Graduate Student Stanford University Stanford, California, United States
Abstract Text: Periodontitis is a risk factor for developing rheumatoid arthritis (RA) with anti-citrullinated protein antibodies (ACPA), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We discovered that patients with RA and periodontitis experienced repeated oral bacteremias, which triggered innate inflammatory pathways that were associated with clinical arthritis flares. These inflammatory pathways included activation of an ISG15+HLADRhi monocyte subset that is expanded in the inflamed RA synovium. Further, the oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPA encoded by RA blood plasmablasts. Together, these results suggest (i) periodontitis results in repeated breaches of the oral mucosa releasing citrullinated oral bacteria into circulation, which (ii) activate innate immune pathways that are observed in inflamed RA synovium and during clinical arthritis flare, and (iii) stimulate recurrent rounds of ACPA expressing B cell activation and somatic hypermutation associated with progression to and persistence of clinical RA.
