Bacteria Found in Gum Disease Linked to RA
A bacteria that causes gum disease may also hold the key to triggering rheumatoid arthritis (RA).
In a new report, investigators at Johns Hopkins say the common denominator in periodontal disease and in many people with RA is Aggregatibacter actinomycetemcomitans.1 An infection with A. actinomycetemcomitans appears to induce the production of citrullinated proteins, which are suspected of activating the immune system and driving the cascade of events leading to RA, noted a press release from Johns Hopkins Medicine.2
"This is like putting together the last few pieces of a complicated jigsaw puzzle that has been worked on for many years," says Felipe Andrade, MD, PhD, the senior study investigator and associate professor of Medicine at the Johns Hopkins University School of Medicine, who also practices at Johns Hopkins Bayview Medical Center.
"This research may be the closest we've come to uncovering the root cause of RA," adds first author Maximilian Konig, MD, a former Johns Hopkins University School of Medicine fellow now at Massachusetts General Hospital.
Gum Disease and Inflammation
Medical investigators have observed a clinical association between periodontal disease and RA since the early 1900s, and over time, researchers have suspected that both diseases may be triggered by a common factor. In the last decade, studies have focused on a bacterium known as Porphyromonas gingivalis. However, while major efforts are currently ongoing to demonstrate that this bacterium causes RA by inducing citrullinated proteins, all attempts by the Johns Hopkins research team have failed to corroborate such a link, said Dr. Andrade.
Instead, his team looked into finding alternative bacterial drivers. For the current study, the team analyzed periodontal samples and observed a similar process of hypercitrullination that has been seen in the joints of patients with RA.
Dr. Andrade explained that citrullination happens naturally in everyone as a way to regulate the function of proteins. But in people with RA, this process becomes overactive, resulting in the abnormal accumulation of citrullinated proteins. This drives the production of antibodies against these proteins that create inflammation and attack a person's own tissues—the hallmark of RA.
Among different bacteria associated with periodontal disease, the research team found that A. actinomycetemcomitans was the only pathogen able to induce hypercitrullination in neutrophils, white blood cells highly enriched with the peptidylarginine deiminase (PAD) enzymes required for citrullination. Neutrophils are the most abundant inflammatory cells found in the joints and the gums of patients with RA and periodontal disease, say the researchers. These cells have been studied for many years as the major source of hypercitrullination in RA.
How Bacteria Initiates Inflammation
A. actinomycetemcomitans initiates hypercitrullination through the bacterial secretion of leukotoxin A (LtxA), a self-defense strategy to kill host immune cells. The toxin creates holes on the surface of neutrophils, noted the investigators, allowing a flux of high amounts of calcium into the cell where concentrations are normally kept low. Since the PAD enzymes are activated with calcium, the abrupt exposure to high amounts of calcium overactivates these enzymes, generating hypercitrullination.
The researchers previously found that a similar type of pore-forming protein that was produced to kill pathogens by host immune cells was driving hypercitrullination in the joints of patients with RA. These findings point to a common mechanism that is poking holes on cells, which may be relevant to the initiation of RA when the disease is being established, says Andrade.
As part of its study, the team developed a test using the bacterium and LtxA to detect antibodies against A. actinomycetemcomitans in blood. Using 196 samples from a large study of patients with RA, the researchers found that almost half of the patients (92 out of 196) had evidence of infection by A. actinomycetemcomitans. Patients with periodontal disease had similar results: approximately 60% were positive, compared with only 11% of healthy controls. More strikingly, exposure to A. actinomycetemcomitans was a major determinant in the production of antibodies to citrullinated proteins in patients with genetic susceptibility to RA, wrote the authors.
Dr. Andrade cautioned that more than 50% of the study participants who had RA had no evidence of infection with A. actinomycetemcomitans, which, he said, may indicate that other bacteria in the gut, lung, or elsewhere could be using a similar mechanism to induce hypercitrullination.
Dr. Andrade further cautioned that his team's study only looked at patients at a single point in time with established RA. To prove cause and effect of A. actinomycetemcomitans and RA, he noted that more research will be needed to track the potential role of the bacteria in the onset and evolution of the disease, which can span decades. "If we know more about the evolution of both combined, perhaps we could prevent rather than just intervene."
Additional Researchers from Johns Hopkins included Kevon Sampson and Antony Rosen, M.D.
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 (NIAMS) 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.