Fetus hoists up Flag

27. January 2009
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During pregnancy mother and child close a non-aggression pact. For quite a while we know details about the control of the mother's immune system. Now researchers show how the control of an astonishing mature defense of the fetus functions works.

Many couples doubt it. For every fiftieth of them all attempts to have a child end with an abortion – in half of the cases without any obvious reasons. But in a successful pregnancy as well many complications are based on the fact that a pile of cells lodges itself in the uterus with at least half of the tissue being someone else’s. Not just transplantation specialists know that often tissue with foreign HLA-antigens only has a chance of survival in the recipient by using strong immunosurpression.

Premature fetal immune system

Very early, the mother makes an acquaintance with the cells of her offspring. Embryonic cells in her blood circulation system lead to a long lasting chimerism. In this close relation between the mother and the growing fetus inside her body, not only she reacts to the alleged intruder making himself at home – also the embryo gets himself an own defense system against impurities and is prepared to fight against them with his own weapons. In the December 5th issue of the science journal Science, researchers at the University of California in San Francisco/USA now describe – in cooperation with the Karolinska Hospital in Stockholm – what holds the immune cells of the fetus back from attacking his own mother.

Until recently many immunologists considered the defense of the fetus as “naïve” – it just barely gets to meet foreign antigens. Moreover the closed area of the uterus is hard to examine. The immune system of the laboratory mouse is still immature and the peripheral lymph nodes sparsely populated by any T-cells. Now the team of Joseph McCune discovered in samples of human lymph nodes that much more maternal cells shape the maturing immune system of the fetus than expected. There they create tolerance against the maternal tissue.

Up to now scientists presumed that mainly clonal deletion had blocked the reaction against the mother, but now the US team discovered another mechanism. Already after the first trimester of the pregnancy many lymphocytes are in the peripheral lymph nodes and the liver of the fetus. But regulatory T-cells suppress an aggressive reaction. When removed from the cell culture, the lymphocytes react against the maternal tissue. The scientists registered a reaction even against the own tissue when accordingly stimulated.

But this belligerence is not only suppressed in the womb. The tests of the researchers show that also in test persons in the age between seven and seventeen, the regulatory T-cells suppress the response against maternal tissue.

Non-classical histocompatibily-antigens grant protection

The examination of the mechanisms preventing the attack against the alleged intruder is more sophisticated. For protection against cytotoxic T-cells the classical HLA-antigens class I and II (in lieu of non-classical HLA-molecules class HLA-G, HLA-F and HLA-E) are missing on the embryonic throphoblasts. Instead you find the fas ligand causing a programmed suicide of cells (apoptosis) presumably signing responsible for the maternal tolerance. After all regulatory T-cells in the immune system of the mother also prevent a response against the unborn child. So the control over unwanted rejection reaction of the mother against her own child reflects in the adolescent.

The findings of McCune and colleagues come for many experts as a surprise as well. If the observations are confirmed the suppressed immune system would explain the lacking effect of early childhood vaccinations in some children. Impurities entering the circulation of the child during pregnancy could possibly create a long lasting tolerance there. “Only 5 to 10 percent of babies born to untreated HIV-infected mothers in the absence of antiretroviral interventions are born infected with HIV. We wonder whether some aspect of the immunological tolerance of the fetal immune system might play a role here,” Joseph McCune noted. The solution of the future for surgeries shortly after birth if the newborn needs a new heart or kidneys might lay in a presentation of the receiver cells already in the womb instead of a strong immunosurpression.

But why does the human being need such an early highly developed immune system? For now this question only allows speculative answers like the one given by Jeff Mold, lead author of the Science-Paper: “The surrounding of the fetus is a very dynamic system changing rapidly during growth. The sense might be to develop a feeling for the own body at an early stage and a tolerance for everything that might appear during this development phase.” Perhaps – as Mold argues – the strong defense in the womb might not be necessary yet. But it allows an immediate protection as soon as the child sees the light of day and has to start fighting against the bad germs.

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