Common Bacterium Triggers Both Periodontitis and Rheumatoid Arthritis

16 Dec 2016
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Common Bacterium Triggers Both Periodontitis and Rheumatoid Arthritis Photo courtesy of the Temple University Kornberg School of Dentistry.

A bacterium that causes chronic inflammatory gum infections also triggers the inflammatory autoimmune response characteristic of chronic, joint-destroying rheumatoid arthritis (RA), according to the Johns Hopkins University School of Medicine. The researchers report that these findings have important implications for the prevention and treatment of RA.

The common denominator identified in periodontal disease and in many people with RA is Aggregatibacter actinomycetemcomitans. An infection with this bacterium 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.

“This is like putting together the last few pieces of a complicated jigsaw puzzle that has been worked on for many years,” said Felipe Andrade, MD, PhD, senior study investigator, associate professor of medicine at the school, and practitioner at Johns Hopkins Bayview Medical Center.

“This research may be the closest we’ve come to uncovering the root cause of RA,” said first author Maximilian Konig, MD, a former Johns Hopkins University School of Medicine Fellow and now a practitioner at Massachusetts General Hospital

Investigators have observed a clinical association between periodontal disease and RA since the early 1900s and have suspected that both diseases may be triggered by a common factor. In the last decade, studies have focused on Porphyromonas gingivalis, found in patients with gum disease.

While major efforts are ongoing to demonstrate that this bacterium causes RA by inducing citrullinated proteins, all attempts by the research team have failed to corroborate such a link, said Andrade. But his team has persisted in finding alternative bacterial drivers, he said, because of intriguing links between periodontal disease and RA.

For this study, the researchers began to search for a common factor that may link both diseases. Initial clues came from the study’s analysis of periodontal samples, where they found that a similar process—hypercitrullination—that had previously been observed in the joints of patients with RA was occurring in the gums of patients with periodontal disease.

While citrullination happens naturally in everyone as a way to regulate the function of proteins, it becomes overactive in people with RA, resulting in the abnormal accumulation of citrullinated proteins, Andrade said. This drives the production of antibodies against these proteins that create inflammation and attack a person’s own tissues, which is the hallmark of RA.

Among different bacterial associated with periodontal disease, the researchers found that A actinomycetemcomitans was the only pathogen able to induce hypercitrullination in neutrophils, an immune white blood cell highly enriched with the peptidylarginine deiminase (PAD) enzymes required for citrullination.

Neutrophils are the most abundant inflammatory cells found in the joints and gums of patients with RA and periodontal disease, said the researchers. These cells have been studied for many years as the major source of hypercitrullination in RA, which affects 1.5 million people nationwide, according to the Centers for Disease Control and Prevention.

A actinomycetemcomitans initiates hypercitrullination through the bacterial secretion of a toxin, leukotoxin A (LtxA), as a self-defense strategy to kill host immune cells. The toxin creates holes on the surface of neutrophils, 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 it overactivates them, generating hypercitrullination.

Previously, the researchers found that a similar type of pore-forming protein 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 in cells, which may be relevant to the initiation of RA when the disease is being established, Andrade said. 

The researchers 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 92 of them had evidence of A actinomycetemcomitans infection.

These results were similar to patients with periodontal disease, with about 60% positivity, but quite different in healthy controls, who only had 11% of people testing positive for A actinomycetemcomitans. More strikingly, the researchers said, exposure to the bacterium was a major determinant in the production of antibodies to citrullinated proteins in patients with genetic susceptibility to RA.

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.

Also, Andrade noted that the study only looked at patients at a single point in time with established RA and that more research will be required to track the potential role of the bacteria in the onset and evolution of the disease, which can span decades, to prove cause and effect of A actinomycetemcomitans and RA.

“If we know more about the evolution of both combined, perhaps we could prevent rather than just intervene,” said Andrade.

The study, “Aggregatibacter actinomycetemcomitans–induced Hypercitrullination Links Periodontal Infection to Autoimmunity in Rheumatoid Arthritis,” was published by Science Translational Medicine.

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