Analyzing blood samples from 21 pregnant women, scientists have mapped the precise timing of changes in immune function and regulation that take place during pregnancy.
The new "immune clock" of pregnancy could guide future researchers as they explore ways to prevent pregnancy-associated disorders, like preterm birth.
Immunological “clock” highlights key immune system features during pregnancy. | Carla Schaffer/ AAAS
"From this type of analysis, we're sort of redefining the timing of pregnancy with immune features, rather than gestational age," said Dr. Brice Gaudilliere, assistant professor of anesthesiology at Stanford University Medical Center, and co-author of the study, presented in the September 1 issue of Science Immunology.
Gaudilliere noted that early labor is a leading cause of infant mortality around the world. "And yet there's no diagnostic test for it," he said. "Now, after having a good understanding of how the immune clock of pregnancy is shared among women, we can perhaps detect how that clock is running early or aberrantly during preterm pregnancy."
During pregnancy, a mother must suppress her own immune system from attacking the fetus, while still maintaining the ability to fight infection — a "seemingly contradictory condition," wrote Pratip K. Chattopadhyay, associate professor of pathology at New York University Medical Center, in a Focus related to the study.
Disrupting this fine balance can result in preterm birth, miscarriage, damage to the fetus and other pregnancy-related complications.
"The immune system is very modular — its cell types and signaling pathways are not acting in isolation — rather, they're working together. So, usually, when one of them is altered, it affects the entire network of immunity," explained head author Nima Aghaeepour, instructor at the anesthesiology department at Stanford University.
Gaudilliere pointed to the way the research was undertaken as a factor in delivering the results. "We're learning that if you take a reductionist approach — how one molecule or signaling pathway may be involved in preterm labor — you kind of run into a dead end. Here, we're proposing a very different approach — really harnessing the power of looking at the entire immune system, multiple signaling pathways and cell types simultaneously, and understanding how these mechanisms all work together and how they eventually interact with other systems within the body," noted Gaudilliere.
After extensively analyzing blood samples from 21 pregnant women during early (one to 12 weeks), middle (13 to 27 weeks) and late (28 to 40 weeks) stages of pregnancy, and at six weeks postpartum, Aghaeepour, Gaudilliere and colleagues identified a total of 984 immune features and 24 immune cell subsets characterizing immune adaptations over the course of pregnancy.
They observed that cell signals responsible for promoting immune responses against the fetus decreased during early pregnancy. During the mid-to-late stages, patterns in adaptive or long-term immunity started to change, such as decreased expression of a critical molecular "switch" that toggles between immune system activation and suppression. The researchers predicted that these changes were related to the mother's effort to tolerate the fetus.
Meanwhile, signals controlling innate or immediate immune responses — the first line of defense against foreign invaders like viruses and bacteria — seemed to stay elevated throughout pregnancy, the researchers found.
The researchers further identified various relationships between multiple cell types and cell signaling pathways, and how they behaved in synchrony over the course of pregnancy. They charted these relationships in massive "webs" of data that visually represent how pregnancy unfolds, from an immunological standpoint.
"We can use this information to detect the abnormal deviation associated with pregnancy-related pathologies. We might even be able to resolve the more simple question of whether you can actually predict the timing of labor in any pregnancies, not just 'normal' ones," said Gaudilliere.
As well, charting the immunological timing of pregnancy may lead the way toward much-needed therapeutic strategies for preterm birth and similar conditions. "In the same way that oncologists have been able to use the power of the immune system to fight cancer, we are hoping that eventually we'll also be able to modify the immune system to improve long-term clinical outcomes during pregnancy," said Aghaeepour.