Background/Purpose: The periodontal pathogen Porphyromonas gingivalishas been associated with the pathogenesis of rheumatoid arthritis (RA) because of its ability to citrullinate mammalian proteins and to induce disease-specific anti-citrullinated peptide antibodies (ACPA). The aim of this study was to investigate the influence of periodontal pathogens on the development of experimental arthritis and the T helper cell balance as a possible underlying mechanism for disease modulation.

Methods: The effect of P. gingivalis and Prevotella nigrescens, the latter lacking citrullinating enzymes, on T cell differentiation and the involvement of Toll-like receptors (TLRs) was studied in vitro using either wild-type or TLR deficient antigen-presenting cells (APCs) and CD4⁺ T cells in co-culture. In vivo, mice with collagen-induced arthritis received five oral inoculations of either P. gingivalis or P. nigrescensevery other day starting from day 14 after immunization. Joint histopathology, synovial gene expression, collagen-specific T cell phenotype and presence of ACPA were analyzed on day 30.

Results: P. gingivalis strongly induced an interleukin-1 driven Th17 differentiation in the co-culture of APCs with CD4⁺ T cells, as measured by FACS and IL-17 production. This Th17 induction strongly depended on TLR2 expression on APCs and was substantially increased in the absence of IL-1 receptor antagonist. Remarkably, the Th17 inducing capacity was shared by another major periodontal pathogen, Prevotella nigrescens, lacking citrullination capability. In addition, both bacteria were weak inducers of Th1 and interferon γ production, which was dependent on TLR2 expression directly on T cells.

When applied in collagen-induced arthritis model through repeated oral inoculations, both P. gingivalis and P. nigrescens promoted antigen-specific Th17 response in vivo and aggravated the severity of arthritis. This occurred under conditions where ACPA against major citrullinated peptide candidates such as α-enolase and vimentin were undetectable. Instead, the levels of IL-17 induced by periodontal pathogens directly correlated with the intensity of arthritic bone erosions. In addition, while P. gingivalis induced local joint-destructive factors such as cathepsin K and matrix metalloproteinase 9 in synovial tissue, P. nigrescenssuppressed the anti-inflammatory IL-4 production by T cells.

Conclusion: Our data reveal a novel mechanism, besides citrullination capability, by which periodontal pathogens influence autoimmune arthritis through direct modulation of the T cell phenotype, with a remarkable impact on bone erosion. This study further supports the relevance of periodontal pathogens in the pathogenesis of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/periodontal-pathogens-directly-promote-autoimmune-experimental-arthritis-by-inducing-a-toll-like-receptor-2-and-interleukin-1-driven-th17-response/