398. DOI: 10.1016/j.arr.2013.05.006. View

10.

Zhou L, Srisatjaluk R, Justus D, Doyle R . On the origin of membrane vesicles in gram-negative bacteria. FEMS Microbiol Lett. 1998; 163(2):223-8. DOI: 10.1111/j.1574-6968.1998.tb13049.x. View

11.

Engstrom M, Eriksson K, Lee L, Hermansson M, Johansson A, Nicholas A . Increased citrullination and expression of peptidylarginine deiminases independently of P. gingivalis and A. actinomycetemcomitans in gingival tissue of patients with periodontitis. J Transl Med. 2018; 16(1):214. PMC: 6069803. DOI: 10.1186/s12967-018-1588-2. View

12.

Leliefeld P, Wessels C, Leenen L, Koenderman L, Pillay J . The role of neutrophils in immune dysfunction during severe inflammation. Crit Care. 2016; 20:73. PMC: 4804478. DOI: 10.1186/s13054-016-1250-4. View

13.

Kim T, Moutsopoulos N . Neutrophils and neutrophil extracellular traps in oral health and disease. Exp Mol Med. 2024; 56(5):1055-1065. PMC: 11148164. DOI: 10.1038/s12276-024-01219-w. View

14.

Liberati A, Altman D, Tetzlaff J, Mulrow C, Gotzsche P, Ioannidis J . The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009; 6(7):e1000100. PMC: 2707010. DOI: 10.1371/journal.pmed.1000100. View

15.

Stobernack T, du Teil Espina M, Mulder L, Palma Medina L, Piebenga D, Gabarrini G . A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses. mBio. 2018; 9(5). PMC: 6212822. DOI: 10.1128/mBio.01704-18. View

16.

Maresz K, Hellvard A, Sroka A, Adamowicz K, Bielecka E, Koziel J . Porphyromonas gingivalis facilitates the development and progression of destructive arthritis through its unique bacterial peptidylarginine deiminase (PAD). PLoS Pathog. 2013; 9(9):e1003627. PMC: 3771902. DOI: 10.1371/journal.ppat.1003627. View

17.

Socransky S, Haffajee A, Cugini M, Smith C, Kent Jr R . Microbial complexes in subgingival plaque. J Clin Periodontol. 1998; 25(2):134-44. DOI: 10.1111/j.1600-051x.1998.tb02419.x. View

18.

Fine D, Markowitz K, Fairlie K, Tischio-Bereski D, Ferrendiz J, Furgang D . A consortium of Aggregatibacter actinomycetemcomitans, Streptococcus parasanguinis, and Filifactor alocis is present in sites prior to bone loss in a longitudinal study of localized aggressive periodontitis. J Clin Microbiol. 2013; 51(9):2850-61. PMC: 3754677. DOI: 10.1128/JCM.00729-13. View

19.

Hajishengallis G, Chavakis T, Lambris J . Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontol 2000. 2020; 84(1):14-34. PMC: 7457922. DOI: 10.1111/prd.12331. View

20.

Abdullah S, Farmer E, Spargo L, Logan R, Gully N . Porphyromonas gingivalis peptidylarginine deiminase substrate specificity. Anaerobe. 2013; 23:102-8. DOI: 10.1016/j.anaerobe.2013.07.001. View