Scientists exploring inflammation in rheumatoid arthritis make unexpected discovery

BOSTON -- What makes joints in people with rheumatoid arthritis, and related conditions like Lyme disease or lupus, so susceptible to attack by the body's immune system, leading to painful flare-ups and deterioration? The answer may surprise you.

The answer did surprise investigators at Joslin Diabetes Center and Massachusetts General Hospital (MGH) in Boston, who gained a novel insight into this question in a recent collaborative study. Their report appeared in the January 29 online issue of Nature Immunology, and is scheduled to appear in the February print edition.

Working with an animal model of rheumatoid arthritis, the researchers discovered that histamine, a small molecule usually associated with asthma and allergy, is produced as part of the inflammatory process during the development of arthritis. Histamine made the blood vessels surrounding the joints especially vulnerable to leakage, and thereby rendered the joints more susceptible to inflammatory attack. The researchers believe that this is true not only in rheumatoid arthritis, but perhaps also in other autoimmune conditions with which arthritis is associated, such as lupus, and in some infectious diseases, like Lyme disease.

"For patients with rheumatoid arthritis, these new findings raise the possibility that medications designed to prevent the blood vessels from becoming leaky might one day be used to delay the onset of arthritis or to prevent flare-ups of disease," said Christophe Benoist, M.D., Ph.D., who led the study together with Diane Mathis, Ph.D., and Ralph Weissleder, M.D., Ph.D. Drs. Mathis and Benoist head Joslin?s Section on Immunology and Immunogenetics, hold the William T. Young Chair in Diabetes Research at Joslin, and are Professors of Medicine at Harvard Medical School. Dr. Weissleder heads the Center for Molecular Imaging Research at MGH and is a Professor of Radiology at Harvard Medical School.

While the Joslin lab focuses its work on type 1 diabetes, arthritis has several related mechanisms. Like type 1 diabetes, rheumatoid arthritis is an autoimmune disease, in which the body's immune system attacks itself as though fighting off an enemy invader.

The Arthritis Foundation reports the number of Americans with arthritis or chronic joint symptoms has risen from 35 million to 66 million (nearly 1 in 3 adults) in 2005. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the lining, or synovium, of the joints. It is one of the most severe forms of arthritis and can lead to long-term joint damage, resulting in chronic pain, loss of function and disability. RA affects 1 percent of the U.S. population or 2.1 million Americans, mostly women.

In their study, the researchers developed a new microscopic imaging method to visualize changes in blood vessel permeability in anesthetized mice. Within minutes following the delivery of arthritis-causing antibodies to the mice, the blood vessels around the joints became temporarily leaky, making it easier for the antibodies to enter the joint spaces. There, the antibodies set off a cascade of inflammatory cells and molecules, eventually resulting in arthritis.

"The big surprise was that the other blood vessels throughout the body did not become leaky, suggesting that there is something special about the vessels in the joints," says Bryce Binstadt, M.D., Ph.D., of Joslin and Children's Hospital Boston, lead author on the study.

In trying to identify the special feature, the investigators made the even more unexpected discovery that histamine was responsible for the joint blood vessel leakiness -- in fact, the researchers could mimic the effect of the antibodies on blood vessel leakiness by just injecting histamine.

Other researchers participating in the study included Pratik R. Patel, Herlen Alencar, M.D., and Umar Mahmood, M.D., Ph.D., of the Center for Molecular Imaging Research, Massachusetts General Hospital; Peter A. Nigrovic, M.D., of Children's Hospital and Brigham and Women?s Hospital, Boston; and David M. Lee, M.D., Ph.D., of Brigham and Women's Hospital.

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This work was funded by grants from the National Institutes of Health. Dr. Binstadt is supported by a Pfizer Postdoctoral Fellowship in Rheumatology/Immunology.

To view this press release online, which includes an image related to this study, click on the following link: http://www.joslin.org/1083_3262.asp

About Joslin Diabetes Center
Joslin Diabetes Center, dedicated to conquering diabetes in all of its forms, is the global leader in diabetes research, care and education. Founded in 1898, Joslin is an independent nonprofit institution affiliated with Harvard Medical School. Joslin research is a team of more than 300 people at the forefront of discovery aimed at preventing and curing diabetes. Joslin Clinic, affiliated with Beth Israel Deaconess Medical Center in Boston, the nationwide network of Joslin Affiliated Programs, and the hundreds of Joslin educational programs offered each year for clinicians, researchers and patients, enable Joslin to develop, implement and share innovations that immeasurably improve the lives of people with diabetes. As a nonprofit, Joslin benefits from the generosity of donors in advancing its mission. For more information on Joslin, call 1-800-JOSLIN-1 or visit http://www.joslin.org/.

About Massachusetts General Hospital
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women?s Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services. For more information, visit http://www.massgeneral.org/.


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