MedicalResearch.com Interview with:
Maximilian F. Konig, MD
Division of Rheumatology,
Johns Hopkins University School of Medicine
Department of Medicine
Massachusetts General Hospital
Harvard Medical School
MedicalResearch.com: What is the background for this study?
Response:The idea that rheumatoid arthritis (RA), an autoimmune disease that leads to chronic joint inflammation and destruction, may be initiated by a bacterial infection is not novel, but has been posited for more than a century. Based on the clinical observation that patients with RA frequently have severe periodontal disease (gum disease), gum inflammation has long been thought to contribute to disease development in RA. However, limited understanding of the mechanisms that fuel and sustain the autoimmune attack in RA made it difficult to pinpoint a specific bacterial trigger.
In recent years, our understanding of the abnormal immune response that attacks the joints in patients with RA has grown exponentially, and we now know that disease-specific autoantibodies (ACPAs) target modified self-proteins (this modification is known as citrullination). It is this abnormal immune response against citrullinated proteins that appears to drive the joint (and sometimes lung) inflammation seen in rheumatoid arthritis. Recent studies from our laboratory at The Johns Hopkins University (led by principle investigator Felipe Andrade, MD, PhD) suggested that an immune cell called the neutrophil, which normally protects us from infection at sites like the oral cavity or anywhere else in the body, also appears to be the source of the proteins attacked in RA. We were therefore interested to understand what drives the association of gum disease, an inflammation commonly triggered by bacteria, with RA.
MedicalResearch.com: What are the main findings?
Response: My colleagues and I in the Division of Rheumatology at Johns Hopkins were able to show that the gums in patients that are infected with the periodontal pathogen Aggregatibacter actinomycetemcomitans (or short: Aa) mimic the rheumatoid joint – in the sense that they harbor the same citrullinated proteins that are recognized and attacked as foreign by the immune system in RA. We then tried to understand how Aa may trigger the production of these molecules.
Aa is an aggressive pathogen. To survive and protect itself against the human defenses, it produces a toxin called LtxA that specifically punches holes into immune cells, thereby killing the neutrophils that patrol the periodontal pocket. When the neutrophil dies, it produces and releases the protein targets that are attacked by the immune system in rheumatoid arthritis. In our study, close to 50% of patients with RA had evidence of Aa infection (as compared to 11% of controls). In the rest of patients, we suspect that different bacteria may be contributing in similar ways; these bacteria may act in the gut or even the lungs. We also found that the strongest genetic risk factor for RA (the HLA-DRB1 shared epitope) only increased the risk of having RA-specific antibodies in those patients that had evidence of Aa infection. It appears as if you need both, the right genetic background and an infection that drives the production of abnormal citrullinated proteins (such as Aa) to develop disease-specific antibodies and possibly RA.
Response: MedicalResearch.com: What should readers take away from your report?
Response: At this point, how these findings are best applied to patients with RA remains to be established and will shape research efforts in the years to come. However, if confirmed, our findings may open the possibility of disease prevention in patients at risk of RA. This could be through Aa eradication by antibiotic therapy and/or periodontal cleaning – or even targeted therapies that inactivate the toxin in the gums. Interestingly, historical therapies to treat RA like gold or minocycline have known antimicrobial effects, suggesting that their efficacy could have been (at least in part) driven by bacterial suppression. While we learn how to translate these findings into therapies, I would suggest that patients with RA maintain good oral hygiene and see a dentist regularly.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: First, our findings need to be replicated independently by other research groups and in different patient cohorts. We will need to learn at what time during their disease course patients with RA develop an infection with Aa. This may require to follow high-risk patient populations over time. While we already developed useful tests to identify Aa infection, we will need to learn how to best eradicate the infection and to what degree this will effect disease severity and outcomes in patients who already have rheumatoid arthritis. These are all exciting questions and the next few years should give us an idea of how much is possible. In an ideal world, we would be able to identify patients at risk and, if infected, eradicate Aa infection in the hope that they will never develop symptomatic RA.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
1. M. F. Konig, L. Abusleme, J. Reinholdt, R. J. Palmer, R. P. Teles, K. Sampson, A. Rosen, P. A. Nigrovic, J. Sokolove, J. T. Giles, N. M. Moutsopoulos, F. Andrade. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Science Translational Medicine, 2016; 8 (369): 369ra176 DOI: 10.1126/scitranslmed.aaj1921
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