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Periodontal pathogens amplify arthritic bone erosion by reducing the TH2 response and promoting a toll-like receptor 2-dependent TH17 phenotype
  1. Shahla Abdollahi-Roodsaz1,
  2. Sabrina Garcia de Aquino2,
  3. Marije Koenders1,
  4. Renoud Marijnissen1,
  5. Birgitte Walgreen1,
  6. Monique Helsen1,
  7. Liduine van den Bersselaar1,
  8. Fernando Cunha3,
  9. Joni Cirelli2,
  10. Wim van den Berg1
  1. 1Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2Department of Diagnosis and Oral Surgery, Periodontic Division, Araraquara Dental School, University of São Paulo, São Paulo, Brazil
  3. 3Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

Abstract

Backgroundand objectives Increased incidence of periodontal disease and association with development of anticitrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis suggest a possible pathologic link between the two diseases. The aim of the present study was to investigate the influence of periodontal pathogens on T helper cell phenotype and disease severity during experimental arthritis.

Materials and methods The effect of periodontal bacteria Porphyromonas gingivalis and Prevotella nigrescens on T cell differentiation and the involvement of toll-like receptors (TLRs) were studied using cells from wild-type and interleukin-1 (IL-1) receptor antagonist deficient mice. Invivo, mice with collagen-induced arthritis received five oral inoculations of either P gingivalis or P nigrescens every other day starting from day 14 after immunisation. Joint histopathology, gene expression in synovium, T cell phenotype and presence of ACPA were analysed on day 30.

Results P gingivalis and P nigrescens strongly induced Th17 differentiation in a co-culture of splenic antigen-presenting cells (APCs) with CD4+ T cells, as measured by fluorescence-activated cell sorting analysis and IL-17 production. This effect was enormously increased in the absence of IL-1 receptor antagonist. In addition, both bacteria significantly lowered the Th2 differentiation, but were weak inducers of Th1. Using IL-1Ra−/− cells derived from TLR knockouts, Th17 induction was found to depend on TLR2, but not TLR4, expression on APCs; whereas the minor Th1 induction was dependent on TLR2 expression directly on T cells. Invivo, oral inoculation with P gingivalis and P nigrescens significantly increased the clinical scores of arthritis. Although no antibodies against CCP2 and citrullinated fibrinogen, α-enolase and vimentin could be detected under this condition, both bacteria substantially increased the intensity of bone erosion specifically, without influencing cartilage destruction. Analysis of T helper cell phenotype in draining lymph nodes upon pan-T cell as well as collagen II stimulations revealed a significant increase of IL-17 production, but not interferon γ. The level of IL-17 induced by periodontal bacteria strongly correlated with the intensity of bone erosion. While P gingivalis was the main inducer of local IL-1β, tumour necrosis factor α and cathepsin K in synovium, only P nigrescens caused a marked reduction of Th2/IL-4 phenotype invivo.

Conclusions This study reveals the modulation of T cell phenotype, in particular Th17 induction, as a relevant pathogenic characteristic of periodontal pathogens irrespective of ACPA induction or possession of citrullinating enzymes (present in P gingivalis, but not P nigrescens). The data further support the relevance of periodontal bacteria in pathogenesis of arthritis, especially with respect to bone erosion.

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