FRI0022 Periodontal pathogens promote autoimmune arthritis by reducing TH2 response and inducing a toll-like receptor 2-dependent TH17 phenotype
Authors: S. Abdollahi-Roodsaz, S. Garcia de Aquino, M. Koenders, R. Marijnissen, B. Walgreen, M. Helsen, L. van den Bersselaar, F. de Queiroz Cunha, J.A. Cirelli, W. van den Berg
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Epidemiologic evidence and the capability of periodontal pathogen <i>Porphyromonas gingivalis</i> to citrullinate mammalian proteins support a link between periodontal disease (PD) and rheumatoid arthritis (RA). Based on the relevance of pathogen-mediated Toll-like receptor (TLR) activation in shaping the T cell response, we reasoned that the interaction between PD and RA may be a direct result of T cell modulation and not necessarily dependent on citrullination capability. <h3>Objectives</h3> The aim of this study was to investigate the influence of periodontal pathogens <i>P. gingivalis</i> and <i>Prevotella nigrescens,</i> the latter lacking citrullinating enzymes, on T helper cell phenotype and the development of experimental arthritis. <h3>Methods</h3> The influence of <i>P. gingivalis</i> and <i>P. nigrescens</i> on T cell differentiation and the TLR involvement were studied using wild-type, and interleukin-1 receptor antagonist (IL-1Ra)/TLR single or double gene deficient cells. In vivo, 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 immunization. Joint histopathology, synovial gene expression, T cell phenotype and presence of anti-citrullinated peptide antibodies (ACPA) were analyzed on day 30. <h3>Results</h3> <i>P. gingivalis</i> and <i>P. nigrescens</i> strongly induced Th17 differentiation in a co-culture of antigen-presenting cells (APCs) with CD4<sup>+</sup> T cells, as measured by FACS and IL-17 production. This effect was highly increased by IL-1Ra deficiency. In addition, both bacteria significantly lowered the Th2 differentiation, but were weak inducers of Th1. Using IL-1Ra<sup>-/-</sup> TLR2<sup>-/-</sup> cells, Th17 induction was found to depend on TLR2 expression on APCs; whereas the minor Th1 induction was dependent on TLR2 expression directly on T cells. TLR4 activation was not involved in Th17 differentiation induced by these bacteria. <i>In vivo</i>, oral inoculation with <i>P. gingivalis</i> and <i>P. nigrescens</i> significantly increased the clinical arthritis scores. Although no antibodies against cyclic citrullinated peptide (CCP)-2, citrullinated fibrinogen, a-enolase and vimentin could be detected under this condition, both bacteria substantially increased the severity of bone erosion. Collagen II stimulation of draining lymph node T cells revealed that <i>P. gingivalis</i> as well as <i>P. nigrescens</i> significantly increased antigen-specific IL-17, but not IFNγ, production. This IL-17 production strongly correlated with the intensity of bone erosion. In addition, <i>P. nigrescens</i> markedly suppressed the anti-inflammatory Th2/IL-4 phenotype <i>in vivo</i>, whereas <i>P. gingivalis</i> was the main inducer of local IL-1b, TNFa and Cathepsin K in synovium. <h3>Conclusions</h3> These data reveal a substantial effect of periodontal pathogens, irrespective of the capability to induce ACPA, on T cell phenotype in the context of arthritis with a remarkable impact on bone erosion. This study further supports the relevance of periodontal pathogens in the pathogenesis of RA. <h3>Disclosure of Interest</h3> None Declared