SAN FRANCISCO — An unfortunate legacy of pregnancy seems to leave women more vulnerable than men to dangerous and disabling autoimmune disorders, including diabetes and multiple sclerosis, scientists report.
In a symposium concerning the self-destructive illnesses--held here earlier this month during the annual meeting of the American Assn. for the Advancement of Science--researchers from four major medical centers offered evidence that bearing children can "seed" a woman's body with cells left over from the fetus. These leftover cells circulate for years in the woman's body, apparently triggering many of the so-called autoimmune diseases, in which the immune system mistakenly attacks the cells and organs.
The presence of the remnant fetal cells could explain why there is such a large difference in the incidence of immune disorders between the sexes. They seem to trigger autoimmunity because half of the genes in the fetal cells are "foreign," contributed by the father.
"Almost all of these diseases are more common in women--by about 75%," said Dr. Noel Rose, a specialist in autoimmunity from the Johns Hopkins Medical Institutions. A few of these disorders, especially diabetes and multiple sclerosis, can be fatal. "So it is not a minor problem" in terms of public health, Rose said.
Even in this era of enormous medical progress, autoimmunity "is a central mystery" still confronting the medical profession, he said.
A discovery that may help resolve the mystery is that "pregnancy is an act of mini-gene transfer," Dr. J. Lee Nelson said.
Half of the genes in the fetal cells "are genes you get that aren't your own," she said. So during pregnancy, women "are exposed to cells from the child, and these can engraft [in her body] and persist indefinitely. Ten, 20 or 30 years later you can still find cells from the babies" in a woman's bloodstream.
For example, she said, studies found that women with the skin disease scleroderma had significantly higher levels of fetal cells circulating in their blood decades after pregnancy than mothers who were unaffected by the disease.
Nelson, from the University of Washington in Seattle, was careful to point out that this association of leftover fetal cells with scleroderma does not prove a cause-and-effect relationship.
Still, such research may soon lead to an explanation for why the autoimmune diseases strike women much more often than men.
According to Rose, the male-to-female ratio for autoimmune diseases is essentially equal during childhood and youth. But later, after sexual maturity, the statistics show such disorders occurring more commonly in women.
For example, "thyroiditis is about equal if it occurs before puberty," he added. "But the women begin to pull ahead later" as they live through their reproductive years.
So, in essence, Rose said, the leftovers from pregnancy seem to account for part of the discrepancy between males and females, but not for all of the difference.
The possibility of a relationship arises because the fetus' cells --containing genes from the father--make the mother's immune system constantly encounter "non-self" genetic signals. So Nelson thinks this means that "pregnancy is an immunological event. It is exposure to a body that is half foreign," and it may be triggering an autoimmune response.
Research has also shown, Nelson said, that the transfer of individual cells between the mother and the infant goes both ways, meaning that some of the mother's cells also get into the fetus.
In addition, a fetus can get some cells from a twin, even a twin who never gets born. This occurs when twin embryos get implanted in the womb but one dies very early. The remaining fetus may end up carrying a few cells from the missing sibling.
Because of recent research into the genetics of autoimmunity, scientists are coming to suspect that the presence of the fetus' "foreign" genes may play some role in causing the self-destructive disorders.
The most important players among the genes seem to be the so-called cellular compatibility genes, those that are involved in rejecting foreign proteins, including implanted organs. These genes are critical for determining whether the immune system "sees" tissues in the body as either "self" or "non-self." And cells that are identified incorrectly as non-self become vulnerable to attack by cells of the immune system.
In Type 1 diabetes, the tissue seen as foreign is the small population of insulin-producing Beta cells on the pancreas. In multiple sclerosis, the targets are nerve cells; the autoimmune reaction attacks the myelin protein that surrounds and insulates nerve fibers. And in arthritis, the tissue that is destroyed is the slippery cartilage in joints, the specialized material needed for smooth movements.
The discovery that women carry cells from their offspring offers a vital clue, and Nelson thinks the latest findings have opened up "a wonderful and exciting area" in biomedical research and "may offer new ways to treat such diseases." Use of agents called monoclonal antibodies, for example, may provide a way to shut down certain immune system cells that attack a specific tissue--without shutting down immunity altogether. Experiments in that direction are already underway.
Nelson added that her research is being aimed first at scleroderma because there are no useful treatments, and in the worst cases it can be fatal.
Dr. Denise Faustman, from the Harvard Medical School, described autoimmunity as "the improper attack of white blood cells against self tissues." And, although genes such as those called the HLA locus are known to be important, autoimmunity is not considered an inherited disorder.
In other words, even though one's genes are inherited, the disease is not.