Studies Reinvigorate RA Mucosal Origins Hypothesis Studies Reinvigorate RA Mucosal Origins Hypothesis

A newly discovered strain of bacteria could play a role in the development of rheumatoid arthritis, according to findings recently published in Science Translational Medicine.

Mice colonized with a strain of Subdoligranulum bacteria in their gut – a strain previously unidentified but now named Subdoligranulum didolesgii – developed joint swelling and inflammation as well as antibodies and T-cell responses similar to what is seen in RA, researchers reported.

Dr Kristine Kuhn

“This was the first time that anyone has observed arthritis developing in a mouse that was not otherwise immunologically stimulated with an adjuvant of some kind, or genetically manipulated,” said Kristine Kuhn, MD, PhD, associate professor of rheumatology at the University of Colorado at Denver, Aurora, who led a team of researchers that also included investigators from Stanford (Calif.) University and Benaroya Research Institute in Seattle.

The findings offer the latest evidence – and perhaps the most compelling evidence – for the mucosal origins hypothesis, the idea that rheumatoid arthritis can start with an immune response somewhere in the mucosa because of environmental interactions, and then becomes systemic, resulting in symptoms in the joints. Anti-citrullinated protein antibodies (ACPA), hallmarks of RA, have been found at mucosal surfaces in the periodontium and the lungs, and there have been reports of them in the intestine and cervicovaginal mucosa as well.

The latest findings that implicate the new bacterium build on previous findings in which people at risk of RA, but without symptoms yet, had an expansion of B cells producing immunoglobulin A (IgA), an antibody found in the mucosa. A closer look at these B cells, using variable region sequencing, found that they arose from a family that includes both IgA and IgG members. Because IgG antibodies are systemic, this suggested a kind of evolution from an IgA-based, mucosal immune response to one that is systemic and could target the joints.

Researchers mixed monoclonal antibodies from these B cells with a pool of bacteria from the stool of a broad population of people, and then pulled out the bacteria bound by these antibodies, and sequenced them. They found that the antibodies had bound almost exclusively to Ruminococcaceae and Lachnospiraceae.

They then cultured the stool of an individual at risk of developing RA and ended up with five isolates within Ruminococcaceae – “all of which belonged to the Subdoligranulum genus,” Kuhn said. When they sequenced these, they found that they had a new strain, which was named by Meagan Chriswell, an MD-PhD candidate and member of the Cherokee Nation of Oklahoma, who chose a term based on the Cherokee word for rheumatism.

Researchers at Benaroya then mixed this strain with T cells of people with RA, and those of controls, and only the T cells of those with RA were stimulated by the bacterium, they found.

“When intestines of germ-free mice were colonized with the strain, we found that they were getting arthritis,” Kuhn said. Photos of the joints show a striking contrast between the swollen joints of the mice given Subdoligranulum didolesgii and those injected with Prevotella copri, another strain suspected of having a link to RA, as well as with another Subdoligranulum strain and a sterile media. Kuhn noted that the P. copri strain did not come from an RA-affected individual.

“We thought that our results closed the loop nicely to show that these immune responses truly were toward the Subdoligranulum, and also stimulating arthritis,” she said.

The researchers then assessed the prevalence of the strain in people at risk for RA or with RA, and in controls. They found it in 17% of those with or at risk for RA but didn’t see it at all in the healthy control population.

Kuhn and her research team, she said, are now looking at the prevalence of the strain in a larger population and doing more investigating into the link with RA.

“Does it really associate with the development of immune responses and the development of rheumatoid arthritis?” she said.

Potential Etiologic Role of P. copri

Another paper, published in Arthritis & Rheumatology by some of the same investigators a week before the study describing the Subdoligranulum findings, tried to ascertain the point at which individuals might develop antibodies to P. copri, which for about a decade has been suspected of having a link to the development of RA.

They found that those with early RA had higher median values of IgG anti–P. copri (Pc) antibodies, compared with matched controls. People with established RA also had higher values of IgA anti-Pc antibodies. Those with ACPA, but not rheumatoid factor (RF), showed a trend toward higher IgG anti-Pc antibodies. Those who were ACPA-positive and RF-positive had significantly increased levels of IgA anti-Pc antibodies and a trend toward higher levels of IgG anti-Pc antibodies, compared with matched controls.

The findings, according to the researchers, “support a potential etiologic role for this microorganism in both RA preclinical evolution and the subsequent pathogenesis of synovitis.”

Kuhn and others in the field say it’s likely that many microbes play a role in the development of RA, and that the P. copri findings only add evidence of that relationship.

“Maybe the bacteria are involved at different parts of the pathway, and maybe they’re involved in triggering different parts of the immune responses,” she said. “Those are all to be determined.”

Dr Dan Littman

Dan Littman, MD, PhD, professor of rheumatology at New York University, who wrote a commentary reflecting on the findings of the Subdoligranulum study, said the results are “another piece of data” adding to the evidence base for the mucosal origins hypothesis.

“It’s by no means proven that this is the way pathogenesis in RA can occur, but it’s certainly a very solid study,” said Littman, who with colleagues published findings in 2013 linking P. copri to RA. “What makes it most compelling is that they seem to be able to show some evidence of causality in the mouse model.”

Before the findings could lead to therapy, he said, more evidence is needed to show that there is a causal link, and on the mechanism at work, such as whether this is something that occurs at the outset of disease or is something that “fuels the disease” by continually activating immune cells contributing to RA.

“If it’s only something that’s involved in the initiation of the disease, you need to catch it very early,” he said. “But if it’s something that continues to provide fuel for the disease, you may be able to catch it later and still be effective. Those are really critical items.”

Eventually, if these questions are answered, bacteriophages could be developed to snuff out problematic strains, or the regulatory response could be targeted to prevent the activation of the B cells that give rise to autoimmunity, he suggested.

“There are multiple steps to get to a therapeutic here, and I think we’re still a long ways from that,” he said. Still, he said, “I think it’s an important paper because it will encourage more people to look at this mechanism more closely and determine whether it really is representative of what happens in a lot of RA patients.”

The study in Science Translational Medicine was supported by grants from the National Institutes of Health, a Pfizer ASPIRE grant, and a grant from the Rheumatology Research Foundation. The Arthritis & Rheumatology study was supported in part by grants from the National Institutes of Health; the American College of Rheumatology Innovative Grant Program; the Ounsworth-Fitzgerald Foundation; Mathers Foundation; English, Bonter, Mitchell Foundation; Littauer Foundation; Lillian B. Davey Foundation; and the Eshe Fund. None of the researchers in either study had relevant financial disclosures. Littman is scientific cofounder and member of the scientific advisory board of Vedanta Biosciences, which studies microbiota therapeutics.

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