Periodontal Disease and RA Connection No Longer a Mystery?

The association between periodontal disease and rheumatoid arthritis has been well established in studies, but now researchers writing in Science Translational Medicinedescribe a mechanism that could explain this association.

“This study provides the first evidence that Aggregatibacter actinomycetemcomitans (Aa) may be mechanistically and clinically important for rheumatoid arthritis,” said the study’s corresponding author, Felipe Andrade, M.D., Ph.D., of the Johns Hopkins University School of Medicine, Baltimore. The article appears in the December 14 issue of the journal. (Click here to read a related Q&A with Dr. Andrade.)

The study, aimed at identifying periodontitis-associated pathogens as potential environmental triggers of autoimmunity in rheumatoid arthritis, found that Aa, but not other candidate pathogens, induced the hypercitrullination in host neutrophils that is associated with autoantigen citrullination in rheumatoid arthritis joints.

Recent studies have implicated mucosal surfaces in the periodontium, gut and lungs as sites of disease initiation in rheumatoid arthritis. In periodontitis, analysis of gingival crevicular fluid (from the gingival sulcus, the space between the tooth and mucosa) has shown extensive protein citrullination, mirroring patterns of cellular hypercitrullination observed in rheumatoid arthritis joints. Citrullination is a natural process for regulation of protein function. However, in individuals with rheumatoid arthritis this process becomes overactive, resulting in hypercitrullination and the abnormal accumulation of citrullinated proteins.

To determine the mechanisms of protein citrullination during periodontal infection, Andrade et al. obtained serum from patients with rheumatoid arthritis, 109 with chronic periodontitis and 100 healthy controls, and assessed disease activity and severity at baseline and two additional time points. Average follow-up was 39 years.

Analysis showed that in healthy subjects without periodontitis, hypercitrullination was minimal. Also, mass spectrometry revealed significant enrichment for inflammatory markers such as immunoglobulin G and immunoglobulin A in periodontal disease (P =0.016 and P = 0.016, respectively). In those with periodontitis, the citrullinome of the periodontal pocket mirrored the protein citrullination spectrum found in the rheumatoid arthritis joint. That included major citrullinated autoantigens targeted in rheumatoid arthritis by disease-specific autoantibodies such as citrullinated actin, a-enolase, heterogeneous nuclear ribonucleoprotein A2/B1, and vimentin, and others.

While several bacterial species strongly associated with periodontitis were enriched in hypercitrullinated periodontitis samples, Andrade et al. identified Aggregatibacter actinomycetemcomitans (Aa) as the only pathogen with the ability to reproduce the repertoire of citrullinated antigens found in the rheumatoid arthritis joint.

Also, they found the pore-forming toxin leukotoxin A to be the molecular mechanism triggering dysregulated activation of citrullinating enzymes in neutrophils, mimicking membrane disrupting pathways in the rheumatoid arthritis joint. In toxin-susceptible cells, leukotoxin A (LtxA) induces plasma membrane permeability and unregulated calcium influx. Furthermore, in colonized individuals, LtxA expression correlated with periodontal disease severity.

Exposure to leukotoxic Aa strains was confirmed in patients with rheumatoid arthritis and was associated with both anticitrullinated protein antibodies and rheumatoid factor. Serum anti-Aggregatibacter actinomycetemcomitans serotype b antibodies were found in 41/196 (21%) patients with rheumatoid arthritis, indicating a systemic immune response to this Aggregatibacter actinomycetemcomitans (Aa) subset. These antibodies were strongly associated with rheumatoid arthritis. In controls without rheumatoid arthritis they were found in only 3% (P<0.001). Andrade et al. note also that almost half (47%) of the patients with rheumatoid arthritis have evidence of infection by Aa, compared with 11% of healthy individuals.

The findings, Andrade et al. state, demonstrate that Aa induces hypercitrullination in neutrophils through LtxA activity, Aa’s principal virulence factor. They comment further, “A role of Aa and pore-forming toxins in generating rheumatoid arthritis autoantigens has critical implications for the development of both primary preventative and therapeutic strategies beyond immunosuppression in this chronic autoimmune disease.”

References:

Maximilian F. Konig, Loreto Abusleme, Jesper Reinholdt, et. al. "Aggregatibacter actinomycetemcomitans–induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis," Science Translational Medicine. Dec. 14, 2016. DOI:10.1126/scitranslmed.aaj1921