MEDICINE: ARTHRITIS : Study of Rats Links Disease to Defect in Brain’s Stress Response
Individuals who are calm and easygoing, unflappable in the face of a crisis, may be more susceptible to arthritis than those who are more excitable, according to a new study by researchers at the National Institutes of Health.
The researchers have traced arthritis susceptibility in rats to a defect in the brain’s regulation of the stress response, the first time the crippling disease has been linked to temperament or behavior.
If their discovery, recently reported in the prestigious Proceedings of the National Academy of Sciences, is confirmed in human studies that are now beginning, it may lead to new ways to screen for arthritis susceptibility and to new treatments directed at stress-sensitive brain circuits.
The discovery is “a very significant observation” that may also have widespread application in the study of other “autoimmune” diseases such as diabetes and multiple sclerosis in which the immune system attacks its host, said endocrinologist Allan Munck of Dartmouth College in Hanover, N.H.
Arthritis, which is characterized by swelling or deterioration of the joints, aches, stiffness and fatigue, is the nation’s primary crippler. More than 1 million Americans develop arthritis each year and an estimated 35 million--one in every seven Americans--suffer its symptoms. It is two to three times as common among women as among men.
Together, the various forms of arthritis account for 27 million lost workdays annually and cost the U.S. economy an estimated $8.6 billion per year, including $4.4 billion in hospital and nursing home services, according to the Arthritis Foundation.
Scientists have long known that certain genes associated with the immune system create a predisposition to arthritis, in which white blood cells severely damage the protective membranes surrounding the joints. Environmental insults to the body--the pounding on the joints caused by jogging, for instance--also trigger arthritis.
Some people with genetic susceptibility do not develop the disease, however, and researchers have long believed that some other factor must be involved. The NIH researchers now believe that they have identified that factor.
Rhematologists Esther M. Sternberg of the National Institute of Mental Health and Ronald L. Wilder of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md., have been working with two strains of rats, one of which is highly susceptible to arthritis and one that isn’t.
When cell walls of streptococcus bacteria are injected into the joints of the one strain of rats, called the Lewis strain, white blood cells from the immune system attack the joints as well as the injected cellular material. They produce swelling and inflammation leading to an arthritis that is “remarkably similar to the human disease,” Wilder said.
But when the same bacterial material is injected into another strain, called the Fischer strain, little or no inflammation occurs and the rats remain healthy. Wilder and others have been searching for many years for the biochemical difference between these two strains of rats in the belief that the knowledge could hold a clue to understanding human arthritis.
Sternberg, in contrast, has been examining ways in which the brain might be involved in arthritis. One way is in the production of hormones called corticosteroids, which are the most potent naturally occurring suppressors of inflammation. The synthetic corticosteroid cortisone, for example, has been used to treat arthritis since the 1940s.
Corticosteroids are produced by the adrenal glands, walnut-sized organs that sit atop the kidneys, in response to a chemical signal secreted by the part of the brain known as the hypothalamus. That signal is a hormone called CRH.
Sternberg’s contribution was the recognition that this process of controlling the immune response is stimulated by production of CRH in response to a chemical released by the white blood cells at the site of the inflammation.
To test the theory, Sternberg and Wilder gave the rats a chemical that blocked CRH production at the same time that they injected the rats with bacterial cells. Within hours after the injection, the arthritis-resistant Lewis rats began getting developing arthritis. By stopping CRH production, the researchers had removed normal restraints on the rats’ immune systems, and they were ravaged by their own runaway immune responses.
Subsequent research showed that the arthritis-prone Fischer rats had a similar, naturally occurring block in CRH production that caused arthritis. “Although the disease is in the joints, the defect is in the brains,” Wilder said.
The defect lies in the region of the brain that controls the animals’ response to stress. The researchers do not yet know if the defect causes any behavioral abnormalities in the Fischer rats because no one had thought to look for such abnormalities before. But Wilder is looking now.
Meanwhile, the researchers are designing studies to determine if the same type of defect--where there is an inadequate response to stress--is present in the brains of humans who develop or are susceptible to arthritis.
“You run into people who panic under trivial conditions,” Wilder said. “Others, nothing seems to upset them.” Those differences in response might be linked to the same type of defect observed in the mice.
The brain defect may also play a role in other autoimmune diseases, such as multiple sclerosis. The arthritis-prone Fischer rats can develop a disease very much like MS if they are injected with ground-up nerve tissue. And British researchers have recently shown that naturally occurring corticosteroids can induce a spontaneous remission from the experimentally induced disease, indicating a link between the brain and immune systems.
Wilder and Sternberg are encouraged about the possibility that a brain defect will be found in humans because NIH researchers have recently shown that defects in CRH production can cause depression, and persistent depression has long been associated with arthritis.
“A number of drugs that they use to correct depression . . . really do reset the immune response,” Wilder said. The new results, he added, “give us new impetus to look at a large variety of drugs, some in use and some sitting on the shelves of research labs at pharmaceutical companies. This gives us a whole new way of attempting to correct arthritis susceptibility.”
Clue to Arthritis’ Cause
Researchers create arthritis in susceptible rats by injecting them with bacterial cell walls. The rats have a brain defect that prevents the synthesis of a hormone called CRH, and white blood cells proliferate freely, damaging the joint. In healthy rats, the process works this way: 1. When researchers inject cell walls into rat joints, white blood cells attack the foregin invader. They also release interleukin-1, which travels to the brain. 2. Interleukin-1 stimulates the brain to secrets CRH. 3. CRH stimulates the adrenal gland to secrete steroids, such as cortisone, that suppress white blood cell activity in the joint. The cell walls are destroyed, but no joint damage occurs.
