Scientists Find Early Clues Into Scleroderma, Develop New Method Of Study

January 06, 1996




Johns Hopkins scientists studying scleroderma may have identified the unique molecular footprints on the biochemical trail leading the immune system to attack its own tissues.

The insight provides major clues into the early stages of the disease and provides a new way to study its development, which may lead to earlier diagnosis and improved treatment, and aid research into other autoimmune conditions, the Hopkins scientists say.

Results are published in the Jan. 6, 1997, issue of The Journal of Experimental Medicine. The study was supported by the Scleroderma Research Foundation.

Scleroderma causes blood vessels to narrow and become irritated; the repeated slowing, stopping and restarting of blood flow produces toxic oxygen products that damage tissues. To investigate how the tissue is damaged and how the immune system is activated, Hopkins scientists used antibodies from the blood of 60 people with scleroderma. They studied the effects of the toxic oxygen products on the specific tissue molecules recognized by the immune system in scleroderma.

Results show that exposure to toxic oxygen products causes certain tissue molecules to break apart, but only in the presence of abnormal amounts of iron, copper, zinc and other metals in the body. Fragmentation of these molecules exposes hidden parts of the molecules that the immune system has never seen. The immune system "sees" the newly exposed parts as foreign invaders and produces antibodies against them. This produces the symptoms of scleroderma.

Scientists pieced together the likely chain reaction activating the immune system by analyzing the circumstances under which the fragments are produced. This reaction centers on the cell's nucleolus, in which both the fragmented molecules and the abnormal amounts of metals become concentrated.

"The autoantibodies (antibodies produced by the immune system that attack the body's own tissue) are a long-lived immunologic memory of this unique reaction," says Antony Rosen, M.D., the study's senior author and an assistant professor of medicine, cell biology and anatomy. "Our novel approach is to use autoantigens (the hidden molecules attacked by the immune system) and autoantibodies as molecular tools to visualize what happens at the start of the disease and to recreate and probe the original circumstances. It serves as a mirror of what is driving the immune system and as a memory of the event that switched on the immune system."

Clinical studies are underway. Hopkins scientists are investigating what causes the abnormal cellular metal accumulation and whether the abnormal metals cause blood vessels to narrow. The team also is studying drugs that might prevent the autoantigens from being fragmented.

Scleroderma, which primarily strikes women between 30 and 60, causes thickening and hardening of the skin and damages arteries, joints and internal organs such as the lungs and kidneys. Its cause is unknown.

Other authors were Livia Casciola-Rosen, Ph.D., and Fredrick Wigley, M.D.

--JHMI--


Johns Hopkins Medicine

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