BERLIN—Interleukin (IL) 23 originating in the gut is a driver of joint inflammation and enthesitis, according to researchers who induced inflammation in mice with overexpression of the cytokine.
The inflammation is a function of IL-23 overproduction and a hypersensitivity of IL-23 at the joints that become inflamed, Jonathan Sherlock, PhD, a researcher at Merck Research Laboratories in Palo Alto, Calif., said here at the European League Against Rheumatism (EULAR) 2012 Annual European Congress of Rheumatology, held June 6–9.
“Our idea is that the gut is producing inflammatory cytokines that circulate and connect with the joint, and we propose that there are tissue resident cells in the joint to account for this,” Dr. Sherlock said during a session highlighting bacteria and autoimmune responses relevant to rheumatology.
The IL-23 findings bring new insight to the link between gut inflammation and joint disease.
“We proposed to look at the enthesis because this is the real focal center of pathology in spondylarthropathy, so it’s different from rheumatoid arthritis,” Dr. Sherlock said.
The prominence of IL-23 can be explained by the misfolding of HLA B27 antigen—which gives rise to IL-23 production—and by the presence of the IL-23 receptor polymorphisms present in joint tissue, Dr. Sherlock suggested. “Either overt inflammatory bowel disease or subclinical ileitis in spondylarthropathy, or perhaps the mucosal infections associated with reactive arthritis, are causing production of IL-23” with the misfolding of HLA B27, he said. These cytokines can circulate and act on tissue resident cells.
Researchers overexpressed IL-23 in adult mice. Enthesitis followed, and, after long-term IL-23 exposure, “extremely destructive arthritis” developed, Dr. Sherlock said.
The development of disease was unaffected even after tumor necrosis factor and IL-6 were blocked, and after CD4 cells were depleted, suggesting that IL-23 is the real driver.
“We propose, therefore, that IL-23 is a unifying factor in spondylarthropathy,” Dr. Sherlock said.
Too Few Bacteria Lead to Problems
Another presentation highlighted the key role of IL-10 in maintaining tolerance to harmless bacteria within the gut—the lack of which can lead to inflammatory bowel disease (IBD), which has genetic links to rheumatoid arthritis and other disorders.
Janneke Samsom, PhD, of the department of pediatric gastroenterology at the Erasmus Medical Center in Rotterdam, the Netherlands, said there has been great progress in recent years in understanding the role of IL-10 in IBD, first in mice and more recently in human patients.
The use of germ-free mice has allowed researchers to see the way in which particular bacteria affect the immune response—and it’s been observed that different bacteria use different mechanisms to achieve the same effect.
In the colon, knocking out IL-10 in the FOXP3 population gives rise to severe inflammation in mice.
It also appears to be just as important in humans. Researchers at Erasmus found that a girl with severe enterocolitis had a mutation within the IL-10 receptor alpha gene. Within samples of her dendritic cells, tumor necrosis factor and IL-6 were not downregulated as in the healthy control cells.
It was also found that IL-10 drastically reduces interferon gamma and IL-17 in the healthy cells, but not in the patient’s cells.
“IL-10 signaling is critical to maintain tolerance…in the human colon,” Dr. Samsom said. She said this could help lead to new insights into the control of TH1 and TH17 cells, which could lead to better-tailored treatments.
A Bigger Role for Bacteria?
John Carter, MD, associate professor and chief of the rheumatology division at the University of South Florida in Tampa, said evidence is emerging that bacteria’s role in reactive arthritis—and even undifferentiated spondylarthropathy in general—might be bigger than researchers have thought.
“One [type of] bacteria can cause a classic triad of symptoms in a certain patient and incomplete or a complete absence of this classic triad of symptoms in another,” he said. “Some patients will have spontaneous remission, some patients will develop chronic disease, all from the same bacteria. So, clearly this is a little more complex than originally thought.”
Ocular serovars might play a big part in Chlamydia-based reactive arthritis, he said. It’s been the prevailing view that the genital serovars were the cause of reactive arthritis because the infection is passed genitally but, “it’s important to remember that very rarely you can actually pass the ocular serovars genitally.”
Researchers at Wayne State University and the University of South Florida analyzed serovars of 36 patients with polymerase chain reaction–confirmed synovial Chlamydia trachomatis and found that they were all ocular serovars, with no genital serovars.1
Dr. Carter noted that there are genetic differences between ocular and genital serovars that might explain ocular serovars’ role in causing arthritis.
“If you think about the clinical symptoms of reactive arthritis, often times you have eye involvement, so perhaps this goes a long way in explaining some of the clinical features,” Dr. Carter said.
These recent discoveries “challenge the notion that these bacteria simply trigger an autoimmune response and do not play a role in disease maintenance,” he says. “And it suggests that perhaps too much emphasis has been placed on the host in terms of disease genesis and maintenance” in post-Chlamydial reactive arthritis.
He also presented evidence suggesting that Chlamydia could be a cause of undifferentiated spondylarthropathy (uSpA).
Researchers at the University of South Florida tested 26 subjects with uSpA for Chlamydia in synovial tissue against 167 controls with osteoarthritis, finding significantly higher levels of Chlamydia in the uSpA patients. Sixty-two percent of them were positive for C. trachomatis, Chlamydophila pneumonia, or both, compared with 12% in the control group.
“Perhaps reactive arthritis can be used as a model for all the spondylarthridities,” Dr. Carter said. “These data suggest a blurring of the line between infection and arthritis.” the rheumatologist
Thomas Collins is a freelance medical writer based in Florida.