During the fourth week of pregnancy, a woman may just be finding out that she is going to have a baby. The fetus is only the size of a poppy seed. But even this early in development, some of the cells that are busy dividing and specializing will eventually become immune system cells. These early immune system cells, called hematopoietic progenitor cells, have proteins on their surface that allow scientists to identify them as precursors of immune system cells. Early in the pregnancy, these cells divide very rapidly, but as the fetus matures, they decrease in the speed with which they multiply and more of them become specialized cell types. Babies born prematurely tend to have greater quantities of these unspecialized progenitor cells than full-term babies.

The early progenitor cells travel through the blood into organs associated with the immune system, such as the liver, spleen and thymus. By the second or third month of pregnancy, some are already becoming T cells. Although these T cells are functional by the third or fourth month of pregnancy, the sterile environment of the womb does not require the fetal immune system to fend off potential pathogens. This is important because one of the most intriguing aspects of the immune system relates to pregnant women (See “Two immune systems, one body” section below).

Macrophages can be found in the fetal intestine by 11 or 12 weeks of gestation, and quantities increase rapidly during the fourth and fifth months of pregnancy. Likewise, B and T cells can be found in the intestine by about 16 weeks of gestation; and by about 19 weeks of gestation, they are organized into specialized lymph nodes in the intestine, called Peyer’s patches.

Two immune systems, one body

If you have read other pages of the "Human Immune System" section or if you have thought about organ donation, one of the things you may realize is that our immune systems are designed to protect us from outside attacks. This means, the immune system must be able to distinguish between “self” and “non-self.”

Babies are not genetically identical to their mothers, so why doesn’t a woman’s immune system attack this “non-self” entity and reject it as foreign tissue? Scientists have not completely figured this out yet, but they do have some important clues. First, because the fetal immune system does not need to function while in the womb, it can safely be suppressed. Second, fetal cells cross the placenta and circulate in the mother. These cells can be detected in the mom between the fourth and fifth week of pregnancy, and they remain for years, even decades, after she has given birth. The presence of genetically distinct cells in an individual, such as the fetal cells found in a mother, is called microchimerism. This exchange of cells from the fetus to the pregnant woman provides another possible explanation as to why a mother’s immune system does not reject the growing fetus.

And, while it is essential that the fetus grow in an environment in which it is not rejected, this is not without consequence for the developing immune system. These consequences become important once the baby leaves the sterility of the womb and encounters the bacteria-rich environment of the vaginal tract and the unsterile world in which we live.

Transitioning from a sterile to a non-sterile environment

In the period after birth, the newborn’s immune system has two immediate hurdles to clear. First, as mentioned above, in the womb, suppression factors kept the fetus’s immune system from competing with maternal immune responses, but it needs to immediately start working upon birth. Second, the fetus’s immune system has not previously responded to any pathogens. In this regard, it is “antigenically inexperienced,” so it needs to gain experience. While these things are happening, the maternal immune system steps up to help in two ways:

1. Via the placenta — Antibodies generated by the mom’s immune system begin to cross the placenta by the 13 weeks of gestation. However, most of the antibodies cross the placenta late in pregnancy during the third trimester, so they will be plentiful at the time of birth. Because of this late transfer, babies born prematurely tend to have lower levels of antibodies circulating in their blood and are, therefore, more susceptible to infections than full-term newborns. The antibodies transferred across the placenta are mostly IgG (see “Adaptive immune system”). While these antibodies provide important protection, they can occasionally cause harm. For example, sometimes maternal antibodies directed against fetal red blood cell proteins can result in anemia and jaundice in the newborn.
2. Via breast milk — Breast milk delivers protective assistance in the form of antibodies, immune system cells, such as macrophages, and other immune-related factors, such as cytokines.  This is particularly true of the milk produced in the first few days after birth, known as colostrum. Studies have found that each milliliter of colostrum contains up to 3 million cells of which about 1.8 million are macrophages. Over time, the components of breast milk change — playing less of a role in protective immunity and more of a role in nutritional value — although the milk still contains about 100,000 cells per milliliter of which about 60,000 are macrophages.
   
   The antibodies transferred via breast milk are mostly IgA. This makes sense because IgA is the type of antibody important for protecting mucosal surfaces, such as the intestine. As the baby’s digestive tract processes the breast milk, maternal antibodies coat the baby’s intestine helping to fend off gastrointestinal viruses. The antibodies contained in both colostrum, and the breast milk that later replaces colostrum, are about 90% IgA in people. While the breast milk of other mammals also contains IgA, the quantities are lower.

