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.
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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.