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A common bacterium links rheumatoid arthritis and gum disease (2016-12-28)

A bacterium known to cause chronic inflammatory gum infections also triggers the inflammatory autoimmune response characteristic of chronic, joint-destroying rheumatoid arthritis (RA). Researchers from Johns Hopkins Medicine have identified the bacterium at play in both conditions, a bacterium called Aggregatibacter actinomycetemcomitans.

The clinical association between the two diseases has been known since the early 1900s, but most research in the past decade has focused on a different bacterium called Porphyromonas gingivalis. The Johns Hopkins research sought alternate explanations.

"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, the senior study investigator and associate professor at the Johns Hopkins University School of Medicine.

For this study, the investigative team with expertise in periodontal microbiology, periodontal disease and rheumatoid arthritis began to search for a common denominator that may link both diseases.

Initial clues came from the study’s analysis of periodontal samples, where they found that a similar process that had previously been observed in the joints of patients with rheumatoid arthritis was occurring in the gums of patients with periodontal disease. This common denominator is called hypercitrullination.

Andrade explains that citrullination happens naturally in everyone as a way to regulate the function of proteins. But in people with rheumatoid arthritis, 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.

The researchers discovered that A. actinomycetemcomitans was the only bacterium capable of inducing hypercitrullination in the most abundant inflammatory cells found in both gum disease and rheumatoid arthritis.

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 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 rheumatoid arthritis.

These findings point to a common mechanism that is poking holes on cells, which may be relevant to the initiation of rheumatoid arthritis and also when the disease is being established, says Andrade.

The study used 196 samples from patients with RA, finding that more than half had evidence of infection by A. actinomycetemcomitans.
The data was similar with the gum disease sample.

Most striking, though, was that exposure to the bacterium appeared to be a major determinant in producing tissue-attacking antibodies in patients genetically susceptible to rheumatoid arthritis.

Konig cautioned that because more than half of the study participants with rheumatoid arthritis showed no evidence of A. actinomycetemcomitans, there could be other bacteria in the gut, lung, or elsewhere using a similar mechanism to induce hypercitrullination.

Andrade further noted that more research is necessary to track the role of the bacterium in the onset and evolution of RA, rather than when the disease is already established.

See also
Gut Microbes Linked to Rheumatoid Arthritis (2013-11-26)

For more information
Science Translational Medicine
Aggregatibacter actinomycetemcomitans–induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis