Study sheds light on why some infants may develop permanent heart damage

November 14, 2003

The study is the first to show that for some infants born to women who produce antibodies commonly found in lupus, maternal circulating cells can migrate to the heart potentially causing a damaging immune response that can lead to permanent heart damage.

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 NewYork 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 some exposed to these antibodies are totally healthy without any heart problems. If babies with this condition have few or no symptoms and many mothers predisposed to give birth to babies with the syndrome have healthy babies. 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 two thirds 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."
Editors' Note -- 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.

Fred Hutchinson Cancer Research Center

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to