The anti-citrullinated protein antibodies (ACPAs) seen in many rheumatoid arthritis (RA) patients -- which serve as a diagnostic marker and could also play an etiologic role -- may have their origin in periodontal disease, researchers said.
Serial blood samples from RA patients with periodontal disease showed the presence of oral bacterial RNA coinciding with elevations in markers of systemic inflammation, and furthermore, the patients carried ACPAs that recognized oral bacterial antigens as well as human proteins, according to William H. Robinson, MD, PhD, of Stanford University in California, and colleagues.
"Our findings indicate that damage of the oral mucosal barrier mediated by [periodontal disease] results in repeated, spontaneous translocation of citrullinated oral bacteria to the blood, which trigger innate and adaptive immune responses in RA associated with systemic disease flares," the group wrote in Science Translational Medicine
In simpler terms, the idea is that bacterial communities lodged below the gumline may breach the normal barrier between the oral cavity and circulation, thus exposing bacterial components to the immune system and provoking antibody responses. These antibodies may then cross-react with self proteins to generate or exacerbate autoimmune conditions.
This is far from the first study to link RA with periodontal disease, however. For example, one study in 2008 (which wasn't the first, either) found that RA patients were at eightfold higher risk of having periodontitis compared with non-RA individuals. Similarly, in 2019, a Korean analysis showed that, while RA wasn't connected to periodontitis in survey data, it was more likely in people experiencing early tooth loss.
But the new study may be the first to suggest a clear causative pathway between dental infections and RA.
Robinson and colleagues conducted a series of studies in several patient cohorts. One of these, at Rockefeller University in New York City, comprised five patients with RA who tested positive for citrullinated proteins and provided blood samples weekly for 1 year, plus additional samples during disease flares. Two of these patients had severe periodontal disease, while the others had no evidence of the condition.
Several dozen other RA patients, some of whom had periodontal disease, were tested at Stanford for plasmablasts and other blood components. A third cohort came from the University of Colorado and comprised individuals with and without periodontal disease, including a group that had moderate-to-severe disease plus RA.
Data from the Rockefeller University group confirmed that oral bacterial components (especially from Streptococcus species) entered the circulation at higher rates in the RA patients with periodontal disease compared with those without. The researchers also determined that during RA clinical exacerbations, expression spiked for genes associated with inflammatory monocyte responses in synovial tissue, but only in the patients with periodontal disease.
The group also conducted experiments in vitro with oral bacterial peptides and monoclonal antibodies derived from human ACPAs. This study showed that some of these RA-associated antibodies bound strongly to the bacterial antigens. Further studies suggested that the primary ACPAs from which the monoclonal versions were engineered had originally targeted bacterial peptides rather than human proteins.
"[T]hese results suggest that some ACPA B cells may originally develop against citrullinated bacterial antigens, followed by affinity maturation and epitope spreading, to bind citrullinated human antigens," Robinson and colleagues wrote.
Still other studies showed that proteins in many species of oral bacteria, including those typical of periodontal disease such as Porphyromonas gingivalis, are highly citrullinated.
Additionally, plasmablasts from RA patients that express ACPAs showed somatic hypermutations -- a factor that helps drive the strength of immune response -- more extensive that those typically seen with vaccinations. These hypermutations also meant that the resulting ACPAs could bind both human and bacterial citrullinated peptides.
"As B cells accumulate on average one nucleotide mutation per each cycle of activation and affinity maturation in the germinal center, the extensive mutation burden of ACPA plasmablasts in RA suggests that they may have been repeatedly restimulated by the recurrent mucosal breaches of citrullinated oral bacteria," Robinson and colleagues speculated.
The researchers stopped short of suggesting clinical implications, but one obvious conclusion is that early routine screening for periodontal disease -- that is, before symptoms such as pain and tooth loosening become apparent -- may identify individuals at increased risk for RA. Such people could then benefit from early intervention.
It's important to note, however, that not all RA patients test positive for ACPAs (in one Swedish study, for example, rates ranged from 50% to 80%), and many if not most RA patients do not develop overt periodontal disease. "Future [research] efforts will focus on elucidating additional mechanisms of flare in patients without oral bacteremia or [periodontal disease]," Robinson's group stated.
Disclosures
The study was funded through the U.S. government and nonprofit foundation grants.
Robinson reported being a founder and member of the Board of Directors and a consultant to Atreca; two co-authors reported holding patent rights to aspects of the technology described in the report, and two others reported relationships with Atreca and Micronoma.
Primary Source
Science Translational Medicine
Source Reference: Brewer RC, et al "Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis" Sci Translat Med 2023; DOI: 10.1126/scitranslmed.abq8476.
