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
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
"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
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
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
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,
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
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
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.
Gut Microbes Linked to Rheumatoid Arthritis
For more information
Science Translational Medicine
hypercitrullination links periodontal infection to
autoimmunity in rheumatoid arthritis