Antibodies that protect the baby, but which were produced in the mother, offer what is known as passive immunity. This relatively short-term help gives the baby’s immune system a chance to start working and finish developing in the period immediately after birth. As these antibodies wane during the first few months of life, the baby’s immune system is ramping up. In this way, mom and baby work together to protect the baby from the many pathogens to which it is exposed in the days and weeks after birth.

The immune system at birth

As described above, we know that at birth, the baby’s immune system has the tools to make an immune response, but we also know that it has some hurdles to clear. So, what does that mean for a baby’s ability to respond to a potential pathogen?

First, and perhaps most importantly, it means that newborns are at increased risk of infection. In fact, about 1 of every 100 bloodstream infections occurs in young infants. And, preterm babies are at even greater risk given that they are lacking some of the protection afforded by maternal antibodies, and their immune systems did not have as much time to mature before birth. This susceptibility is one of the reasons that new parents are advised to contact their child’s doctor immediately if a baby less than 2 months of age develops a fever.

Second, young infants are at greater risk for particular types of infections, particularly infections caused by what are known as encapsulated bacteria, such as Group B Streptococcus (GBS), Staphylococcus, Klebsiella species, Haemophilus influenzae type b (Hib), meningococcus, and pneumococcus. 

Let’s think about this from the perspective of the innate and adaptive immune responses:

Innate immunity at birth

The non-specific immune response is characterized by phagocytic cells, such as neutrophils and macrophages (See “Parts of the Immune System”). While newborns have both of these types of cells, they are limited in quantity. This is particularly true of neutrophils, which are often the first responders against pathogens and a primary component of pus. If a newborn gets an infection, their immune system cannot keep up with the need for additional neutrophils, enabling the pathogen to quickly gain the upper hand. And, while macrophage levels are supplemented to some extent by breast milk, by the time an infection has reached the point of depleting neutrophils, the baby will likely require medical care to overcome the assault.  By about 2 months of age, babies are able to overcome this vulnerability.

Adaptive immunity at birth

Because this part of the immune response is characterized by specificity and because a newborn’s immune system lacks “antigenic experience,” virtually every pathogen is new. At its surface, this means that an immune response driven by antigen-presenting cells, B cells, and T cells will take longer to develop.

But the reality is even more complex. Two types of B cell responses occur. They are called “T cell dependent” and “T cell independent” based on their need for T cell help.

• T-cell dependent B cell responses need T cell help to generate antibodies. Several factors make this process less efficient in newborns:
  • Interactions between antigen-presenting cells and T cells are not as effective in the newborn, so T cells are not as effectively stimulated.
  • As a result, T cells produce lower levels of cytokines, the molecules which direct the adaptive immune response.
  • Further, the ratios of different types of T cells are different in newborns compared with adults. Specifically, newborns have lower levels of cytotoxic T cells which are important for killing cells infected with viruses.
  • Together, these result in lower levels of antibody production.
  • Antibody production in this situation is further hindered by the fact that it is a new immune response, as memory immune responses do not exist in a newborn that has not been exposed to pathogens prior to birth.
• T cell-independent B cell responses do not require T cell help. Rather, B cells are activated by lipopolysaccharides or repeating proteins found on the surface of a pathogen, such as the complex sugars that encapsulate some bacteria. Unfortunately, in newborns, these responses are diminished. This directly relates to a young infant’s increased susceptibility to bacteria, such as meningococcus, pneumococcus and Hib.

What does this mean for vaccines?

So, now you might be wondering, if newborns can’t make good immune responses, why immunize them? In order for a baby to be protected, it has to have a certain level of immunity, depending upon the pathogen. In the case of early immunizations, such as hepatitis B, the baby’s immune system is capable of making an immune response that is, in most cases, “good enough” to protect it. Later doses of these vaccines enhance the protection by creating memory responses at a time when the immune system is better functioning. You can think of these early immunizations as priming a pump. At first, just a little bit of water appears, but it is enough that you know the system is working. Later, the pump will function more efficiently producing larger quantities of water to allow you to fill your bucket.

Of interest, because young babies are particularly susceptible to bacterial infections like pneumococcus, Hib, and meningococcus, clinicians were anxious to protect them. Scientists ultimately figured out that if they attached a harmless protein to the bacteria, the baby’s immune system could make a T cell-dependent B cell response and be protected earlier than if we waited for the T cell-independent functionality to develop. Now, clinicians — and parents — can better protect young infants from much of the suffering, hospitalization, and death that used to result from bacterial infections that occurred shortly after birth.

References

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