Impaired Periodontitis-Induced Cytokine Production by Peripheral Blood Monocytes and Myeloid Dendritic Cells in Patients with Rheumatoid Arthritis: A Case–Control Study
<p>Gating strategy to identify peripheral blood monocytes and myeloid dendritic cells (mDCs). Monocytes (blue events) were identified based on their typical FSC/SSC characteristics (<b>A</b>), which lay between neutrophils (yellow events) and lymphocytes (identified in orange), together with high expression of CD45 (<b>B</b>), CD33 (<b>C</b>), HLA-DR (<b>D</b>) and CD14 (<b>E</b>,<b>F</b>). The mDCs (pink events) presented FSC/SSC values between those of monocytes and lymphocytes (<b>A</b>), along with lower levels of CD45 (<b>B</b>), and higher levels of CD33 (<b>C</b>) and HLA-DR (<b>D</b>), compared to monocytes; mDCs do not express CD14 (<b>E</b>,<b>F</b>). The percentages of monocytes and mDCs producing TNF-α (<b>E</b>) or IL-6 (<b>F</b>) were also evaluated. Light pink events correspond to eosinophils and gray events correspond to the remaining (non-identified) peripheral blood cells.</p> "> Figure 2
<p>Graphical representation of the correlation matrix of the frequency and function of IL-6 and monocyte and dendritic cell producers of TNF-α and PAD2/4 activity, anti-RgpB IgG, <span class="html-italic">P. gingivalis</span> CFU, mean PD and mean CAL. The figure shows correlation coefficients r (scale on the right); p-values are shown as asterisks (* < 0.05; ** < 0.01; *** < 0.001). CAL = clinical attachment loss; CFU = colony-forming units; IL-6 = interleukin-6; mDCs = myeloid dendritic cells; MFI = mean fluorescence intensity of positive cells; PAD = peptidylarginine-deiminase; PD = probing depth; <span class="html-italic">P. gingivalis</span> = <span class="html-italic">Porphyromonas gingivalis</span>; RgpB = arginine-specific gingipain; TNF-α = tumor necrosis factor-α; % = percentage of positive cells.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Setting
2.2. Patient Recruitment and Selection
2.3. Periodontal Assessment
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- Probing depth (PD): The distance, in millimeters, from the gingival margin to the deepest point of the periodontal pocket/sulcus. Each patient is represented by the mean PD measured at all sites.
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- Gingival recession: The distance, in millimeters, from the cement–enamel junction to the gingival margin. PD and gingival recession were measured with a straight periodontal probe (PCP15, Hu-Friedy, Chicago, IL, USA).
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- Bleeding on probing (BoP): the percentage of sites that exhibit bleeding at 30 s after probing.
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- Plaque index (PI): the percentage of tooth sites exhibiting dental plaque.
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- Clinical attachment loss (CAL): Scores for PD and gingival recession were summed to retrieve the CAL at each site. Each patient was represented by the mean CAL of all site measures.
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- Maximum PD and Maximum CAL: the arithmetic mean of the two highest PD and CAL site measurements.
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- Periodontal inflamed surface area (PISA): an estimation of the total periodontal inflamed area, in square millimeters, based on the six-point PD measurements and presence or absence of BoP, processed by a freely downloadable spreadsheet [23].
