Periodontal medicine : oral inflammatory conditions with special emphasis on immunological aspects
Systemic effects of periodontal disease have been a subject of interest for the past century, with intense focus converging since the past decade. Both rheumatoid arthritis (RA) and periodontal disease (PD) are immuno-inflammatory diseases with osteolysis as its hallmark feature. Activated T cells are known to modulate osteoclastogenesis. This thesis aimed to analyze the influence of PD on systemic inflammatory and immunological markers in both PD and RA subjects. Periodontal parameters, clinical (PI, BOP, PPD 3-<5mm and PPD ≥5mm) and radiographic (marginal bone loss or MBL) were investigated in four groups: RA with PD, RA without PD, PD and healthy groups. Immunosuppression of T cell activation via targeted surface protein was also studied.
AIMS: Study I aimed to investigate the expression and functional importance of low-density lipoprotein receptor-related protein1 (LRP1) in T cells. Study II aimed to investigate serum cytokines, chemokines, growth factors, enzymes and costimulatory proteins in association with periodontal conditions in PD and RA subjects. Study III aimed to investigate the serum markers osteopontin (OPN), tumor necrosis factor receptors 1 (TNFR1) and 2 (TNFR2) receptor activator of nuclear factor‐kappa B ligand (RANKL) and RANKL/ osteoprotegerin (OPG) ratio and compare them in PD and RA groups. Study IV aimed to investigate the severity of both PD and RA and investigate a correlation between glycemia and periodontal disease parameters using ΣPPD Total and ΣPPD Disease index.
RESULTS: Study I showed that T cells shed LRP1, which probably explains the low LRP1 expression in T cells. Shedding of LRP1 antagonizes T cell adhesion to integrin ligands and TCR-induced activation. Integrin ligands and CXCL12 antagonize shedding through a TSP-1-dependent pathway, whereas ligation of CD28 antagonizes shedding independent of TSP-1. The disappearance of LRP1 from the cell surface may provide basic immunosuppression at the T-cell level. Study II showed significant positive correlations for ST1A1, FGF-19 and NT-3 whereas EN-RAGE, DNER, CX3CL1 and TWEAK associated inversely with BOP, PPD≥ 5mm and MBL but positively with number of teeth. CD markers (CD244, CD40, CDCP1, LIF-R, IL-10RA, CD5 and CD6) were found to be associated with BOP, shallow and deep pockets, MBL and number of teeth, either directly or inversely. CCL8, CX3CL1, CXCL10, CXCL11, CCL11, CCL4, CCL20, CXCL5, CXCL6, and CCL23 were positively associated with number of teeth. Other growth factors were directly associated with MBL (HGF) and number of teeth (VEGF-A, LAP TGFbeta-1). Study III showed OPN, TNFR1, TNFR2 and RANKL serum levels were the highest in the RA group with PD, while the RA group without PD were comparable to PD subjects only. The RANKL/OPG ratios were comparable between PD group and both RA groups with and without PD. Serum RANKL levels were associated with and PPD ≥ 5mm. Study IV showed that the indices correlated strongly with number of deep pockets. DAS28 score correlated positively with RF in RA subjects with and without PD. Serum levels of HbA1c were higher in PD, RA with PD and without PD subjects as compared to the healthy group. HbA1c levels associated positively with PPD Total, PPD Disease, and MBL. Tooth adjusted PPD Total correlated with all periodontal parameters except for shallow pockets.
CONCLUSIONS: This thesis shows that periodontal disease is mirrored by a range of systemic immune markers, particularly those involved in inflammation. Furthermore, peripheral osteoclastogenesis is a feature of PD, comparable to RA. Overall, this thesis signifies the peripheral involvement of host immune system in combating PD essentially as an osteolytic disease and the need to approach PD measurement via a novel continuous index. The thesis also shows evidence that LRP1 controls motility, adhesion and activation in T cells.
List of scientific papers
I. J. Panezai, E. Bergdahl, K-G. Sundqvist. T-cell regulation through a basic suppressive mechanism targeting low-density lipoprotein receptor-related protein 1. Immunology. 2017;152: 308–327.
https://doi.org/10.1111/imm.12770
II. J. Panezai, A. Ghaffar, M. Altamash, K-G. Sundqvist, P-E. Engström, A. Larsson. Correlation of serum cytokines, chemokines, growth factors and enzymes with periodontal disease parameters. PLoS ONE. 2017; 12(11): e0188945.
https://doi.org/10.1371/journal.pone.0188945
III. J. Panezai, A. Ghaffar, M. Altamash, P-E. Engström, A. Larsson. Periodontal Disease influences osteoclastogenic bone markers in subjects with and without rheumatoid arthritis. PLoS ONE. 2018; 13(6):e0197235.
https://doi.org/10.1371/journal.pone.0197235
IV. J. Panezai, A. Ali, A. Ghaffar, D. Benchimol, M. Altamash, B. Klinge, A. Larsson, P-E. Engstrӧm. Probing Pocket Depth Total Index, Glycated Hemoglobin and Disease Severity Measurements in Subjects with and without Rheumatoid Arthritis. [Submitted]
History
Defence date
2018-12-07Department
- Department of Dental Medicine
Publisher/Institution
Karolinska InstitutetMain supervisor
Engström, Per-ErikCo-supervisors
Larsson, Anders; Sundqvist, Karl-Gösta; Klinge, Björn; Altamash, MohammadPublication year
2018Thesis type
- Doctoral thesis
ISBN
978-91-7831-240-5Number of supporting papers
4Language
- eng