How a Periodontal Infection Might Trigger RA

Janis C. Kelly

December 29, 2016

A pathogen linked to periodontal disease might trigger production of autoantigens that set off and sustain inflammatory immune responses in the joints in rheumatoid arthritis (RA), according to new research published online December 14 in Science Translational Medicine.

The research team was led by Maximilian F. Konig, MD, and Felipe Andrade, MD, PhD, both from the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

The landmark study supports the hypothesis that bacterial pathogens play key roles in some cases of RA. The new data are expected to catalyze research efforts in primary prevention and in treatment strategies not based on immunosuppression. The findings also open a new window onto the interaction between RA genetic susceptibility and environmental triggers.

Dr Andrade, who is associate professor of medicine at Johns Hopkins University, told Medscape Medical News that these findings provide concrete evidence for a mechanism through which a pathogen might trigger the autoimmune and mucosal changes associated with RA.

Dr Konig, who is now at Massachusetts General Hospital, Boston, said in a news release, "This research may be the closest we've come to uncovering the root cause of RA."

The pathogen perpetrator is Aggregatibacter actinomycetemcomitans (Aa), formerly known as Haemophilus actinomycetemcomitans. Aa is a Gram-negative, facultative anaerobe found in 62% of chronic periodontitis cases.

The research team focused on possible effects of Aa infections on citrullination (conversion of the amino acid arginine in a protein into the amino acid citrulline), part of the normal machinery for regulating protein function. Citrullination creates novel epitopes and "neoantigens" on common proteins, which in turn induce autoantibodies and are removed by the immune system.

In RA, citrullination can become excessive and mediates damage to the joint tissues.

Anticitrullinated protein antibodies are a hallmark of RA, and many are present early in the disease process. These antibodies are associated with erosive joint destruction and greater disease activity, and positivity at the time of diagnosis is a predictor of more aggressive disease.

In earlier work, Dr Andrade's group discovered that RA synovial fluid cells have an unusual pattern of citrullination, affecting a broad range of proteins of different molecular weights. The researchers determined that this "hypercitrullination" was not induced by events associated with normal histone citrullination (a common step in neutrophil activation and death). Dr Andrade said this surprising finding suggested that the citrullination occurring in the rheumatoid joint differs qualitatively and quantitatively from the normal physiological citrullination. RA hypercitrullination is induced by two immune-mediated membranolytic pathways, mediated by perforin and by the membrane attack complex.

Periodontal disease (periodontitis) is common in patients with RA, and periodontal pathogens such as Porphyromonas gingivalis have been suspected of triggering autoimmunity, but have not been definitively linked to a causative mechanism. For the present study, the researchers first used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid both in patients who had periodontitis and in healthy control patients. This showed that samples from the patients with periodontitis contained hypercitrullinated autoantigens that mirrored those found in the rheumatoid joint.

Drilling down further, the researchers found that among the microbial species detected in the hypercitrullinated samples, only Aa induced hypercitrullination in host neutrophils, the most abundant inflammatory cells found in the joints and the gums of patients with RA and periodontal disease. This was the work of the pore-forming leukotoxin A (LtxA), the major virulence factor of Aa Basically, LtxA pokes a hole in the neutrophil cell membrane, allowing calcium to pour into the cell and drive activation of the peptidylarginine deiminase enzymes that mediate neutrophil hypercitrullination.

"LtxA distinctly induced generation of citrullinated RA autoantigens, suggesting that Aa-mediated neutrophil damage in the context of periodontal infection may be sufficient to generate the antigenic determinants recognized by disease-specific autoantibodies in RA," the authors write.

Thomas Van Dyke, DDS, PhD, vice president for clinical and translational research and chair of the Department of Applied Oral Sciences at the Forsyth Institute, Cambridge, Massachusetts, told Medscape Medical News that the idea that microbes involved in periodontal disease might trigger autoimmune diseases such as RA is interesting and has been reported before, with a different organism. Dr Van Dyke, who was not involved in the current study, is an expert on basic immunology related to inflammatory periodontal infections, with research focused on the regulation of the innate immune response by active endogenous pathways.

Dr Van Dyke said, "The association between citrullination was reported in a recent review by George Hajishengallis, DDS, PhD, where other studies showing an association between P gingivalis–mediated citrullination and induction of anticitrullinated protein antibodies in rheumatoid arthritis are cited." Dr Van Dyke cautions that these reported associations do not demonstrate cause and effect and that a role for citrullination resulting from either P gingivalis or Aa in rheumatoid arthritis remains to be demonstrated.

Dr Konig and colleagues screened stored samples from 196 patients with established RA in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis (ESCAPE-RA) cohort for Aa exposure. They found evidence for exposure to leukotoxic strains of Aa in 47% of patients with established RA, suggesting a "strong clinical association" of Aa with both RA and periodontal disease and "clinically relevant exposure to Aa" in a subset of patients with RA.

Furthermore, Dr Andrade said, "Exposure to Aa is strongly associated with the development of autoantibodies in people who at genetic risk for RA. The genetic risk is given by the HLA-DRB1 shared epitope alleles, not by HLA-DRB3." He described the new data as "like putting together the last few pieces of a complicated jigsaw puzzle that has been worked on for many years."

However, Dr Andrade emphasized that more than half of the patients with RA had no evidence of Aa infection. This might indicate that other bacteria (such as Staphylococcus aureus, which secretes the pore-forming toxin Panton-Valentine leucocidin) also might contribute to RA hypercitrullination, he said.

The big unanswered questions involve the potential role of Aa in the onset and evolution of RA. "The most important point is to directly demonstrate that the bacterium is the cause of RA. This will require further studies both in animal models and in patients," Dr Andrade said.

The authors conclude, "A role of Aa and pore-forming toxins in generating RA autoantigens has critical implications for the development of both primary preventative and therapeutic strategies beyond immunosuppression in this chronic autoimmune disease."

This research was funded by the Jerome L. Greene Foundation, the Donald B. and Dorothy L. Stabler Foundation, Fundación Bechara, Rheumatology Research Foundation, National Institute of Arthritis and Musculoskeletal and Skin Diseases under grant numbers R01AR069569 and AR050026-01, the National Institute of Dental and Craniofacial Research (NIDCR) under grant numbers DE021127-01 and R37 DE12354, and the Intramural Research Program of the NIDCR. Dr Andrade and Dr Konig submitted an invention disclosure (D14433) by the Johns Hopkins University that covers the use of antibodies to Aa LtxA for the diagnosis and treatment of patients with Aa infection. Dr Andrade received a grant from MedImmune. One coauthor is now a full-time employee of AbbVie. The remaining coauthors and Dr Van Dyke have disclosed no relevant financial relationships.

Sci Transl Med. Published online December 14, 2016. Abstract

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