Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis

Abstract Introduction: Clinical studies suggest a direct influence of periodontal disease (PD) on serum inflammatory markers and disease assessment of patients with established rheumatoid arthritis (RA). However, the influence of PD on arthritis development remains unclear. This investigation was undertaken to determine the contribution of chronic PD to immune activation and development of joint inflammation using the collagen-induced arthritis (CIA) model. Methods: DBA1/J mice orally infected with Porphyromonas gingivalis were administered with collagen II (CII) emulsified in complete Freund’s adjuvant (CFA) or incomplete Freund’s adjuvant (IFA) to induce arthritis. Arthritis development was assessed by visual scoring of paw swelling, caliper measurement of the paws, mRNA expression, paw micro-computed tomography (micro-CT) analysis, histology, and tartrate resistant acid phosphatase for osteoclast detection (TRAP)-positive immunohistochemistry. Serum and reactivated splenocytes were evaluated for cytokine expression. Results: Mice induced for PD and/or arthritis developed periodontal disease, shown by decreased alveolar bone and alteration of mRNA expression in gingival tissues and submandibular lymph nodes compared to vehicle. P. gingivalis oral infection increased paw swelling and osteoclast numbers in mice immunized with CFA/CII. Arthritis incidence and severity were increased by P. gingivalis in mice that received IFA/CII immunizations. Increased synovitis, bone erosions, and osteoclast numbers in the paws were observed following IFA/CII immunizations in mice infected with P gingivalis. Furthermore, cytokine analysis showed a trend toward increased serum Th17/Th1 ratios when P. gingivalis infection was present in mice receiving either CFA/CII or IFA/CII immunizations. Significant cytokine increases induced by P. gingivalis oral infection were mostly associated to Th17-related cytokines of reactivated splenic cells, including IL-1β, IL-6, and IL-22 in the CFA/CII group and IL-1β, tumor necrosis factor-α, transforming growth factor-β, IL-6 and IL-23 in the IFA/CII group. Conclusions: Chronic P. gingivalis oral infection prior to arthritis induction increases the immune system activation favoring Th17 cell responses, and ultimately accelerating arthritis development. These results suggest that chronic oral infection may influence RA development mainly through activation of Th17-related pathways

Oral Porphyromonas Gingivalis Infection Increases Arthritis Severity and Progression.

Periodontitis is a polymicrobial oral infection characterized by the destruction of tooth supporting structures that may influence rheumatoid arthritis. Porphyromonas gingivalis (P. gingivalis), a bacterium implicated in the etiology of periodontitis, has shown variation in inducing T-cell responses depending on the clinical strain. In this study, we determined the differences between the systemic responses of different P. gingivalis strains that have important clinical representation. We also determined the effect of chronic periodontal disease on immune activation during collagen-induced arthritis (CIA) development in mice. Our results confirmed that the strains of P. gingivalis A7A1-28, W50, and W83 had the ability to colonize the oral cavity of mice, induce periodontal disease, and change the expression profile of splenocytes. We found that splenic anti-inflammatory IL-10 expression was associated with the least amount of alveolar bone loss. Our results showed that P. gingivalis had the ability to activate dendritic cells and express IL-12, IL-6, and TGF-β in vitro. Orally, P. gingivalis induced a local Thelper (h)1-Th2-Treg response. CIA immunizations also resulted in periodontal bone loss. Prior P. gingivalis oral infection resulted in a trend for increased serum Th17/IFN-γ ratio and increased splenocyte numbers (splenomegaly) in mice induced for collagen-induced arthritis. In the complete Freund’s adjuvant (CFA) model, P. gingivalis infection induced a greater number of osteoclasts and tissue swelling once arthritis affected the entire paw in the CFA model of disease. In the incomplete Freund’s adjuvant (IFA) model for arthritis, P. gingivalis increased pannus formation, bone destruction, and osteoclast numbers. Together, our results indicate that chronic oral infection with P. gingivalis prior to arthritis induction altered Th cell-mediated responses and increased Th17 responses in collagen-induced arthritic mice. These results are important in furthering our understanding for the potential of an oral chronic infection in altering arthritis in susceptible patients, and may have important implications for developing future preventive periodontal and RA therapies.PHDOral Health SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97835/1/julmarch_2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97835/2/julmarch_1.pd