2.4. Rheumatological Assessment
2.5. Sampling
2.6. Laboratory Procedures
2.7. Immunofluorescent Staining
2.8. Flow Cytometry Data Acquisition and Analysis
2.9. Statistics
3. Results
3.1. Patients’ Characteristics
HEALTHY (n = 10) | PERIO (n = 10) | PERIO+RA (n = 17) | Difference Test | |
---|---|---|---|---|
Age (years); median (IQR) | 57.50 (5.00) | 61.00 (8.00) | 60.00 (31.00) | p = 0.351 (a) |
Male, % (N) | 40.00% (4) | 40.00% (4) | 35.29% (6) | NA |
CRP (mg/L); median (IQR) | 1.57 (1.94) | 1.78 (1.29) | 3.63 (8.31) | p = 0.010 # (a) |
PAD2 activity (AU); median (IQR) | 9254.41 (3003.08) | 10,288.53 (2990.20) | 9607.18 (1993.03) | p = 0.521 (a) |
PAD4 activity (AU); median (IQR) | 28,804.56 (5650.33) | 32,874.34 (10,135.41) | 40,471.99 (22,299.97) | p = 0.001 ## (a) |
DAS28-CRP; median (IQR) | NA | NA | 2.36 (2.14) | NA |
Anti-CCP2 IgG AU; median (IQR) | 1.65 (1.70) | 1.42 (4.04) | 44.65 (540.82) | p <0.001 ### (a) |
RA therapy | ||||
csDMARDs; % (N) | NA | NA | 94.12%; (16) 6 Methotrexate only 1 Leflunomide only 1 Salazopyrin only 3 Methotrexate + Hydroxychloroquine 1 Methotrexate + Leflunomide 1 Methotrexate + Sulfasalazine 2 Methotrexate + Hydroxychloroquine + Sulfasalazine 1 Sulfasalazine + Leflunomide | NA |
Periodontitis | ||||
Stage II grade B (N) | NA | 0 | 2 Gen | NA |
Stage III grade B (N) | NA | 1 Loc; 5 Gen | 4 Loc; 2 Gen | NA |
Stage IV grade B (N) | NA | 2 Gen | 6 Gen | NA |
Stage IV grade C (N) | NA | 2 Gen | 3 Gen | NA |
Mean PD (mm); median (IQR) | NA | 3.05 (1.33) | 3.10 (0.85) | p = 1.000 (b) |
Mean CAL (mm); median (IQR) | NA | 3.30 (3.15) | 3.80 (1.85) | p = 0.421 (b) |
Maximum PD (mm); median (IQR) | NA | 6.00 (2.00) | 6.00 (2.00) | p = 0.059 (b) |
Maximum CAL (mm); median (IQR) | NA | 6.50 (2.00) | 7.00 (1.00) | p = 0.695 (b) |
BoP (%); median (IQR) | NA | 44.50 (35.00) | 44.00 (31.00) | p = 0.960 (b) |
PI (%); median (IQR) | NA | 95.50 (28.00) | 100.00 (13.00) | p = 0.052 (b) |
PISA (mm2); median (IQR) | NA | 603.60 (491.75) | 508.10 (934.95) | p = 0.547 (b) |
P. gingivalis CFU (AU); median (IQR) | NA | 69,510,040.00 (113,308,278.00) | 41,538,657.10 (85,053,344.84) | p = 0.177 (b) |
T. forsythia CFU (AU); median (IQR) | NA | 144,441,559.50 (132,924,713.80) | 27,981,448.19 (28,824,916.76) | p < 0.001 (b) |
P. intermedia CFU (AU); median (IQR) | NA | 23,316,940.08 (35,611,641.55) | 32,127,107.24 (66,825,460.65) | p = 0.902 (b) |
Anti-RgpB IgG; median (IQR) | 267.30 (252.20) | 507.10 (761.35) | 261.36 (471.05) | p = 0.099 (a) |
Anti-Kgp IgG; median (IQR) | 107.66 (220.04) | 823.93 (976.30) | 423.73 (1015.47) | p = 0.017 #### (a) |
3.2. Relative Quantification of Peripheral Blood Monocytes and Myeloid Dendritic Cells
3.3. Functional Alterations on Peripheral Blood Monocytes and Myeloid Dendritic Cells
3.3.1. Frequency of Monocytes Producing IL-6 and TNF-α
3.3.2. Frequency of Myeloid Dendritic Cells Producing IL-6 or TNF-α
3.3.3. Expression of IL-6 and TNF-α by Monocytes
3.3.4. Myeloid Dendritic Cells’ Expression of IL-6 and TNF-α
HEALTHY (n = 10) | PERIO (n = 10) | PERIO+RA (n = 17) | Differences between Groups (a) | |||||||
---|---|---|---|---|---|---|---|---|---|---|
