The mother's immune system has to ignore the nine-month embryonic squatter as it grows. (Otherwise, a quick eviction in the form of a miscarriage usually ensues.) But such maternal tolerance can backfire, scientists now say.
Indeed, new evidence suggests that fetal cells left over from pregnancy can linger in a woman's body for decades. When these cells are remnants of the fetus's own developing immune system, they can cause diseases in the mother that were previously thought to be autoimmune, in which the individual's immune system attacks his or her other tissues.
In the April 23 issue of the New England Journal of Medicine, Sergio A. Jimenez and his colleagues at Thomas Jefferson University in Philadelphia report that they found fetal immune cells in skin lesions taken from women with the disorder systemic sclerosis. Taken together with previous studies, the new report is shaking up the standard view among scientists of what causes autoimmune diseases.
Systemic sclerosis affects roughly 150,000 people in the U.S.--mostly women between the ages of 30 and 60. People with a subset of the disease called scleroderma (meaning hard skin) produce excess connective tissue called collagen and develop thickened, taut skin as result. For some, the thickenings are only of cosmetic concern, but in others they restrict movement. In patients with systemic sclerosis, the thickening extends to joints, arteries and internal organs, such as the gastrointestinal tract, lungs, kidneys and heart. Many people with the more aggressive forms of systemic sclerosis die of cardiopulmonary or kidney failure within five years of diagnosis; only about 50 percent live for 10 years afteri their diagnosis.
Researchers have been studying the link between fetal cells and autoimmune disease since 1996, when Diana W. Bianchi of Tufts University and her colleagues reported that not only can women carry fetal cells in their blood for as long as 27 years after pregnancy, but many actually do. Bianchi and her co-workers identified fetal cells in women who had given birth to sons. Because women do not have Y chromosomes, it was easy for the researchers to detect the male fetal cells in the mother's blood simply by looking for DNA sequences from the Y chromosome.
In February, J. Lee Nelson of the Fred Hutchinson Cancer Research Center in Seattle and her colleagues used the same technique to tie fetal cells to scleroderma. In a paper published in the journal the Lancet, Nelson's group reported that women with scleroderma had more than ten times as many fetal cells in their blood as women without the disease.
Nelson and her coworkers concluded that scleroderma is analogous to graft-versus-host disease (GVHD), a possible complication of bone marrow transplantation. In GVHD, immune cells called T-cells from the donor bone marrow attack the tissues of the recipient, causing some of the same symptoms as those seen in systemic sclerosis.
Not everyone accepts that idea. In an editorial accompanying Nelson's Lancet paper, Ken Walsh of Churchill Hospital in Oxford, England, called the similarities between scleroderma and GVHD "peripheral." "There is no proof that any [bone marrow] transplant recipient ever developed scleroderma," he wrote.
But the new report by Jimenez's group strengthens the apparent link between systemic sclerosis and GVHD. Like Nelson's group, the researchers found Y chromosome DNA sequences in the blood of 32 of 69 women with systemic sclerosis and in only 1 of 25 healthy women. Jimenez and his colleagues also found Y chromosome sequences in the skin lesions of 11 of 19 affected women.
Jimenez says that he and his colleagues have early indications that the fetal cells containing the Y chromosome sequences are T-helper cells, which secrete substances called cytokines. Cytokines are chemical messengers that activate the immune system. He speculates that these cells arise from immature fetal stem cells, which cross over into the mother's circulation and then mature. "It's still pretty much a hypothesis that needs to be explored," Jimenez adds. "We need to see how mature the cells we've found are."
If Jimenez and his coworkers are right, it could revolutionize therapy for systemic sclerosis and scleroderma, which now consists of nothing more than blood pressure-lowering drugs to slow kidney damage. Jimenez says that if future studies confirm that fetal T-helper cells are to blame, researchers might one day use cytokine-blocking drugs to treat the diseases. And if they can identify distinguishing molecules on the surfaces of the fetal cells, those molecules could serve as the basis for vaccines that would wake up the mother's immune system and sic it on the foreign cells.
The new study doesn't explain why all women with fetal cells in their circulation--however many that might be--don't get systemic sclerosis. Jimenez acknowledges that environmental factors, such as exposure to toxins, must also play a role. "You must have a second event to activate the fetal T-cells," he says. "The mere presence of the cells can't account for the disease."
Nor does the study suggest what might cause systemic sclerosis among the relatively few men who develop the disease, and exactly how the fetal T-helper cells cause the overproduction of collagen that leads to the skin thickening and other symptoms of systemic sclerosis.
Nevertheless, Jimenez is optimistic that researchers have turned a corner when it comes to understanding systemic sclerosis and scleroderma. "For many years, we've been going in circles studying scleroderma," Jimenez says. "Now it looks like we might just be getting somewhere."