Periodontal pathogens amplify arthritic bone erosion by reducing the TH2 response and promoting a toll-like receptor 2-dependent TH17 phenotype
Authors: Shahla Abdollahi-Roodsaz, Sabrina Garcia de Aquino, Marije Koenders, Renoud Marijnissen, Birgitte Walgreen, Monique Helsen, Liduine van den Bersselaar, Fernando Cunha, Joni Cirelli, Wim van den Berg
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> 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. <h3>Materials and methods</h3> The effect of periodontal bacteria <i>Porphyromonas gingivalis</i> and <i>Prevotella nigrescens</i> 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 <i>P gingivalis</i> or <i>P nigrescens</i> 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. <h3>Results</h3> <i>P gingivalis</i> and <i>P nigrescens</i> strongly induced Th17 differentiation in a co-culture of splenic antigen-presenting cells (APCs) with CD4<sup>+</sup> 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<sup>−/−</sup> 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 <i>P gingivalis</i> and <i>P nigrescens</i> 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 <i>P gingivalis</i> was the main inducer of local IL-1β, tumour necrosis factor α and cathepsin K in synovium, only <i>P nigrescens</i> caused a marked reduction of Th2/IL-4 phenotype invivo. <h3>Conclusions</h3> 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 <i>P gingivalis</i>, but not <i>P nigrescens</i>). The data further support the relevance of periodontal bacteria in pathogenesis of arthritis, especially with respect to bone erosion.