Why Doesn’t a Mother’s Immune System Reject the Fetus?

Immune system fetus

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The developing child is a foreign organism within you, so why doesn’t your immune system reject it? Rejection happens, after all, with a transplanted organ –if the recipient does not take appropriate medications that suppress the immune system, or if the organ is mismatched. Unless a donated organ comes from an identical twin, its cells express proteins that the immune system of the recipient (also called the host) sees as foreign. Proteins seen this way by the immune system are called antigens and this is what triggers rejection. We should expect rejection in pregnancy, because an embryo, or later a fetus, should be antigenic. A developing child is not your clone, after all. Though it carries your genes, it also carries genes of the father, with multiple parts of the maternal and paternal genomes shuffled around.

But normally, a fetus is not rejected. Once a pregnancy takes hold, the developing embryo holds sway within the endometrium, promoting changes that facilitate growth and development to the fetal stage. The new life form draws nutrients from, and deposits waste into, the maternal circulation, just like a parasite.

Or, like a cancer. Cancer comes from a person’s own cells, but it’s a genetic alteration. Cancer cells should be antigenic, so the immune system should attack, and usually it does. Researchers think that your immune system is constantly ridding the body of cancerous cells that could produce cancer, but don’t, because they are kept in check. But when the immune defenses are overwhelmed, that’s when tumor growth goes out of control. One reason could be that the cancer learned how to trick the immune system, in a sense, telling it to recognize the cancer cells as self.

Considering the cancer immune evasion, some researchers have realized that a similar phenomenon might occur in pregnancy. Like cancer, an embryo comes from your own body. It has your genetics, but modified in ways that make it foreign, though it convinces your immune system to lay low.

The mystery is not totally solved yet, but some clues and answers have been accumulating. The mother secretes several protein substances that researchers think may suppress the immune response within the womb. Studies on different animal species show that there is a migration of special cells that modulate the immune response and signal the immune system to leave the developing child alone. In mice, for example, cells similar to the precursors of red blood cells migrate from the spleen to the uterus, where they may be modulating the immune response. Overall, there is a kind of immunosuppression going on during pregnancy, both in the womb and to some extent throughout the body.

Earlier, we said that normally fetuses are not rejected; the same is true of an embryo that has implanted in the uterus and is well underway to becoming a fetus. But most human pregnancies never make it this far. Often, pregnancy aborts spontaneously, very early in the embryonic phase, often before a woman even knows that she is pregnant. Only a minority of fertilizations result in a term pregnancy, producing a child. In many cases, early pregnancy loss may be the body’s way of filtering out bad pregnancies, because the embryo has a genetic condition that’s either lethal, or would result in a severe birth defect. The immune system may or may not be involved in rejecting such defective embryos. In some cases, however, a healthy embryo or fetus may be attacked, leading to pregnancy loss, or severe birth defects, because the immune system sees the developing child as foreign.

The most common such condition is called Rh incompatibility, which has to do with proteins on the surface of red blood cells. Probably, you have heard about blood typing. There are many types of blood groups, each based on a different system of red blood cell surface protein. Discovered by Karl Landsteiner in 1900, the ABO groups constitute the most well-known blood group system. In the late 1930s and early 40s, Landsteiner, and his colleague Reuben Ottenberg, discovered the Rh group, of which one protein, the D antigen, is vital in pregnancy. This is because a mother’s immune system can attack a fetus, if she and the fetus are not Rh-compatible.

Let’s unpack what we mean by not compatible. The problem comes in when the mother is Rh-negative, meaning that her red blood cells lack the D antigen. That happens, because she lacks the gene for D, but if the father is Rh-positive than she can produce a fetus expressing D antigen on its cells. If this happens just once, there’s no problem. Some mixing of fetal and maternal blood toward the end of pregnancy merely primes the mother’s immune system, teaching it to make antibodies against D antigen. But the child is born long before her immune system can do any harm. If she later gets pregnant with a second Rh-positive embryo, now there is a big problem, since her immune system has been primed to attack and is ready to do so in a big way. The good news is that the condition is well understood, there’s easy screening for it and there is a treatment –an antibody called RhIg that is injected to Rh-negative mothers.

That’s a success story, though it’s only the tip of the iceberg when it comes to the immunology of pregnancy. But the potential for such research is enormous. Might the study of maternal immunity lead ultimately to a solution for cancer?

David Warmflash
Dr. David Warmflash is a science communicator and physician with a research background in astrobiology and space medicine. He has completed research fellowships at NASA Johnson Space Center, the University of Pennsylvania, and Brandeis University. Since 2002, he has been collaborating with The Planetary Society on experiments helping us to understand the effects of deep space radiation on life forms, and since 2011 has worked nearly full time in medical writing and science journalism. His focus area includes the emergence of new biotechnologies and their impact on biomedicine, public health, and society.

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