SEATTLE — Nov. 17, 2003 — A new study may shed light on why some infants born to women who produce antibodies commonly found in lupus patients develop an autoimmune disease that can cause permanent heart damage. The study was published in the Nov. 15 issue of The Lancet.
The study, led by Dr. Anne Stevens, a researcher at Fred Hutchinson Cancer Research Center, looked at infants who died of heart block, a particularly severe form of the disease, known as neonatal lupus syndrome.
Stevens and colleagues at the University of Washington in Seattle and the Hospital for Joint Diseases in New York found that each newborn's heart was partly made up of cells from their mother that had transferred during pregnancy.
The study is the first to show that circulating cells from the mother — which the scientists suspect to be stem cells that normally regenerate only blood tissue — can migrate to the heart, where they develop into heart muscle. The researchers 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 at Fred Hutchinson in the laboratory of Dr. Lee Nelson. "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 most infants exposed to these antibodies are totally healthy without any heart problems. If we can answer these questions, it may help us to develop a way to intervene in order to prevent damage to the baby's heart."
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 own body. The syndrome is the most common of three autoimmune diseases known to affect newborn babies, and 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 these infants whose disease affects the heart die of the syndrome, while the other live normal lives with pacemakers that are inserted shortly after birth or 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.
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. Although women with lupus as well as those who suffer from another autoimmune disorder — known as Sjogren's syndrome — produce the two antibodies, they can also be found in women with no symptoms, but may develop it later in life. The anti-Ro and anti-La factors 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 two percent of the women with the antibodies give birth to babies with heart block. The percentage for skin rash may be similar, but is unknown.
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. All autopsy records and tissue samples were provided by Children's Hospital and Regional Medical Center in Seattle 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.
According to Stevens, it is not yet known how the maternal cells came to be incorporated into the fetal hearts.
"The cells that pass from mother to fetus are assumed to be circulating cells, which are presumably blood cells," said Stevens. "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 Fred Hutchinson Cancer Research Center, 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.
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."
This study was funded by the National Institute of Allergy and Infectious Diseases. Additional support was provided by National Institute of Arthritis and Musculoskeletal and Skin Diseases to the National Research Registry for Neonatal Lupus. Co-authors on the study were 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 and researcher at the Hospital for Joint Diseases in New York where she directs the Research Registry for Neonatal Lupus; and Dr. J. Lee Nelson a rheumatologist and researcher at Fred Hutchinson Cancer Research Center.
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Fred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical and research partners, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 38 nationwide. For more information, visit the center's Web site at www.fhcrc.org.