Objective Periodontal disease (PD) is an established risk factor for rheumatoid arthritis (RA). The objective of this study is to identify how oral bacterial infections occurring in damaged periodontal tissue in PD can lead to joint inflammation and destruction in RA. Methods Four separate commensal oral bacteria species were cultured with human neutrophils to induce NETosis. The resultant NETs contained neutrophil-derived peptidylarginine deiminase 4 (PAD4) which, within the NET milieu, became activated and mediated citrullination of both bacterial and neutrophil self-proteins. Citrullination was evaluated by adding rabbit anti-citrulline antibody followed by Alexa fluor-647 conjugated anti-rabbit IgG secondary antibody. Results Our data demonstrate that citrullinated oral bacteria induce TLR9-Syk-mediated human B cell activation, differentiation, proliferation, and antibody secretion, including the development of plasmablasts secreting anticitrullinated protein antibodies (ACPAs). Some ACPAs bind citrullinated oral bacteria to form immune complexes that can activate monocyte-derived macrophages in vitro to differentiate into CD11b + CD64 + proinflammatory macrophages that secrete TNFα and IL-6. In contrast ACPA citrullinated-antigen complexes inhibit differentiation of anti-inflammatory MerTK hi TREM2 hi LYVE1 hi macrophages that clear apoptotic cells and promote tissue repair. These data suggest immune complexes formed by ACPAs binding citrullinated antigens augment pro-inflammatory responses and inhibit anti-inflammatory response. Conclusion Our data support the hypothesis that in RA patients with PD, citrullinated oral bacteria breach damaged periodontal tissue to enter the circulation and induce both innate and adaptive proinflammatory responses that promote synovial tissue destruction.
Acharya et al. (2026) studied this question.