Session Title: Rheumatoid Arthritis: Human Etiology and Pathogenesis II
Session Type: Abstract Submissions (ACR)
Background/Purpose: The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA) and the severity of periodontitis can affect the level of arthritis. Porphyromonas gingivalis is one of the main bacteria causing periodontitis, it can citrullinate proteins and DNA from this bacterium is present in RA synovium. Our aim was to determine if there are differences in the innate immune response against P. gingivalis between healthy controls and RA patients.
Methods: We isolated monocytes from healthy controls, RA patients and psoriatic arthritis (PsA) patients and cultured them into monocyte-derived dendritic cells (DCs). DCs were stimulated with a set of bacteria possibly involved in RA (range of gram-negative and positive bacteria) including the periodontal bacteria P. gingivalis and Prevotella intermedia and single Toll-Like receptor (TLR) agonists (e.g. Pam3CSK4 and LPS). To determine which pathways could be involved in the different response between RA patients and healthy controls, P. gingivalis stimulation was performed in the presence of CXCR4 or CR3 blocking antibodies.
Results: TNFα production was significantly decreased by DCs from RA patients as compared to healthy controls upon stimulation with P. gingivalis, but not with any of the other bacteria tested. PsA patients were included as a diseased control group and did not differ from healthy controls, suggesting a RA specific deregulated response to P. gingivalis. The TNFα production upon P. gingivalis stimulation was similar in all medication groups and was not correlated with the presence of auto-antibodies, disease activity or erosions. P gingivalis is mainly recognized via TLR2 and TLR4, of which the signaling pathways can be affected by simultaneous binding of the bacterium to CXCR4 or CR3. All these receptors were not differentially expressed between RA patients and healthy controls. Cytokine production upon specific TLR2 and TLR4 stimulation were not different between patients and controls and P. gingivalis stimulation was not affected by blocking of CXCR4. Blocking of CR3 however decreased the TNFα production by DCs from healthy controls to the level of the RA patients. The TNFα production in RA patients was not significantly decreased further by blocking of CR3, indicating that decreased signaling via CR3 is involved in the aberrant TNFα response towards P. gingialis by DCs from RA patients.
Conclusion: DCs from RA patients produce less pro-inflammatory cytokines upon P. gingivalis stimulation, which may be caused by defective CR3 signaling. The decreased cytokine response to P. gingivalis could facilitate its survival subsequently leading to a chronic systemic inflammatory status and the breakthrough of tolerance thereby facilitating RA onset.
K. C. Santegoets,
M. H. Wenink,
W. B. van den Berg,
T. R. Radstake,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impaired-tnfa-production-by-dendritic-cells-from-rheumatoid-arthritis-patients-upon-contact-with-porphyromonas-gingivalis/