Are you the oldest sibling? Take note – there may be a reason why your mother prefers your younger siblings to you… at least in one sense. Chances are, your mother’s later pregnancies were easier than her first one. This is supported by new research from the laboratory of Sing Sing Way at Cincinatti Children’s Hospital Medical Center, which adds to a growing body of work linking a decrease in pregnancy-associated complications to improved suppression of the maternal immune system during pregnancy.

At first glance, this seems counterintuitive. Decreasing the vigor of the immune system’s response during pregnancy would seem a dangerous invitation to infection. This is why the CDC lists pregnant women among the at-risk populations who should be vaccinated against seasonal influenza. They emphasize that pregnant women are particularly susceptible for flu-related complications such as pneumonia [1].

Immunosuppression may be dangerous in the case of infection. However in pregnancy, a foreign body – a fetus – is growing inside the mother. The mother’s immune system must be trained to accept the foreign paternal material as a non-threat just as it accepts cells and tissue arising from the mother’s own DNA. Complications ranging from spontaneous miscarriage to preeclampsia, a dangerous elevation in blood pressure, may arise when this tolerance is impaired by an inadequately suppressed immune system [2]. Sing Sing Way and colleagues discovered a surprising contributor to improved maternal immunosuppression: a prior pregnancy.

Examining the Immune System

The immune system can be compared to the body’s military. During an injury or an attack by infectious pathogens, physical barriers such as the skin or the mucus membranes that line the respiratory, gastrointestinal, and urogenital tracts act as the first line of defense. Components of the fast-acting innate immune system work to clear away the invaders or damaged tissue quickly and non-specifically when these defenses are breached.

Meanwhile, a more advanced branch of the immune system – the adaptive immune system – designs a targeted strike. The adaptive immune system sends out a specific team of immune cells depending on the nature of attack — bacteria, virus, parasite or fungus. This adaptive branch of the immune system is the branch that develops a memory of past infections. A few of the cells that have been successful in defeating an infection will persist even after the infection is cleared. These are able to rapidly proliferate upon a subsequent challenge by the same pathogen. This immune memory forms the basis for many vaccinations.

In order to prevent inadvertent injury to our own bodies, the immune system must make a key distinction between the body’s own citizens, referred to as ‘self’ tissue, and foreign invaders. Pregnancy, however, blurs the line between self and foreign; a fetus arises from half maternal DNA (self) and half paternal DNA (foreign). As the fetus develops and remodels, it shed particles that are released into the mother’s circulation [3].  These expose her to molecules encoded by the foreign paternal DNA. The mother’s immune system therefore must strike a balance between tolerating this foreign antigen and simultaneously protecting the mother and the developing fetus from infection.

The first pregnancy boosts tolerance

According to the work by Dr. Way and his colleagues, a way that the mother’s immune system manages to walk the fine line between protection and tolerance is by generating a form of tolerant immune memory of the fetal tissue. One of the specific teams of cells that the adaptive immune branch sends out is composed of regulatory T cells or T regs. T regs are crucial for keeping the immune system from over-reacting; they tell the other teams of cells to scale back their response, for example, as an infection is dying down. If one team of cells misguidedly decides to attack a self-tissue, T regs also specific for this self-tissue may help to inhibit that inadvertent attack. This keeps the immune system from continuing to attack when someone’s recovered from a cold, for example, or in most cases from attacking one’s own organs.

The novelty of this work is that in the case of pregnancy, these T regs specifically respond to the fetal antigen released into the mother’s circulation and are crucial for telling the rest of the immune system to avoid attacking the fetus.  A sub-population of these fetal antigen-specific T regs persists after the first pregnancy. During the second pregnancy, these cells rapidly proliferate, thereby suppressing an anti-fetus immune attack more promptly, specifically, and successfully the second time around.

Way and colleagues are paving the way for future examinations of pathological outcomes in pregnancy by elucidating how a pregnancy occurs successfully in the first place.  This work suggests that complications arising from immune hyper-activation could perhaps be mitigated by expanding this population of fetal-specific T regs, and provides hope for increasing both successful birthrates and maternal tolerance to firstborns, in every sense of the word.

Rachel Becker is a graduate student in Immunology at Harvard University.


1. Centers for Disease Control and Prevention, “Seasonal Influenza (Flu): What you should know for the 2012-2013 Influenza Season.” <>

2. Mayo Clinic Diseases and Conditions, “Preeclampsia: Causes.” <>

3. Reviewed in: Munoz-Suano, A., et al (2011). “Gimme Shelter: The immune system during pregnancy.” Immunological Reviews, Vol. 241: 20-38.

Links of Interest

Telis, Gisela. “Mom’s Immune System Primed and Ready for Second Baby,” ScienceNOW. September 26, 2012. <>

Rowe, JH et al., “Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.” Nature Vol 490, October 4 2012.

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