Immune system changes during pregnancy are precisely timed

Stanford Medicine| Fri Sep 01 11:31:39 EDT 2017
Immune system changes during pregnancy are precisely timed

With an advanced statistical modeling technique, introduced for the first time in this study, the scientists then described in detail how the immune system changes throughout pregnancy.

“This algorithm is telling us how specific immune cell types are experiencing pregnancy,” Gaudilliere said.

Instead of grouping the women’s blood samples by trimester for analysis, their model treated gestational age as a continuous variable, allowing the researchers to account for the exact time during pregnancy at which each sample was taken. The mathematical model also incorporated knowledge from the existing scientific literature of how immune cells behave in nonpregnant individuals to help determine which findings were most likely to be important. The model improved understanding of the immune system much as mapping software that knows which streets are one-way gives better driving directions. “If there are several models that are statistically equivalent, we are interested in the model that is most consistent with our existing knowledge of immunology,” said Aghaeepour.

The study confirmed immune features of pregnancy that were already known. For instance, the scientists saw that natural killer cells and neutrophils have enhanced action during pregnancy. The researchers also uncovered several previously unappreciated features of how the immune system changes, such as the finding that activity of the STAT5 signaling pathway in CD4T cells progressively increases throughout pregnancy on a precise schedule, ultimately reaching levels much higher than in nonpregnant individuals. The STAT5 pathway is involved in helping another group of immune cells, regulatory T cells, to differentiate. Interestingly, prior research in animals has 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 deliver 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 where deviation from the norm would be maximal with pathology.”

It’s really exciting that an immunological clock of pregnancy exists.

“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 work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

Other Stanford authors of the study are 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.

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.

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