% of Cells | MFI | % of Cells | MFI | % of Cells | MFI | % of Cells | MFI | |||
% Monocytes (in whole blood); Median (IQR) | 3.25 (1.25) | NA | 3.53 (0.82) | NA | 3.48 (2.78) | NA | p = 0.874 | NA | ||
Basal | IL-6 | Total; Median (IQR) | 4.82 (5.58) | 1214.50 (394.25) | 9.75 (14.71) | 2088.00 (1134.50) | 5.28 (12.25) | 1611.00 (1069.50) | p = 0.285 | p = 0.026 # |
TNF-α | Total; Median (IQR) | 2.47 (8.80) | 3246.50 (1621.25) | 8.92 (15.87) | 7407.00 (9474.50) | 5.07 (11.44) | 3231.50 (1940.50) | p = 0.313 | p = 0.350 | |
Activated | IL-6 | Total; Median (IQR) | 74.05 (49.55) | 1403.00 (602.00) | 59.00 (24.80) | 4634.00 (5178.75) | 48.50 (83.63) | 1316.00 (1569.05) | p = 0.554 | p = 0.008 ## |
TNF-α | Total; Median (IQR) | 67.80 (41.65) | 5517.00 (5469.50) | 85.30 (14.35) | 24,053.00 (11,056.00) | 82.60 (22.90) | 13,421.00 (18,218.00) | p = 0.204 | p = 0.007 ### | |
% mDCs (in whole blood); Median (IQR) | 0.13 (0.10) | NA | 0.03 (0.11) | NA | 0.04 (0.04) | NA | p = 0.032 #### | NA | ||
Activated | IL-6 | Total; Median (IQR) | 40.90 (42.00) | 1040.00 (433.75) | 32.85 (47.45) | 1894.50 (1476.75) | 12.80 (52.50) | 672.00 (652.00) | p = 0.373 | p = 0.109 |
TNF-α | Total; Median (IQR) | 21.80 (29.50) | 3645.00 (1998.00) | 44.80 (31.35) | 8041.00 (5192.00) | 48.90 (22.45) | 8230.00 (7970.50) | p = 0.004 ##### | p = 0.002 ###### |
3.4. The Impact of the Studied Clinical, Microbiological and Serological Parameters on Frequency and Function of Monocytes and Dendritic Cells
3.5. The Impact of Periodontitis Severity on Frequency and Function of Monocytes and Dendritic Cells in Patients with Periodontitis and RA
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Forward (5′->3′) | Reverse (5′->3′) | |
---|---|---|
P. gingivalis 16S | AGGCAGCTTGCCATACTGCG | ACTGTTAGCAACTACCGATGT |
T. forsythia 16S | GCGTATGTAACCTGCCCGCA | TGCTTCAGTGTCAGTTATACCT |
P. intermedia 16S | GACCAAAGATTCATCGGTGGAG | CACGCTACTTGGCTGGTTC |
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Silva, D.S.; Laranjeira, P.; Silva, A.; Silva, I.; Kaminska, M.; Mydel, P.; de Vries, C.; Lundberg, K.; da Silva, J.A.P.; Baptista, I.P.; et al. Impaired Periodontitis-Induced Cytokine Production by Peripheral Blood Monocytes and Myeloid Dendritic Cells in Patients with Rheumatoid Arthritis: A Case–Control Study. J. Clin. Med. 2024, 13, 5297. https://doi.org/10.3390/jcm13175297
Silva DS, Laranjeira P, Silva A, Silva I, Kaminska M, Mydel P, de Vries C, Lundberg K, da Silva JAP, Baptista IP, et al. Impaired Periodontitis-Induced Cytokine Production by Peripheral Blood Monocytes and Myeloid Dendritic Cells in Patients with Rheumatoid Arthritis: A Case–Control Study. Journal of Clinical Medicine. 2024; 13(17):5297. https://doi.org/10.3390/jcm13175297
Chicago/Turabian StyleSilva, Daniela S., Paula Laranjeira, Ana Silva, Isabel Silva, Marta Kaminska, Piotr Mydel, Charlotte de Vries, Karin Lundberg, José António P. da Silva, Isabel P. Baptista, and et al. 2024. "Impaired Periodontitis-Induced Cytokine Production by Peripheral Blood Monocytes and Myeloid Dendritic Cells in Patients with Rheumatoid Arthritis: A Case–Control Study" Journal of Clinical Medicine 13, no. 17: 5297. https://doi.org/10.3390/jcm13175297