T Cell-Dependent Arthritic Bone Erosion is Induced by Periodontal Pathogens

Methods: The effect of Porphyromonas gingivalis (P.g.) and Prevotella nigrescens (P.n.) on T cell differentiation and the involvement of Toll-like receptors (TLRs) were studied using cells from wild-type and interleukin-1 receptor antagonist deficient mice. In vivo, collagen-induced arthritis mice received five oral inoculations of P.g. or P.n. started from day 14 after immunization. Joint histopathology, synovial gene expression, T cell phenotype, cytokine and anti-citrullinated protein antibodies (ACPA) production were analyzed on day 30.

Results: P.g. and P.n. strongly induced Th17 differentiation and IL-17 production in a co-culture of splenic antigen-presenting cells (APCs) with CD4+ T cells. This effect was increased in the absence of IL-1 receptor antagonist. Both bacteria significantly lowered Th2 differentiation and were weak inducers of Th1. Using IL-1Ra-/- cells from TLR knockouts, Th17 induction was dependent on TLR2, but not TLR4, expression on APCs; whereas the minor Th1 induction depended on TLR2 of T cells. In vivo, periodontal pathogens significantly increased the clinical scores of arthritis, even without detection of ACPA. Both bacteria substantially increased bone erosion without affecting cartilage destruction. T helper cell phenotype in draining lymph nodes upon pan-T cell or collagen II stimulations revealed a significant increase of IL-17, but not IFNγ. The IL-17 levels were strongly correlated with bone erosion. P.g. exclusively induced MMP-9 and Cathepsin K in synovium, while only P.n. markedly reduced Th2/IL-4 phenotype in vivo.

Conclusion: This study reveals the modulation of T cell phenotype as a relevant pathogenic role of periodontal pathogens on arthritis irrespective of ACPA induction, with a special bacterial effect on bone erosion correlated with IL-17 induction.