Rheumatoid arthritis and periodontitis are two prevalent chronic inflammatory diseases in humans and are associated with each other both clinically and epidemiologically. Recent findings suggest a causative link between periodontal infection and rheumatoid arthritis via bacteria-dependent induction of a pathogenic autoimmune response to citrullinated epitopes. Here we showed that infection with viable periodontal pathogen Porphyromonas gingivalis strain W83 exacerbated collagen-induced arthritis (CIA) in a mouse model, as manifested by earlier onset, accelerated progression and enhanced severity of the disease, including significantly increased bone and cartilage destruction. The ability of P. gingivalis to augment CIA was dependent on the expression of a unique P. gingivalis peptidylarginine deiminase (PPAD), which converts arginine residues in proteins to citrulline. Infection with wild type P. gingivalis was responsible for significantly increased levels of autoantibodies to collagen type II and citrullinated epitopes as a PPAD-null mutant did not elicit similar host response. High level of citrullinated proteins was also detected at the site of infection with wild-type P. gingivalis. Together, these results suggest bacterial PAD as the mechanistic link between P. gingivalis periodontal infection and rheumatoid arthritis.

In subjects with periodontitis, P. gingivalis infection may be responsible for inducing autoimmune responses that characterize rheumatoid arthritis.

Objectives To investigate the role of the periodontal pathogen Porphyromonas gingivalis in rheumatoid arthritis (RA) etiology, we have analysed the antibody response to P. gingivalis virulence factor arginine gingipainB (RgpB) in relation to anti-citrullinated protein antibodies (ACPA), smoking and HLA-DRB1 shared epitope (SE) alleles, in patients with periodontitis (PD) and RA, and in controls. Methods Anti-RgpB IgG was measured by ELISA in 65 PD patients and 59 non-PD controls, and in 1,975 RA cases and 377 non-RA controls from the Swedish population-based case-control study EIRA (Epidemiological Investigation of RA). Autoantibody status, smoking habits and genetic data were retrieved from the EIRA database. Differences in antibody levels were examined using Mann-Whitney U test. Unconditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for the association of anti-RgpB IgG with different RA subsets. Results Anti-RgpB antibody levels were significantly elevated in PD compared to non-PD; in RA compared to non-RA; and in ACPA-positive RA compared to ACPA-negative RA. There was a significant association between anti-RgpB IgG and RA (OR=2.96; 95% CI: 2.00–4.37), which was even stronger than the association between smoking and RA (OR=1.37; 95% CI: 1.07–1.74), and in ACPA-positive RA, there were interactions between anti-RgpB antibodies and both smoking and SE. Conclusion Our study suggests that the previously reported link between PD and RA could be accounted for by P. gingivalis infection, and we conclude that P. gingivalis is a credible candidate for triggering and/or driving autoimmunity and autoimmune disease in a subset of RA.

PAD4-mediated citrullination of E2F-1 transcription factor and its interplay with acetylation affects inflammatory gene expression.

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum cytokines and antibody subtypes. In lymph node cells from the arthritic mice treated with BB-Cl-amidine, there was a decrease in total cell numbers but an increase in the proportion of Th2 cells. BB-Cl-amidine had a pro-apoptotic effect on all Th subsets in vitro with Th17 cells appearing to be the most sensitive. We suggest that these immunoregulatory effects of PAD inhibition in CIA are complex, but primarily mediated by transcriptional regulation. We suggest that targeting PADs is a promising strategy for the treatment of chronic inflammatory disease.