Researchers hope that the work will ultimately lead to new treatments.
In some women, scleroderma, a potentially life-threatening skin disease that can affect joints and internal organs, may be linked to long-dormant fetal cells stirring an immune system reaction.
Sergio Jimenez, M.D., Dorrance H. Hamilton Professor of Medicine and professor of biochemistry and molecular pharmacology, and his colleagues at Jefferson Medical College of Thomas Jefferson University in Philadelphia, have found evidence suggesting that fetal cells bringing about graft-versus-host-disease (GVHD) reactions may be involved in some cases of systemic sclerosis, a form of scleroderma, an autoimmune disease. Systemic sclerosis strikes about three to eight times more women than men, usually between the ages of 45 and 55. GVHD is a sometimes dangerous complication seen when the body’s immune system rejects a bone marrow transplant.
"What’s unusual is that in classic chronic graft-versus-host disease, the clinical picture looks like scleroderma. The skin becomes hard and thick," Dr. Jimenez says. "These findings may open up some potentially new and important avenues in the treatment of scleroderma." He and his colleagues report their findings April 23 in the New England Journal of Medicine.
Dr. Jimenez and his co-workers examined 69 women with systemic sclerosis who had been pregnant for the presence of the male-specific Y chromosome. A female fetal cell would be virtually impossible to detect with current technology, he points out. They found male DNA in the blood of 32, or 46 percent, of the women. The Y chromosome DNA was present in only one of 25 normal women. The scientists also found Y chromosome sequences in skin biopsies in 11 of 19, or 58 percent, of the women tested. Nine of the 11 women were known to have had male children.
"We were surprised by the high number of women’s skin samples showing the Y chromosome," he says.
But an important question remains: what would activate the chronic GVHD reaction?
"It seems clear that a second event, such as an environmental exposure, is needed. It could be a virus, or radiation, chemicals, toxins--we just don’t know. But the fetal cell-GVHD association would explain why it [scleroderma] is more common in women and why at that age after many women have had children. We’ve known about cells from the baby going to the mother, and vice versa, but we didn’t know cells could survive in the circulation for decades," he says.
The next step, Dr. Jimenez says, is to try to determine whether the fetal cells might actually cause the GVHD, and in turn, systemic sclerosis. "We’re trying to isolate the cells that carry the male chromosome and see what kinds of cells they are," he says.
"We would like to show that those cells are stimulating the pathogenesis of scleroderma. If these foreign cells are involved in the pathogenesis of disease, you can create a vaccine or try some other way to eliminate them from the body.
"The study describes the presence of fetal cell levels in scleroderma, and suggests the possibility that systemic sclerosis can be produced this way. This needs to be explored further."
Some 300,000 Americans have scleroderma, which is actually categorized as two main diseases: localized scleroderma and systemic sclerosis. The former affects only the skin. Systemic sclerosis can affect the internal organs, skin and the body’s small blood vessels. Scleroderma can be devastating; some aggressive forms of the disease can result in death after only a few months.
In autoimmune diseases, the normally protective immune system reacts against the body in abnormal ways. In scleroderma, the immune system interacts with the body’s blood vessels and fibroblasts, cells that help make collagen, resulting in an excess of collagen. No one understands how, but these events lead to the hallmarks of scleroderma: thickened skin and damage to vessels and internal organs.
The work was funded by the National Institute of Arthritis, Musculoskeletal and Skin Diseases, the National Institute of Child Health and Human Development and the Scleroderma Foundation.
Journal
New England Journal of Medicine