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New research shows that a periodontal pathogen may trigger autoimmunity in rheumatoid arthritis. It appears to trigger a cascade that is known to lead to autoantigen citrullination in the RA joint.
Johns Hopkins researchers have identified a periodontal pathogen - aggregatibacter actinomycetemcomitans (Aa) - as a possible bacterial trigger of autoimmunity in rheumatoid arthritis.
The research was presented by Maximilian F. Konig on Nov. 13 at the American College of Rheumatology annual meeting in Washington, D.C.
"We identified the pore-forming toxin LtxA as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways known to sustain autoantigen citrullination in the RA joint," Dr. Konig wrote in his presentation.
His research is designed to explore the relationship between the periodontal microenvironment, mechanisms that underlie mucosal inflammation and autoimmunity in rheumatoid arthritis. “A bacterial etiology of rheumatoid arthritis has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation, particularly the gingiva, the gut and the lungs. The common occurrence of periodontal dysbiosis in rheumatoid arthritis suggests that oral pathogens may trigger the production of anti-citrullinated protein antibodies (ACPAs) and arthritis in susceptible individuals,” he wrote in his abstract presentation.
The team found a “surprising” relationship between the presence of aggregatibacter actinomycetemcomitans (Aa), anti-citrullinated protein antibodies and rheumatoid factor. They discovered a susceptibility to rheumatoid arthritis was in part dependent on exposure to the Aa leukotoxin pointing to a two-hit model for rheumatoid arthritis etiology.
Dr. Konig and colleagues point to a possible relationship between bacteria in particular mucosal pathogens and developing rheumatoid arthritis. Gingival crevicular fluid was collected from patients with and without periodontitis and studies with immunoblotting and mass spectrometry in an effort to detect both citrullinated proteins and identify the microbial environment in health and disease. Antibodies to aggregatibacter actinomycetemcomitans (Aa) and Aa leukotoxin were quantified in rheumatoid arthritis patients numbering 196, and controls without disease or periodontitis numbering 37.
Periodontitis was defined by the presence of citrullinated autoantigens that were similar to immune targets in rheumatoid arthritis. They found that the autoantigens in the oral mucosa were similar to patterns found in the rheumatoid joint. This similarity points to the mucosa as a potential starting point for rheumatoid arthritis.
Aggregatibacter actinomycetemcomitans found in periodontitis patients triggered hypercitrullination in host neutrophils while other pathogens did not. Further Aa leukotoxin was implicated as the mechanism utilized by Aggregatibacter actinomycetemcomitans to cause citrullinating enzymes in neutrophils to lose regulation in ways similar to membranolytic citrullination found in the rheumatoid joint.
The rheumatoid arthritis group was found to have been exposed to Aggregatibacter actinomycetemcomitans significantly more (43%) than controls without periodontal disease (8% p<0.0001).
“Aggregatibacter Actinomycetemcomitans-Induced Hypercitrullination Links Periodontal Infection to Autoimmunity in Rheumatoid Arthritis,” Maximilian F. Konig. 2016 American College of Rheumatology annual meeting. Nov. 13, 2016. Abstract 913.