|NATIONAL INSTITUTES OF HEALTH||National Institute of Arthritis and Musculoskeletal and Skin Diseases|
|November 30, 1994||Contact: Elia Ben-Arii
Office of Scientific and
In a novel study on the causes of some forms of arthritis, researchers have now shown in animals that both a bacterial trigger and genetic susceptibility are necessary for the disease to occur. This discovery is the fruit of a research effort that began with a study to determine if a human gene called HLA-B27 was the major cause of a group of rheumatic disorders called spondyloarthropathies.
Earlier studies showed that rats carrying the human HLA-B27 gene develop joint inflammation (arthritis) and other symptoms characteristic of the human spondyloarthropathies. In an article in the December issue of the Journal of Experimental Medicine, researchers now report that when these B27 transgenic rats are raised in a germfree environment, they no longer develop arthritis.
"HLA-B27 is the tightest genetic link to complex, acquired human disease yet known," said Dr. Michael D. Lockshin, acting director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), which helped support this research. "These latest experiments show that, although the gene plays a central role, intestinal bacteria are needed to cause the arthritis."
HLA-B27 has long been known to be a marker for the spondyloarthropathies. People who inherit the HLA-B27 gene have a markedly increased risk of developing one of these disorders, which can affect multiple organ systems.
Four years ago, Dr. Joel Taurog, Dr. Robert Hammer and colleagues at the University of Texas Southwestern (UTSW) Medical Center in Dallas introduced the human HLA-B27 gene into laboratory rats in an attempt to create a model system for studying the role of HLA-B27 in the spondyloarthropathies. To the researchers' surprise, these transgenic rats spontaneously developed a series of symptoms that bear a striking resemblance to the HLA-B27-associated human disorders. These symptoms include joint inflammation, inflammation of the intestine, skin and nail lesions that resemble psoriasis, and male genital inflammation.
The HLA-B27 gene is the molecular blueprint cells use to build the HLA-B27 protein. All cells of an individual bear a characteristic set of HLA protein markers, or tissue types, which play a crucial role in control and function of the immune system. Scientists have known since 1973 that a large number of patients with spondyloarthropathies carry the HLA-B27 gene. In that year, researchers reported that over 90 percent of patients with ankylosing spondylitis have this tissue type. From 50 percent to 80 percent of patients with other types of spondyloarthropathy also carry this marker. In contrast, only about 8 percent of the general population have the HLA-B27 tissue type.
Arthritis researchers believe that many rheumatic diseases result from a combination of genetic factors that determine susceptibility and bacterial or other environmental triggers. Researchers already know that some forms of spondyloarthropathies, termed reactive arthritis, are triggered by certain types of infections, particularly in individuals with HLA-B27. "We knew from studies in humans that there are disease-causing bacteria such as Salmonella that can trigger arthritis. What we didn't know was whether normal gut [intestinal] bacteria could do this," Taurog said. "The ability to raise the HLA-B27 rats in a germfree environment allowed us to test this hypothesis." Normally the large intestine in both humans and rats is full of benign bacteria, but rats raised and kept in a germfree environment do not have any bacteria in their gastrointestinal tract.
Now, Taurog, Hammer and colleagues from UTSW and the University of Wisconsin, Madison, report that when HLA-B27 transgenic rats are raised in a completely germfree environment, the rats no longer develop the arthritis and inflammatory bowel disease, whereas skin and genital inflammation still occur. These results provide strong evidence that normal intestinal bacteria play an important role in the development of B27-associated intestinal and joint inflammation, but not in development of the psoriasis-like skin and nail lesions or genital inflammation.
"This is the epitome of a disease in which there are two crucial elements—genetic and environmental," says Taurog. "Not just pathogenic [disease-causing] bacteria but normal bacteria can apparently trigger the disease. The gut bacterial system is very complex—there are many different types of bacteria," he says. Finding out which types of bacteria trigger arthritis in these rats, and just how these bacteria contribute to the disease process, is the next step. "This gives us a system where we can reduce the variables. We have gone from a highly complex system to one where we can introduce defined types of bacteria one by one and try to reproduce the disease. If we can do this successfully, then we will have made major progress," says Taurog.
Once they find the specific types of bacteria that trigger arthritis, the researchers plan to study the immune response to these bacteria in HLA-B27 rats and in normal rats. A variety of experiments in animals and in the test tube can be done to get at the mechanism by which bacteria trigger disease. Finding this out could lead to development of highly specific treatments to prevent arthritis and intestinal inflammation in people who carry the HLA-B27 gene.
Spondyloarthropathies comprise a spectrum of rheumatic diseases, most of which affect the joints of the spine. Several of these disorders, which cause painful inflammation, predominantly affect young men but also can afflict young women and children. They include ankylosing spondylitis, which can lead to stiffening and fusion of the spine; juvenile spondyloarthropathy, which affects children and adolescents; reactive arthritis, including Reiter's syndrome, which as noted above follows infection and may strike the urinary or genital tract, eyes, and skin, as well as the spine and large peripheral (nonspinal) joints; arthritis associated with psoriasis; and enteropathic arthropathy, in which inflammation of the bowel (such as Crohn's disease and ulcerative colitis) is almost always accompanied by peripheral joint inflammation.
Support for this research was also provided by the National Institute of Diabetes and Digestive and Kidney Diseases, the Crohn's and Colitis Foundation of America, Glaxo Research Institute, and the Fondo de Investigaciones Sanitarias of Spain.
The researchers at the University of Texas Southwestern Medical Center in Dallas who participated in this work are: Joel D. Taurog, William A. Simmons, Ming Zhou, and José Luis Fernández-Sueiro (Harold C. Simmons Arthritis Research Center); Robert E. Hammer (Howard Hughes Medical Institute); and James A. Richardson (Department of Pathology). The researchers at University of Wisconsin, Madison, are JoAnne T. Croft and Edward Balish.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health, leads and coordinates the Federal research effort in all forms of arthritis by conducting and supporting research projects, research training, clinical trials, and epidemiologic studies, and by disseminating information on research results.
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For more information on spondyloarthropathies:
- Spondylitis Association of America
Sherman Oaks, California
Media Inquiries: (818) 981-1616
Public Information: 1-800-777-8189