A precarious bond before birth

A new Clinical Research Division study is the first to show that circulating cells that pass from a pregnant mother to her unborn child can migrate to the fetal heart, where they develop into heart muscle. Researchers suspect that the transferred cells are likely to be stem cells that normally regenerate only blood tissue.

The findings emerged from an analysis led by Dr. Anne Stevens and colleagues of infants who died of a severe form of a rare autoimmune disease known as neonatal lupus syndrome, which in a fraction of cases causes permanent heart damage. The disease occurs in some children born to women who produce antibodies often found in patients with lupus and other autoimmune diseases.

The hearts of each of the newborns who died consisted partly of cells that had transferred from their mother during pregnancy. The scientists do not yet know whether the maternal cells trigger a destructive immune response by the unborn fetus, leading to heart inflammation, or whether the maternal cells migrate to the heart in an attempt to repair existing damage.

"We don't know if the maternal cells are harmful or helpful in these infants," said Stevens, a research associate in Dr. Lee Nelson's laboratory and a pediatric rheumatologist. "Maternal cells routinely pass into the fetus during pregnancy, and in most cases cause no harm.

"What we'll need to determine next is whether in fact these cells actually contribute to the onset of this disease, and if so, under what circumstances, since some babies exposed to these antibodies are totally healthy without any heart problems. If we can answer these questions, it may help us develop a way to intervene to prevent damage to the baby's heart."

The study appears in the Nov. 15 issue of The Lancet. Co-authors are Heidi Hermes, a technician in Nelson's lab; Dr. Joe Rutledge, professor of laboratory medicine at the University of Washington and Children's Hospital and Regional Medical Center; Dr. Jill Buyon, a rheumatologist at the Hospital for Joint Diseases in New York; and Nelson. The research received funding from the National Institute of Allergy and Infectious Diseases and the National Institute for Arthritis and Musculoskeletal and Skin Diseases, which provides support for the National Research Registry for Neonatal Lupus, directed by Buyon.

Like other autoimmune diseases, neonatal lupus syndrome is caused by an inappropriate reaction of the immune system against the tissue of one or multiple organs in a person's body. The syndrome is the most common of three autoimmune diseases known to affect newborn babies. Symptoms can range from mild rashes that disappear shortly after birth to severe heart damage that results from inflammation and scarring. About one fifth of infants whose disease affects the heart die of the syndrome, while the others live normal lives with pacemakers that are inserted shortly after birth or at some point later in life.

Scientists do not know why some individuals develop autoimmune diseases-which include disorders such as lupus, multiple sclerosis and rheumatoid arthritis-although they suspect that a genetic component may be involved. Previous work from Nelson's laboratory has found an association between the autoimmune disease scleroderma and the presence of trace fetal cells that persist in women who have borne children as well as women and men who harbor cells from their own mothers.

Autoimmune antibodies

Neonatal lupus syndrome can develop in the unborn children of women whose immune systems produce two antibodies-called anti-Ro and anti-La-which react against two proteins found in the cells of all individuals. Women with lupus and another autoimmune disease called Sjogren's Syndrome produce the two antibodies, which may also be found in women who are clinically well but who may develop either disease later in life. The anti-Ro and anti-La antibodies can pass from the mother to the fetus, although the presence of the antibodies alone, in either the mother or fetus, is not sufficient to trigger disease in the unborn child. Only about 2 to 5 percent of women who produce the anti- bodies give birth to children with the heart damage.

To determine whether maternal cells might play a role in neonatal lupus syndrome, Stevens and colleagues identified four male infants that had died prior to or shortly after birth from heart damage and whose mothers produced anti-Ro and anti-La antibodies. They also identified four control infants who had died of other causes. Children's Hospital and Regional Medical Center provided the autopsy records and tissue samples after families consented to participate in the study. Male infants were chosen so that maternally derived cells, which contain two X chromosomes, could be easily distinguished from the infant cells, which have one X and one Y chromosome.

Researchers found maternal cells in 15 of 15 tissue sections of heart from babies who had died of the autoimmune disease but only in two of eight sections from the control infants. The maternal cells were present at much higher levels in the neonatal lupus hearts than in controls. Most of the maternal cells produced proteins characteristic of heart muscle.

Stevens said researchers do not know how the maternal cells incorporated into the fetal hearts.

"The cells that pass from mother to fetus are assumed to be circulating cells, which are presumably blood cells," she said. "We think that the cells that are developing into heart tissue are hematopoietic stem cells, which normally give rise to immune-system cells."

Several recent studies, including one published by Dr. Charles Murry, an associate professor of pathology at the University of Washington, and Dr. David Myerson, a pathologist in the Clinical Research Division, have found that heart tissue can be regenerated from cells outside of the heart. The study involved male heart transplant recipients who had received donor hearts from females but were later found to have reconstituted heart tissue comprised of male cells that presumably had originated from non-cardiac tissue in the transplant recipient. Stevens' study is the first to demonstrate that circulating maternal cells during pregnancy can reconstitute heart tissue in the fetus.

Stevens said that if the maternal cells are what provoke a harmful immune response from the fetus, researchers may someday be able to block the damage by creating antibodies that target and destroy the maternal cells before the baby's immune system can mount a response.

A scientific mystery

To further analyze the onset of neonatal lupus syndrome, Stevens is now conducting a study of twins and triplets in which only one of the siblings develops the disease as well as examining whether other organ systems besides the heart may be affected.

"We also hope to address why some autoimmune disease symptoms don't occur until the children get older," she said. "Based on studies of stem cell transplantation, we suspect that the maternal cells are preferentially regenerated when an organ repairs damaged tissue and that this larger population of maternal cells may be enough to stimulate an 'autoimmune' reaction in the child."

Stevens said that it is a great scientific mystery as to why there is so much cell circulation between mother and fetus.

"It may be that the passage of cells helps to prime the baby's immune system-which would be a beneficial event," she said. "But for reasons we still have yet to discover, in some individuals, it may cause disease."