A new study lead by Felipe Andrade, M.D., Ph.D. from the Johns Hopkins University Division of Rheumatology provides new evidence that a bacterium known to cause chronic inflammatory gum infections also triggers the inflammatory autoimmune response also found in the joints of patients with the chronic, joint-destroying autoimmune disease, rheumatoid arthritis (RA). These new findings have important implications for the prevention and treatment of RA.
Why was this study done?
How was this study done?
The study began by searching for common factors that may link periodontal disease and RA. Initial clues came from the study of periodontal samples, where the authors found that a similar process that had previously been observed in the joints of patients with RA was occurring in the gums of patients with periodontal disease. This common process is called “hypercitrullination”. Citrullination occurs naturally in everyone as a way to regulate the function of proteins. However, in people with RA, this process becomes overactive, resulting in hypercitrullination and the abnormal accumulation of citrullinated proteins. This drives the production of antibodies against these proteins that create inflammation and attack the joints in patient with RA.
What were the major findings?
Among different periodontal bacteria, the study identified that only one called Aggregatibacter actinomycetemcomitans (Aa) could trigger hypercitrullination in human white blood cells, the major source of citrullinated proteins in RA. Aa causes hypercitrullination by secretion of a toxin called leukotoxin A (LtxA) that pokes holes in white blood cells as a self-defense strategy to kill host immune cells. Further studies demonstrated that almost half of the patients with RA have evidence of infection by Aa, compared with 11% of healthy individuals. More strikingly, exposure to Aa was an important factor for production of antibodies to citrullinated proteins in patients with genetic susceptibility to RA.
What is the impact of this work?
Current treatment with steroids, biologic drugs and physical therapy are effective for reducing or slowing the crippling and painful joint deformities in some, but not all patients with RA. This study sheds new light on the longstanding relationship between gum disease and RA by identifying hypercitrullination as a common process that unites these two seemingly unrelated conditions. Learning more about how this process starts and causes the immune system to attack proteins in the joint may lead to new ways to treat and even prevent RA in the future.
This research was supported by:
Rheumatology Research Foundation, Fundación Bechara, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under grant numbers R01AR069569 and AR050026-01, the National Institute of Dental and Craniofacial Research (NIDCR) under grant numbers DE021127-01 and R37 DE12354, and the Intramural Research Program of the NIDCR.
Link to original research article:
Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K, Rosen A, Nigrovic PA, Sokolove J, Giles JT, Moutsopoulos NM, Andrade F. Sci Transl Med. 2016 Dec 14;8(369):369ra176.