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Johns Hopkins Team Identifies Link Between Periodontal Disease, Rheumatoid Arthritis

NEW YORK (GenomeWeb) – A team led by researchers at Johns Hopkins University has identified a link between periodontal disease and rheumatoid arthritis.

In a study published this week in Science Translational Medicine, the scientists found that patients with periodontitis exhibited patterns of autoantigen hypercitrullination similar to those found in RA patients and that the bacteria Aggregatibacter actinomycetemcomitans (Aa), specifically, caused hypercitrullination in patient neutrophils, indicating a possible role of Aa in triggering the disease.

RA is characterized by the development of patient autoantibodies against citrullinated proteins, but, as the STM authors noted, the "factors that underlie loss of tolerance to citrullinated proteins and disease initiation in RA remain elusive."

Recent work, they said, has "suggested mucosal surfaces, specifically the periodontium, the gut, and the lungs, as sites of disease initiation in RA," and, they added, RA sufferers also frequently have periodontal disease. This suggests that pathogens involved in periodontitis might also be involved in RA.

To investigate this possibility, the researchers used mass spectrometry to analyze gingival crevicular fluid (GCF) from patients with periodontal disease and healthy controls. This analysis found that GCF from periodontal disease patients had significantly higher expression of inflammatory markers and was enriched for citrullinated proteins, with "the citrullinome of the periodontal pocket in periodontitis mirror[ing] the spectrum of protein citrullination found in the RA joint, including major citrullinated autoantigens targeted by disease-specific autoantibodies in RA."

They also used mass spec to look for proteomic signatures of bacteria present in the samples, finding several species with links to periodontal disease. The researchers then considered whether any of these species might be capable of activating human peptidylarginine deiminase enzymes (PADs), which are responsible for protein citrullination. They incubated neutrophils with the various periodontal disease-linked bacteria they had identified, finding that incubating with Aa but no other pathogens generated hypercitrullination patterns like those observed both in the GCF of periodontitis patients and the synovial fluid of RA patients.

The authors noted, as well, that "citrullination was not detected in bacteria alone or control neutrophils, demonstrating that hypercitrullination is dependent on both bacterial factors and components of the host immune cell."

Investigating the mechanisms through which Aa might cause hypercitrullination, the researchers focused on leukotoxin A (LtxA), the organism's major virulence factor, hypothesizing that this factor might dysregulate PAD activation by disrupting neutrophil membranes and allowing an inflow of extracellular calcium. Adding a blocking antibody against leukotoxin A stopped neutrophil hypercitrullination, suggesting that, indeed, LtxA does drive that process.

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