The Immune System and Pregnancy Complications

Many researchers have been investigating how to prevent miscarriages, stillbirths, and other pregnancy complications. In a study published today in Cell Reports, researchers show that a mother’s immune system behaves differently between a first and second pregnancy, and may play a role in pregnancy complications.

“We don’t understand at a cellular and molecular level what causes miscarriages or preterm births, mainly because we don’t know how pregnancy works normally,” says senior author Sing Sing Way of Cincinnati Children’s Hospital Medical Center.

A mother’s immune system is altered during pregnancy to prevent a fetus from being rejected by the body. It is a delicate immunological balance that, if disrupted, could cause a miscarriage or multiple miscarriages. And unfortunately, that balance too often becomes disrupted by environmental exposures or physiological changes that lead to pregnancy complications.

“First and subsequent pregnancies work very differently and understanding these differences can lead to improved therapies that target the unique immunological perturbations that occur in first and later pregnancies,” Way explains. He and his team show in their new study that the immune pathways that promote a healthy first pregnancy are not the same pathways that promote later pregnancies.

The authors discuss how pregnancy causes physiological exposure (and often re-exposure) to foreign fetal allo-antigens, which are expressed by the developing fetus. These allo-antigens interact directly with the mother’s immune system. The consequences after pregnancy are highly varied, they note.

The researchers found evidence of both alloimmunization where the immune system attacks and expanded tolerance phenotypes where it does not. Their data show that pregnancy primes accumulation of fetal-specific maternal CD8+ T cells, and that mothers remember their babies immunologically in that these cells persist as an activated memory pool after she gives birth.

Expression of two proteins, PD-1 and LAG-3, by memory T cells reminds the cells to again be tolerant of the developing fetus again during subsequent pregnancies. But molecular disruptions that neutralize expression of these proteins unleash the activation of fetal-specific CD8+ T cells, causing miscarriage selectively during subsequent—but not first—pregnancies.

Image: This illustration outlines the delicate physiological balancing act a mother's immune system must pull off to prevent a fetus from being rejected by the body. Image courtesy of Cincinnati Children's.