NIAID Now | January 05, 2023
Research by NIAID grantees strongly suggests that immune responses to a newly discovered species of gut bacteria may cause some cases of a common autoimmune disease called rheumatoid arthritis, or RA. The findings were recently published in Science Translational Medicine.
In people with RA, their own antibodies and T cells attack their joints, especially in the hands, wrists, and knees. This leads to inflammation, pain, and swelling in the joint lining. Over time, RA progresses to irreversible joint tissue damage, chronic pain, loss of function, and deformities. Scientists do not know what causes RA despite extensive efforts to understand the earliest stages of this disease.
Some RA research has focused on understanding what triggers the development of the antibodies and T cells that attack the joints. Several studies have suggested that the production of joint-targeting antibodies starts at mucosal surfaces, such as the lining of the mouth, airways, and gut, more than a decade before symptoms arise and might be stimulated by bacteria at these sites. Until now, however, the bacterial culprit remained unknown.
In the new study, investigators isolated antibody-secreting cells called plasmablasts from the blood of people at risk for RA and found that the antibodies produced by these cells recognized certain bacteria in the gut microbiome of these individuals. The researchers identified a previously unknown bacterial species targeted by these antibodies, which they named Subdoligranulum didolesgii. This bacterium was present in the feces of four out of 24 people who were either at risk for or diagnosed with RA but absent from the feces of 12 healthy people.
The scientists hypothesized that a mucosal immune response to S. didolesgii in the gut might progress to a body-wide immune response. To test their hypothesis, the researchers gave mice an oral dose of the bacterium and monitored their immune and physical responses. The mice developed antibodies and T cells that attacked their joints and led to visible joint swelling. In addition, the immunologic changes that the scientists observed in the mice extended over time from the gut mucosa to sites throughout the body.
Taken together, the findings suggest that in some people with RA, immune responses to S. didolesgii in the gut may trigger the production of antibodies and T cells that circulate throughout the body and attack the joints, leading to chronic inflammation. Thus, it appears that RA may develop because immune-system targets shared by S. didoglesgii and joint tissue have a similar structure or amino-acid sequence.
Didolesgi is the Cherokee word for arthritis or rheumatism and was proposed as the name for the newly discovered bacterium by the study’s first author, Meagan E. Chriswell, B.S., who is an enrolled member of the Cherokee Nation of Oklahoma. Ms. Chriswell, an M.D./Ph.D. candidate in immunology at the University of Colorado Anschutz Medical Campus in Aurora, and Kristine A. Kuhn, M.D., Ph.D., an associate professor of medicine at the university, led the research.
The study was co-funded by NIAID and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, both part of the National Institutes of Health.
Reference: ME Chriswell, et al. Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum. Science Translational Medicine DOI: 10.1126/scitranslmed.abn5166 (2022).