New research reinforces the hypothesis that the gut microbiome triggers mucosal and systemic immune responses in patients with rheumatoid arthritis. The research, published in Arthritis & Rheumatology May 2017, found that subgroups of patients with RA have differential immunoglobulin G (IgG) or IgA immune reactivity with Prevotella copri, an intestinal microbe that appears to be specific for the disease.1 These observations “provide evidence of the immune relevance of P copri in the pathogenesis of RA,” the investigators say.
Lead author Annalisa Pianta, PhD, at Massachusetts General Hospital and Harvard Medical School, says the research she and her colleagues conducted found that about half of patients with RA have T and B cell responses to P copri. Their responses were either IgA antibody responses to P copri, “suggestive of a mucosal immune response, or IgG antibodies to the organism, suggestive of a systemic immune response,” Dr. Pianta says.
For the study, the investigators developed an unbiased, discovery-based approach to identify novel, immunogenic T cell epitopes in patients with chronic inflammatory arthritis. They obtained synovial tissue, synovial fluid mononuclear cells or peripheral blood mononuclear cells from five patients to use for isolation of HLA-DR-presented peptides.
Implicated peptides and their source proteins were tested for immunoreactivity in a larger number of patients, which included a cohort with new-onset RA from whom clinical information, peripheral blood mononuclear cells, serum samples and, for some, synovial fluid samples were available. For comparison, researchers obtained serum samples and peripheral blood mononuclear cells from patients with Lyme arthritis. They also used serum samples from patients with other types of arthritis or connective tissue disease as well as from healthy control subjects.
P copri DNA was detected in synovial fluid in three of the five patients tested who were positive for IgG P copri antibodies, Dr. Pianta says. “These responses appeared to be specific for RA and were not found in patients with other rheumatic diseases or in healthy control subjects.” The frequencies of P copri antibody responses were similar in patients with new-onset RA and those with chronic RA, “suggesting that, once initiated, these antibody responses may persist for years,” the researchers reported.
Previous research by Scher et al in 2013 reported an overexpansion of P copri in patients with new-onset untreated RA compared with patients with chronic RA or psoriatic arthritis or healthy controls.2 According to Dr. Pianta, this “implies that gut dysbiosis may lead to gut inflammation or vice versa, but the reasons for dysbiosis are not yet known. Since P copri overexpansion seems to occur primarily in patients with RA, this likely explains why antibody responses to P copri were rarely found in patients with other rheumatic diseases,” Dr. Pianta says.
“In our study, RA patients had either IgG or IgA antibody responses, but rarely both. Patients with P copri antibodies usually had ACPAs [anti-citrullinated protein antibodies], whereas patients with P copri IgG antibodies less frequently had such autoantibodies.
“This suggests that ACPA responses may help initially to control the containment of commensals in the gut, whereas patients lacking ACPA responses may have spread of P copri beyond the gut, accompanied by microbial IgG responses and evidence of P copri DNA in joints,” Dr. Pianta says. The antibody levels to B fragilis and E coli were similar or lower in patients with RA than in patients with other arthritides or in the healthy control group. Also, there was little overlap between patients with P gingivalis antibodies and those with P copri antibodies, she says.
The P copri antibody responses were primarily found in women in this study. In a comparison between the cohorts of new-onset and chronic RA who did or did not have IgG or IgA antibody responses to the microbes, 45 of the 50 patients with P copri antibody responses were female compared with 60 of the 86 patients who lacked those responses.
When information from the two cohorts was combined, P copri-negative patients had a sex ratio of 2.3 to 1 in favor of women, close to the ratio of 3 to 1 that is commonly reported in RA cohorts, according to the investigators. The patients with P copri antibody responses had a female sex ratio of 9:1, which implies the organism may substantially contribute to the female predominance in RA, they said.
“Why the antibody responses were found primarily in women is not yet clear,” Dr. Pianta says. “One possibility is that the gut microbiota may differ between men and women. Additional studies will be needed to clarify this specific aspect.”
Implications for Diagnosis, Treatment
According to Dr. Pianta, research indicates that testing for IgG antibody responses to P copri may help identify patients “who are negative for ACPA and/or rheumatoid factor (RF), thereby supporting the diagnosis in seronegative RA patients. This may help in earlier DMARD [disease-modifying anti-rheumatic drug] treatment for this group of patients.”
The research findings suggest that bowel pathology may be a feature of the disease in a subgroup of patients. P copri “may spread from the bowel in repeated waves over a period of years, perhaps explaining the persistence of antibody responses to P copri in patients with chronic RA,” the investigators say.
“We currently think about RA as an autoimmune joint disease rather than a disease that also involves immune responses to commensal organisms in mucosal sites, including those in the gut or mouth,” Dr. Pianta says. “Proof of concept opens new possibilities for treatment. For example, targeted antibiotic regimens, probiotics or diet alterations may come to have an adjunctive role in treatment of RA, in addition to DMARD therapy. However, further study will be required before such interventions can be recommended.”
The next step in research, according to Dr. Pianta, is gaining a better understanding of the nature of gut dysbiosis and how it is linked to joint pathology. “For example, it will be important to determine whether molecular mimicry between microbial and host T cell epitopes may link mucosal and joint immune responses,” she says.
Kathy Holliman, MEd, has been a medical writer and editor since 1997.
References
- Pianta A, Arvikar S, Strle K, et al. Evidence of the immune relevance of Prevotella copri, a gut microbe in patients with rheumatoid arthritis. Arthritis Rheumatol. 2017 May;69(5):964–975.
- Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013 Nov 5;2:e01202.