A actinomycetemcomitans may be a trigger for autoimmune response, rheumatoid arthritis
Compared with healthy individuals, patients with rheumatoid arthritis appear to have a disproportionately high incidence of periodontal disease and infection. While the association has been established for some time, a 2016 study published in Science Translational Medicine has identified the potential link between the two — an aggressive bacterium called Aggregatibacter actinomycetemcomitans. In certain patients with a genetic susceptibility, infection with A. actinomycetemcomitans may trigger an autoimmune response that leads to rheumatoid arthritis.
“There are people who have inflammation of the gums and others who have true periodontal disease,” Maximilian F. Konig, MD, an internist at Massachusetts General Hospital, told Healio Rheumatology. “Aggregatibacter actinomycetemcomitans (Aa) is a rather aggressive bacterium that is highly associated with periodontal disease. But obviously, only a subset of patients with Aa gum infection end up developing rheumatoid arthritis (RA).”
Konig discussed the complex factors that link periodontal disease and RA, how Aa may act as a trigger, and how this autoimmune cascade could be interrupted.
Question: How could the bacterium Aa trigger RA?
Answer: For many years now, it has been thought that RA is a disease in which strong environmental factors influence an individual’s genetic susceptibility to develop arthritis. The way we think of Aa as a possible trigger for RA is similar: in a patient with the right genetic background to develop rheumatoid arthritis, Aa may act as an environmental agent to initiate disease. In RA, a lot of the genetic susceptibility is conveyed by HLA-DRB1 shared epitope alleles. Through these molecules, the body presents everything it encounters to the immune system. These can be short protein sequences from viruses, bacteria, fungi, or even its own cells. The immune system surveys these protein samples and “decides” whether they are foreign invaders to attack, or whether they are part of your own body to tolerate.
Patients with RA have a unique version of these immune molecules that present protein samples from bacteria, viruses, or self-proteins. These so-called shared epitope molecules likely allow for the presentation of uniquely modified self-proteins. This modification is called citrullination, and proteins modified in this way are described as citrullinated. Presentation of these citrullinated self-proteins leads to their attack in patients with RA. This autoimmune response can be measured as anti-citrullinated protein antibodies (ACPAs) in the blood. We think this attack against citrullinated proteins causes the damage we see in RA.
Q: How does the Aa bacterium interact with this genetic predisposition?
A: In patients with RA, some citrullinated proteins are targets of an autoimmune response. For this response to occur, these citrullinated proteins must be generated and accumulate. Aa has the unique ability to attack immune cells, such as neutrophils, in a way that triggers the cells to produce abundant amounts of citrullinated self-proteins. When exposed to a bacterial toxin of Aa (LtxA), neutrophils undergo a form of cell death that we named leukotoxic hypercitrullination. In patients who carry shared epitope alleles, hypercitrullination may trigger the autoimmune response that is characteristic of RA.
This combination of genetic predisposition and chronic bacterial infection with Aa may thus result in the generation of citrullinated proteins, autoimmunity, and ultimately arthritis.
Q: How does a patient get exposed to Aa bacteria?
A: Just like other pathogens you encounter while eating, drinking or riding public transportation, you may pick up Aa from someone who already has the infection. For many people, exposure to this bacterium may not cause much harm. In others, Aa gets a foothold in their gums. This may be due to predisposition, virulence of the individual Aa strain, or through continual exposure, such as a significant other with Aa infection. In fact, these dynamics have been well studied in Northern Africa, where extremely aggressive strains of Aa are prevalent. If infected with such an aggressive strain, you can see the impact over relatively short periods of time. These patients develop severe periodontal disease as early as their adolescence and may have such significant inflammation that they lose teeth. Patients tend to mount a strong immune response against the bacterium, which we can measure in the blood. Some develop an ongoing infection with this bacterium, while others can clear it.
Q: Do patients who have this infection usually present for care due to their symptoms?
A: My suspicion is that most patients do not present for treatment. This is especially true for colonization with less virulent strains. Moreover, Aa has been underappreciated as an important initiating factor for chronic periodontal disease. If a patient goes to a dentist for evaluation, periodontal disease or inflammation may be apparent. Although Aa screening is performed for research studies, this testing is generally not routine.
Q: Can this infection resolve itself without treatment? Can treating and eliminating the infection prevent the patient from going on to have RA?
A: We think that some people may resolve periodontal infection without treatment, and others do not. Unfortunately, Aa as a cause of or contributor to chronic periodontal disease is understudied. Regarding the elimination of Aa infection to prevent RA, we do not know the answer yet. If this bacterium is a trigger of RA, long-standing infection would put individuals with a genetic predisposition at risk.
Chronic exposure to and killing of neutrophils by Aa may results in the generation of abundant citrullinated self-proteins. This causes the immune system to go awry and recognize these modified self-proteins as foreign. An autoimmune attack ensues. The immune system then produces autoantibodies against citrullinated self-proteins. As a result, the patient may ultimately develop tissue inflammation that we clinically identify as rheumatoid arthritis. This process – form autoantibodies to developing joint pain and inflammation – can take many years. If we eradicated Aa early in this process, before an autoimmune process is established, you could possibly prevent RA.
Q: What would happen if the autoimmune response had already begun?
A: This is a fascinating question. We postulate that triggers of the autoimmune response in RA may act 10 years or even 20 years before the onset of disease. I am unsure what would happen if we eradicated Aa in a person with an ongoing immune response against citrullinated proteins and active infection. The person could either progress to RA, or the autoimmune response would subside and the person may never develop RA. Our hope is to identify people with this abnormal immune response early, remove possible triggers (such as Aa infection), and prevent RA.
Q: How do you identify which patients are at risk to develop RA?
A: The marker we are most commonly measuring is called anti-citrullinated protein antibody (or ACPA for short). In the clinical setting, it is measured with a specific assay called the CCP assay. When measured this way, they are called anti-CCP antibodies. These antibodies are currently the most specific diagnostic marker for RA, and their occurrence often precedes the onset of symptomatic disease by many years.
Q: Do clinicians ask about a patient’s periodontal health when RA is suspected?
A: If you are in a university setting with the intention to study the interplay of periodontal disease and RA, then yes. Patients may be offered to undergo comprehensive oral examination to diagnose periodontal disease and determine infection with specific bacterial species. However, the typical rheumatologist would not be equipped to assess the presence of periodontal disease. They may take note of general oral health, but determining the presence of periodontitis, inflammation or infection requires the expertise of a dentist.
Q: What are the implications of these findings about periodontal disease and anti-citrullinated protein antibodies for future RA treatments?
A: Currently, there are no RA treatments available that target potential disease triggers. This is precisely why the research into initiation of RA is important. People have long noticed the association of RA with periodontal disease; smoking has been identified as another environmental factor. However, we are just beginning to appreciate why periodontal disease may be associated with RA. This is where our recent study comes in.
Right now, when a patient with RA presents with joint inflammation and destruction, we treat the patient by suppressing the immune system. The available drugs are rather crude ways to decrease inflammation, but they are not addressing the source of the autoimmune process. My hope is that, over the next few years, we will shift our approach from treating ongoing damage to preventing damage in the first place by taking away drivers of RA. — by Jennifer Byrne
For more information:
Maximilian F. Konig, MD, can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114; email: firstname.lastname@example.org.
Disclosure: The studies were performed in the laboratory of Felipe Andrade, MD, PhD at the Johns Hopkins University School of Medicine. Konig reports no relevant financial disclosures.
Konig MF, et al. Sci Transl Med. 2016; doi:10.1126/scitranslmed.aaj1921.