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Pregnant immune system is precisely timed
New research from the March of Dimes Prematurity Research Center at Stanford University, aims to understand why preterm births happened and how they can be prevented. Nearly 10 percent of U.S. infants are born prematurely, arriving three or more weeks early, but physicians have not had a reliable way to predict premature deliveries.
"Pregnancy is a unique immunological state. We find that the timing of immune system changes follows a precise and predictable pattern in normal pregnancy."
Scientists at the Stanford University School of Medicine have completed the first-ever characterization of the meticulously timed immune system changes in women that occur during pregnancy. Their findings are published in Science Immunology and reveal how an immune clock of pregnancy may help predict preterm births.
Although physicians have long known an expectant mother's immune system adjusts to prevent her body from rejecting her fetus, no full investigation of these changes, nor listing of their tightly controlled timing had been done. "Ultimately, we want to be able to ask, 'Does your immune clock of pregnancy run too slow or too fast?'" explained Gaudilliere.
"It's really exciting that an immunological clock of pregnancy exists. Now that we have a reference for normal development of the immune system throughout pregnancy, we can use that as a baseline for future studies to understand when someone's immune system is not adapting to pregnancy the way we should expect," says Nima Aghaeepour PhD, the study's lead author and instructor in Anesthesiology, Perioperative and Pain Medicine."
Prior research at Stanford and elsewhere suggested that inflammatory immune responses may help trigger early labor. If scientists can identify an immune signature of impending preterm birth, they should be able to design a blood test to detect it.
The study used blood samples collected from 18 women who had full-term pregnancies. Each woman gave four blood samples — one during each trimester of pregnancy and one six weeks after delivery. Samples from an additional group of 10 women with full-term pregnancies were used to validate the findings. Researchers used mass cytometry, a technique developed at Stanford, to simultaneously measure up to 50 properties of each immune cell in all of the collected blood samples. They then counted the types of immune cells, assessed what signaling pathways were most active in each cell, and determined how the cells reacted to being stimulated using compounds that mimic infection with viruses and bacteria.
With the advanced statistical modeling technique, introduced for the first time in this study, scientists can describe in detail how the immune system changes throughout pregnancy.
"This algorithm is telling us how specific immune cell types are experiencing pregnancy," Gaudilliere explained. Instead of grouping the women's blood samples by trimester for analysis, the Stanford model treated gestational age as a continuous variable, with the exact time each sample was taken during pregnancy. The mathematical model compared that information with existing literature on how immune cells behave in non-pregnant women. The comparison helped determine which findings were most likely to be important.
The study supported immune features of pregnancy already known. For example, natural killer cells and neutrophils have enhanced action during pregnancy. But, they also uncovered previously unappreciated features, such as the activity of the STAT5 signaling pathway. STAT5 in CD4+T cells progressively increases throughout pregnancy in a precise manner, reaching levels much higher than in nonpregnant individuals. STAT5 helps another group of immune cells, regulatory T cells, to differentiate. Of interest, prior research in animals had also indicated that regulatory T cells are important for maintaining pregnancy.
The next step will be to conduct similar research using blood samples from women who delivered their babies prematurely to see where their trajectories of immune function differ from normal.
"We're especially interested in understanding more precisely what is happening very early and very late in pregnancy," Gaudilliere said. "We'd like to see if there is really a switch we can catch, a sweet spot of deviation from the norm..."
"The immune system does not act in isolation, and we're now very interested in profiling its interplay with other aspects of mothers' biology, such as their genetics, metabolism and the body's microbial communities, to come up with a holistic biological clock of pregnancy," Aghaeepour added.
The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling–based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2–dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.
Other authors of the study: Stanford basic life science research associate Edward Ganio; postdoctoral scholars David McIlwain, PhD, and Mohammad Ghameni, PhD; life sciences researcher Amy Tsai; research nurses Martha Tingle and Robin Okada; Dyani Gaudilliere, DMD, clinical assistant professor of surgery; clinical fellow Quentin Baca, MD, PhD; clinical research coordinator Leslie McNeil; David Furman, PhD, adjunct professor at Stanford's Institute for Immunity, Transplantation and Infection; Ronald Wong, PhD, senior research scientist; Virginia Winn, MD, associate professor of obstetrics and gynecology; Maurice Druzin, MD, professor of obstetrics and gynecology; Yasser El-Sayed, MD, professor of obstetrics and gynecology; Cecele Quaintance, administrative director of the March of Dimes Prematurity Research Center at Stanford; Ronald Gibbs, MD, clinical professor of obstetrics and gynecology; Gary Darmstadt, MD, professor of neonatal and developmental pediatrics; Gary Shaw, DrPH, professor of pediatrics; David Stevenson, MD, professor of pediatrics and director of Stanford's March of Dimes center; Robert Tibshirani, PhD, professor of biomedical data science and of statistics; Garry Nolan, PhD, professor of microbiology and immunology; David Lewis, MD, professor of pediatrics; and Martin Angst, MD, professor of anesthesiology, perioperative and pain medicine. Brice Gaudilliere, Winn, El-Sayed, Shaw, Stevenson, Tibshirani, Nolan and Lewis are members of Stanford's Child Health Research Institute. Scientists from Ghent University in Belgium also contributed to this work.
The research was supported by the March of Dimes Prematurity Research Center at Stanford, the Bill and Melinda Gates Foundation, the Ovarian Cancer Research Fund, the Canadian Institute of Health Research, the International Society for Advancement of Cytometry, the National Institutes of Health (grants 1K23GM111657, 5R01AI10012104, U19AI057229 and 1U19AI100627), the Stanford Child Health Research Institute, the Mary L. Johnson Research Fund, the Christopher Hess Research Fund, and the Food and Drug Administration.
Nolan holds a patent on the mass cytometry technology, which is manufactured by Fluidigm. He also holds equity in Fluidigm.
Stanford's Department of Anesthesiology, Perioperative and Pain Medicine also supported the work.
The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med.stanford.edu/.
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The first and only statistical model of the human immune system during pregnancy
has been created, and may lead to blood tests that can predict premature births.
Image Credit: Science Immunology