Differential effects of periodontal microbiome on the rheumatoid factor induction during rheumatoid arthritis pathogenesis

Abstract

Association between exposure to periodontal bacteria and development of autoantibodies related to rheumatoid arthritis (RA) has been widely accepted; however, direct causal relationship between periodontal bacteria and rheumatoid factor (RF) is currently not fully understood. We investigated whether periodontal bacteria could affect RF status. Patients with preclinical, new-onset, or chronic RA underwent periodontal examination, and investigation of subgingival microbiome via 16S rRNA sequencing. Degree of arthritis and RF induction was examined in collagen-induced arthritis (CIA) mice that were orally inoculated with different periodontal bacteria species. Subsequently, single-cell RNA sequencing analysis of the mouse spleen cells was performed. Patients with preclinical RA showed an increased abundance of the Porphyromonadacae family in the subgingival microbiome compared to those with new-onset or chronic RA, despite comparable periodontitis severity among them. Notably, a distinct subgingival microbial community was found between patients with high-positive RF and those with negative or low-positive RF (p=0.022). Oral infections with the periodontal pathogens P. gingivalis and Treponema denticola in CIA mice similarly enhanced arthritis score, but resulted in different levels of RF induction. Genes related to B cell receptor signaling, B cell proliferation, activation, and differentiation, and CD4+ T cell costimulation and cytokine production were involved in the differential induction of RF in mice exposed to different bacteria. In summary, periodontal microbiome might shape RF status by affecting the humoral immune response during RA pathogenesis.

Factors associated with the composition of the gut microbiome in patients with established rheumatoid arthritis and its value for predicting treatment responses

“…The peptidylarginine deiminase (PPAD) enzyme of P. gingivalis is suggested as the underlying mechanism due to its citrullination activity and subsequent induction of ACPA [ 14 ]. Moreover, the periodontal microbiota is associated with the level of rheumatoid factor which affect humoral immune responses [ 17 ]. Recently, a virulence toxin, Leukotoxin A, of Aggregatibacter actinomycetemcomitans was shown to induce dysregulation of human PAD enzymes, thereby increasing endogenous citrullination [ 18 ].…”